Clinical assessment and treatment of diabetes in patients with chronic kidney disease

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ERC: enfermedad renal crónica; FGe: filtrado glomerular estimado; KDIGO: Kidney Disease Global Outcomes. Cociente albúmina/creatinina 1mg/g=0,113mg/mmol; 30mg/g (3,4mg/mmol). Los colores muestran el riesgo relativo ajustado para 5 sucesos: mortalidad global, mortalidad cardiovascular, fracaso renal tratado con diálisis o trasplante, fracaso renal agudo y progresión de la enfermedad renal. El menor riesgo corresponde al color verde, seguido del armarillo (riesgo «moderadamente aumentado»), color naranja («alto riesgo») y rojo («riesgo muy alto»)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J. Carretero Gómez, J.C. Arévalo Lorido" "autores" => array:2 [ 0 => array:2 [ "nombre" => "J." "apellidos" => "Carretero Gómez" ] 1 => array:2 [ "nombre" => "J.C." 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Fernández-Codina, J. Fernández-Fernández, A. Fernández-Pantiga" "autores" => array:4 [ 0 => array:2 [ "nombre" => "A." "apellidos" => "Fernández-Codina" ] 1 => array:2 [ "nombre" => "J." "apellidos" => "Fernández-Fernández" ] 2 => array:2 [ "nombre" => "A." 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Carretero Gómez, J.C. Arévalo Lorido" "autores" => array:2 [ 0 => array:4 [ "nombre" => "J." "apellidos" => "Carretero Gómez" "email" => array:1 [ 0 => "juanicarretero@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "J.C." "apellidos" => "Arévalo Lorido" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Medicina Interna, Hospital Comarcal de Zafra, Badajoz, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Evaluación clínica y tratamiento de la diabetes en pacientes con enfermedad renal crónica" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1243 "Ancho" => 2500 "Tamanyo" => 254535 ] ] "descripcion" => array:1 [ "en" => "Staging of chronic kidney disease according to the 2012 KDIGO guidelines. Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; KDIGO, Kidney Disease Global Outcomes. Albumin/creatinine ratio 1mg/g=0.113mg/mmol; 30mg/g (3.4mg/mmol). The colors show the adjusted relative risk for 5 events: overall mortality, cardiovascular mortality, renal failure treated with dialysis or transplantation, acute renal failure and progression of the kidney disease. Green indicates the lowest risk, followed by yellow (“moderately increased” risk), orange (“high risk”) and red (“very high risk”)." ] ] ] "textoCompleto" => "BackgroundType2 diabetes mellitus (DM2) is the main cause of chronic kidney disease (CKD) in our setting. Patients with DM2 and CKD have greater morbidity and mortality and risk of hypoglycemia than those with normal renal function. The repercussions of DM2 on the health of the population is based on its high prevalence, high socioeconomic cost due to the microvascular and macrovascular complications and its high mortality rates.MethodologyA systematic search was conducted of PubMed with the following keywords: heart failure, diabetes, hospitalization, mortality. We assessed experimental studies with control groups and observational studies. An individualized search was also conducted for each antidiabetic drug, adding the term “diabetic nephropathy”.Epidemiology and prevalenceThe prevalence of DM2 in Spain has been estimated according to the Diabet@s study at 14% of the adult population.<a class="elsevierStyleCrossRef" href="#bib0295">1</a> Worldwide, the prevalence of diabetes is estimated at 3–4% of the population.<a class="elsevierStyleCrossRef" href="#bib0300">2</a> In parallel with the increase in the incidence of diabetes, there has been an increase in terminal CKD associated with diabetes. According to the Spanish Society of Nephrology, DM2 was the reason for starting renal replacement therapy (RRT) in 24.7% of patients in 2010.<a class="elsevierStyleCrossRef" href="#bib0305">3</a>Some 25–40% of patients with diabetes will present some degree of kidney disease. The prevalence of microalbuminuria, proteinuria and reduced glomerular filtration can reach 36%, 8% and 22% respectively, starting 20–25 years after the diagnosis.<a class="elsevierStyleCrossRef" href="#bib0310">4</a> The presence of albuminuria is a predictor of CKD.<a class="elsevierStyleCrossRef" href="#bib0315">5</a>Classification of chronic kidney diseaseAn annual screening of renal function using the estimated glomerular filtration rate (eGFR) and albumin/creatinine ratio (ACR)<a class="elsevierStyleCrossRef" href="#bib0320">6</a> is recommended. The 2012 Kidney Disease Improving Global Outcomes (KDIGO) guidelines<a class="elsevierStyleCrossRef" href="#bib0325">7</a> recommend the use of the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI).<a class="elsevierStyleCrossRef" href="#bib0330">8</a>The Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines<a class="elsevierStyleCrossRef" href="#bib0335">9</a> define CKD as the presence for at least 3 months of an eGFR ≤60mL/min/1.73m2 structural renal lesions (histological abnormalities in the renal biopsy) or functional renal lesions (albuminuria, urinary sediment abnormalities) that might cause a reduction in eGFR.The new CKD prognostic classification proposed by KDIGO<a class="elsevierStyleCrossRef" href="#bib0325">7</a> and based on eGFR stages and albuminuria is shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Etiopathogenesis and pathophysiology of diabetic kidney diseaseDiabetic kidney disease (DKD), previously known as diabetic nephropathy, refers to kidney disease caused by diabetes.<a class="elsevierStyleCrossRef" href="#bib0340">10</a> Chronic hyperglycemia, through tissue glycosylation (including glomerular and mesangial cells), is the determining factor. Three hypotheses have been proposed for this condition: nonenzymatic glycosylation and advanced glycosylation end products, protein kinase C activation and aldose reductase pathway acceleration.<a class="elsevierStyleCrossRef" href="#bib0345">11</a>This condition occurs 5–10 years after the DM2 diagnosis, and its progression is influenced by factors such as the activity of the renin-angiotensin-aldosterone system (RAAS), race, microalbuminuria, arterial hypertension (AHT), obesity,<a class="elsevierStyleCrossRef" href="#bib0350">12</a> dyslipidemia and nicotine addiction. Renal hyperfiltration (eGFR≥135mL/min/1.73m2) is a marker of intraglomerular hypertension and a risk factor for onset and progression.<a class="elsevierStyleCrossRef" href="#bib0355">13</a>With time, functional and structural changes in the nephron lead to hemodynamic changes, cell proliferation and hypertrophy, onset of albuminuria and proteinuria in intermediate phases up to CKD, as we can see in the following diagram:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">-Stage 1. Renal hypertrophy and hyperfiltration<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010">•Increased kidney size</li><li class="elsevierStyleListItem" id="lsti0015">•Increased eGFR</li></ul></li><li class="elsevierStyleListItem" id="lsti0020">-Stage 2. Kidney injury with no clinical evidence<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0025">•Thickening of the basal membranes and increased mesangial volume</li><li class="elsevierStyleListItem" id="lsti0030">•Various histological patterns in DM2</li><li class="elsevierStyleListItem" id="lsti0035">•Intermittent microalbuminuria</li></ul></li><li class="elsevierStyleListItem" id="lsti0040">-Stage 3. Intermittent diabetic kidney disease<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0045">•Persistent microalbuminuria</li><li class="elsevierStyleListItem" id="lsti0050">•Start of AHT</li><li class="elsevierStyleListItem" id="lsti0055">•No reduction in eGFR</li></ul></li><li class="elsevierStyleListItem" id="lsti0060">-Stage 4. Established diabetic kidney disease<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0065">•Presence of proteinuria or macroalbuminuria</li><li class="elsevierStyleListItem" id="lsti0070">•AHT in most cases</li><li class="elsevierStyleListItem" id="lsti0075">•Loss of eGFR starts</li><li class="elsevierStyleListItem" id="lsti0080">•Characteristic histological lesions: diabetic glomerulosclerosis, interstitial fibrosis, tubular atrophy, arteriolar hyalinosis</li></ul></li><li class="elsevierStyleListItem" id="lsti0085">-Stage 5. Renal failure<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0090">•Progressive loss of eGFR</li><li class="elsevierStyleListItem" id="lsti0095">•AHT and diabetic retinopathy present almost continuously</li><li class="elsevierStyleListItem" id="lsti0100">•Onset of uremic symptoms and associated complications</li></ul></li></ul>In <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A, we can observe the changes in the nephron that are produced in DKD, both at the intraglomerular and vascular level (afferent and efferent arterioles).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>In recent years, the “nonproteinuric phenotype” has become frequent, that is, progression to CKD without developing proteinuria.<a class="elsevierStyleCrossRefs" href="#bib0360">14,15</a>Glycemic control for patients with chronic kidney disease. The importance of the new oral diabetes drugsThe main guidelines recommend individualized glycemic control for patients with CKD. For example, the American Diabetes Association recommended in its last revision an HbA1c objective <8% for patients with comorbidities including CKD.<a class="elsevierStyleCrossRef" href="#bib0370">16</a> The National Kidney Foundation guidelines (KDOQI guidelines) recommend an HbA1c control objective >7% for patients with a high risk of hypoglycemia, short life expectancy and comorbidities including CKD.<a class="elsevierStyleCrossRef" href="#bib0375">17</a>Other than glycemic control and AHT control, only RAAS inhibition has been shown to have a renoprotective effect. In recent years, the emergence of new oral antidiabetic drugs (ODAs), such as dipeptidyl peptidase-4 inhibitors (DPP4Is), glucagon-like peptide-1 (GLP-1) agonists and sodium-glucose cotransporter inhibitors (SGLT2Is), with effects beyond glycemic control (weight control, antihypertensive and hypouricemic effect), has represented a benefit both for macrovascular and microvascular disease in patients with DM2. The 3 drug groups have a high safety profile, making them drugs of choice for DKD.<a class="elsevierStyleCrossRef" href="#bib0375">17</a>It is important to understand the definitions and outcomes at the renal level of the main studies with ADOs in DKD.<a class="elsevierStyleCrossRef" href="#bib0345">11</a><ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0105">-Normal renal function: eGFR >90mL/min/1.73m2, albumin excretion <30mg/d or ACR <30mg/g confirmed in 3 measurements.</li><li class="elsevierStyleListItem" id="lsti0110">-With kidney disease:</li><li class="elsevierStyleListItem" id="lsti0115">-eGFR >90mL/min/1.73m2 with microalbuminuria (30–300mg/d) or ACR 30–300mg/g.</li><li class="elsevierStyleListItem" id="lsti0120">-Macroalbuminuria defined as an albumin excretion ≥300mg/d or ACR≥300mg/g confirmed in 3 measurements.</li></ul>Similarly, the primary outcomes in clinical trials refer to...<ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0125">-Doubling of baseline creatinine levels.</li><li class="elsevierStyleListItem" id="lsti0130">-CKD: eGFR <15mL/min/1.73m2 for 3 months or more, need for RRT or kidney transplantation.</li><li class="elsevierStyleListItem" id="lsti0135">-Death (all-cause, cardiovascular, sudden death), nonfatal infarction or stroke.</li></ul>The secondary outcomes are...<ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0140">-Onset, progression or regression of microalbuminuria.</li><li class="elsevierStyleListItem" id="lsti0145">-ACR value at the end of treatment or change between the start and end of treatment.</li><li class="elsevierStyleListItem" id="lsti0150">-Creatinine clearance or eGFR at the end of treatment or change between the start and end of treatment and change in eGFR at 1 year of follow-up.</li></ul><a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B shows the various action levels of the new ODAs that have shown renal protection.Alpha-glucosidase inhibitorsMiglitol and acarboseThese drugs delay the absorption of complex carbohydrates in the intestines, decreasing the postprandial glucose peak. These drugs are contraindicated in stage 4 CKD.SulfonylureasSulfonylureas are contraindicated in cases of severe renal failure. Their main adverse effects are hypoglycemia, which can be severe, and weight gain.<a class="elsevierStyleCrossRef" href="#bib0380">18</a>MeglitinidesRepaglinide and nateglinideBoth have a short half-life. Repaglinide is more potent and is eliminated by the bile duct and can therefore be used in any grade of CKD and in dialysis. Despite having hepatic metabolism, nateglinide forms active metabolites that are cleared by the kidneys and is therefore not recommended in CKD. The main secondary effect of both drugs is hypoglycemia.<a class="elsevierStyleCrossRef" href="#bib0385">19</a>ThiazolidinedionesPioglitazoneAn insulin sensitizer that stimulates glucose uptake by the muscle and adipose tissue. Reduces gluconeogenesis and fatty acid synthesis at the hepatic level. The drug is metabolized in the liver and excreted in feces and is therefore not contraindicated in CKD. Its main adverse effects are water retention (its use is not recommended in heart and hepatic failure), distal bone fractures in women and a debatable increase in the incidence of bladder cancer.<a class="elsevierStyleCrossRef" href="#bib0390">20</a>BiguanidesMetforminApproved by the FDA in 1973. It was not until 2016 that the warnings were revised on its use in CKD, concluding that it is safe in patients with mild to moderate CKD, adjusted to eGFR (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0395">21</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>A recent systematic review on the use of metformin in patients with moderate to severe CKD and heart failure or chronic liver disease showed a reduction in all-cause mortality.<a class="elsevierStyleCrossRef" href="#bib0400">22</a> The data regarding the risk of lactic acidosis in patients with CKD are limited, but the overall risk is low.<a class="elsevierStyleCrossRef" href="#bib0405">23</a>Dipeptidyl peptidase-4 inhibitorsDPP4Is are a safe and effective treatment option, with a low risk of hypoglycemia and few adverse effects. The DPP4 receptor is expressed in several segments of the nephron and in the interstitial tubule (segments S1-S3), with anti-inflammatory effects, immune system activation, sodium regulation and kidney fibrosis regulation (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B).<a class="elsevierStyleCrossRef" href="#bib0410">24</a> The 5 compounds reduce HbA1c levels by approximately 0.5% in patients with stage 3–4 CKD<a class="elsevierStyleCrossRef" href="#bib0415">25</a> and decrease urinary albumin excretion, regardless of the blood pressure or blood glucose control.<a class="elsevierStyleCrossRef" href="#bib0420">26</a>SitagliptinThis was the first DPP4I marketed in 2006. With an 80% renal elimination rate, dosage adjustments of up to 5mg/d are needed for eGFRs of 30–50mL/min/m2 and 25mg/d for eGFRs <30mL/min/1.73 m2.Data on the possible beneficial effect of sitagliptin on the kidneys mostly comes from uncontrolled observational studies. Arjona Ferreira et al. randomized 426 patients to sitagliptin (50mg for moderate renal failure or 25mg for severe renal failure) or 10-mg glipizide for 54 weeks.<a class="elsevierStyleCrossRef" href="#bib0425">27</a> The reduction in HbA1c levels was 0.8% and 0.6% for sitagliptin and glipizide, respectively. The combined objective of an HbA1c reduction >0.5% with no weight gain or hypoglycemia was achieved in 37.5% and 14.2% of cases, respectively. Both the reduction in eGFR (3.9 vs. 3.3mL/min/1.73m2) and the percentage of patients who developed renal failure (18.8% vs. 11.0%) were similar in the 2 groups. In another small study with 36 patients lasting 6 months, sitagliptin (50mg/d) decreased HbA1c levels 0.7% and the ACR, in normoalbuminuria, microalbuminuria and macroalbuminuria, with no changes in eGFR. In another randomized study with 85 patients assigned to 50-mg sitagliptin versus other ODAs, only sitagliptin lowered the ACR in patients with normoalbuminuria, revealing a potential preventive and protective effect in the initial stages of DKD.<a class="elsevierStyleCrossRef" href="#bib0420">26</a> In the Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin (TECOS), designed to assess the effect of sitagliptin on the cardiovascular prognosis of patients with diabetes and cardiovascular disease, sitagliptin was not inferior to placebo in the primary objective (hazard ratio [HR], 0.98; 95% confidence interval [95% CI] 0.88–1.09, p<.001).<a class="elsevierStyleCrossRef" href="#bib0430">28</a> After stratifying the patients by renal function, the rate of cardiovascular events increased as the eGFR decreased, with an adjusted HR for stages 2, 3a and 3b compared with stage 1 of 0.93 (95% CI 0.82–1.06), 1.28 (95% CI 1.10–1.49) and 1.39 (95% CI 1.13–1.72), respectively. The reduction in renal function was similar in both groups, with a marginal but constant reduction (-1.3mL/min/1.73m2) in the treatment group.<a class="elsevierStyleCrossRef" href="#bib0435">29</a>LinagliptinThis drug has the lowest renal elimination and does not require dosage adjustments in CKD. The drug is currently being analyzed in 2 studies: the Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus (CARMELINA) versus placebo<a class="elsevierStyleCrossRef" href="#bib0440">30</a> and the Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Early Type 2 Diabetes (CAROLINA),<a class="elsevierStyleCrossRef" href="#bib0445">31</a> whose results will be published between 2018 and 2020. Sixty percent of the included patients have an eGFR <60mL/min/1.73m2, and 15% have an eGFR <30mL/min/1.73m2. In a meta-analysis of three 24-week, placebo-controlled studies, linagliptin consistently lowered HbA1c levels at all stages of renal function: 0.63% for normal eGFR (>90mL/min/1.73m2), 0.67% for an eGFR of 60–90mL/min/1.73m2 and 0.53% for an eGFR of 30–60mL/min/1.73m2, with renal function remaining stable.<a class="elsevierStyleCrossRef" href="#bib0450">32</a> In a phase-III study by Groop et al. that added linagliptin to the conventional treatment of patients with diabetes treated with RAAS inhibitors, the percentage change in the ACR curve was 32% with linagliptin compared with 6% with placebo.<a class="elsevierStyleCrossRef" href="#bib0455">33</a> These results were not confirmed in the Modification of Albuminuria in Type 2 Diabetes Subjects with Renal Disease with Linagliptin (MARLINA T2D) study,<a class="elsevierStyleCrossRef" href="#bib0460">34</a> where the change was −11.0% (95% CI −16.8 to −4.7) with linagliptin and −5.1% (95% CI, −11.4 to 1.6) with placebo, an overall difference of −6.0% (95% CI, −15.0 to 3.0; p=.1954).SaxagliptinFor saxagliptin, the dosage needs to be reduced for patients with moderate to severe renal failure (2.5mg/d). This dosage is approved in the US for patients on hemodialysis but not in Europe. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus trial (SAVOR-TIMI53),<a class="elsevierStyleCrossRef" href="#bib0460">34</a> designed to assess the cardiovascular safety of saxagliptin, showed noninferiority versus placebo in the primary objective (HR, 1.00; 95% CI 0.89–1.12, p<.001). In a post hoc analysis, saxagliptin showed an improvement in ACR for all categories, for normoalbuminuria, microalbuminuria and macroalbuminuria (p=.02, p<.001 and p=.05, respectively), with no variations in the eGFR.<a class="elsevierStyleCrossRef" href="#bib0465">35</a>AlogliptinFor alogliptin, the dosage should be adjusted according to renal function: 12.5mg/d for stage 3 CKD and 6.25mg/d for stages 4–5. In the Cardiovascular Mortality in Patients With Type 2 Diabetes and Recent Acute Coronary Syndromes (EXAMINE) study,<a class="elsevierStyleCrossRef" href="#bib0470">36</a> designed as a noninferiority study for patients with diabetes and a cardiac ischemic event in the previous 15–90 days, alogliptin was not inferior to placebo for the primary objective (HR, 0.96; 95% CI 0.96–1.16; p<.001), with similar changes in eGFR and the need for dialysis. Twenty-nine percent of the patients had eGFR <60mL/min/1.73m2.VildagliptinVildagliptin requires a dosage adjustment with eGFR <50mL/min/1.73m2. No cardiovascular safety studies have been performed for vildagliptin. However, the Galvus in Addition to Metformin vs. TZD/metformin in T2DM (GALIANT) retrospective analysis showed that the safety and efficacy of vildagliptin versus metformin for patients with eGFR between 50 and 80mL/min/1.73m2 was similar to that for patients with preserved renal function.<a class="elsevierStyleCrossRef" href="#bib0475">37</a> Lukashevich et al. randomized 515 patients with moderate (eGFR of 30–50mL/min/1.73m2) or severe CKD (eGFR <30mL/min/1.73m2) to vildagliptin or placebo and observed a similar reduction in HbA1c (−0.5% vs. −0.6%), with no increase in hypoglycemia or greater eGFR deterioration.<a class="elsevierStyleCrossRef" href="#bib0480">38</a>Glucagon-like peptide-1 agonists (GLP-1 RA)GLP-1 RAs act by increasing insulin secretion, inhibiting glucagon secretion by alpha-pancreatic cells, slowing gastric emptying and inducing satiety. Their use was initially associated with worsening renal function, due to adverse gastrointestinal effects or in patients with heart failure, pancreatitis, infections or the concomitant use of diuretics, angiotensin-converting enzyme inhibitors or nonsteroidal anti-inflammatory drugs.The GLP-1 receptor is expressed almost exclusively in the vascular tree of the kidneys. Through the reduction in NHE3 (sodium/hydrogen exchanger) activity via the protein kinase A (PKA) pathway, DPP4Is inhibit the tyrosine kinase A (TKA) pathway, increasing natriuresis and osmotic diuresis. Through the GLP-1 receptor pathway, DPP4Is reduce the resistance of the afferent arteriole and increase the resistance of the efferent arteriole, decreasing the hydrostatic pressure in the Bowman capsule and increasing it on the glomerular level. They also act through nitric oxide and other vascular factors that mediate renal hyperfiltration (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B).<a class="elsevierStyleCrossRef" href="#bib0485">39</a>The GLP-1 RAs currently approved by the FDA/EMA are liraglutide, lixisenatide, exenatide LAR, albiglutide and dulaglutide. The first 3 have completed their cardiovascular safety studies.LixisenatideLixisenatide does not require dosage adjustment for eGFR of 60–90mL/min/1.73m2. Monitoring is recommended for eGFR of 30–59mL/min/1.73m2. This drug is contraindicated for eGFR of 15mL/min/1.73m2.In the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA),<a class="elsevierStyleCrossRef" href="#bib0490">40</a> lixisenatide did not increase the incidence of cardiovascular events compared with standard treatment (13.4% vs. 13.2%; HR, 1.02; 95% CI 0.89–1.17, p<.001). In a subanalysis of the ELIXA study, lixisenatide did not significantly improve the microalbuminuria or eGFR levels. Although a benefit was initially observed in the treatment branch (34% vs. 34%), mainly in patients undergoing treatment with drugs that inhibit RAAS, after adjusting for baseline and at 3 months of HbA1c, the reduction was not statistically significant (p=.07). The Effect of Lixisenatide on the Renal System (ELIXIRS) study is currently underway to assess the behavior of this drug on renal function and on biomarkers.<a class="elsevierStyleCrossRef" href="#bib0495">41</a>LiraglutideLiraglutide does not require dosage adjustments in any stage of CKD.In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) study, liraglutide was superior to placebo in the primary endpoint (HR, 0.87; 95% CI 0.78–0.97; p<.01).<a class="elsevierStyleCrossRef" href="#bib0500">42</a> In a secondary analysis to assess the renal prognosis, the combined outcome of persistent or new onset macroalbuminuria, doubling of serum creatinine values, terminal CKD or death due to renal causes clearly favored liraglutide (HR, 0.78; 95% CI 0.67–0.92; p<.003). The benefit was mainly observed at the expense of a reduction in macroalbuminuria (HR, 0.74; 95% CI 0.60–0.91; p<.004). The eGFR readings improved, mainly for baseline eGFR <60mL/min/1.73m2, with no increase in adverse events. The renal protective mechanism appears to be multifactorial, involving glycemic control, blood pressure control and weight loss.<a class="elsevierStyleCrossRef" href="#bib0505">43</a>Exenatide – LARExenatide LAR is not indicated for eGFR <30mL/min/1.73m2.In the Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in T2D (EXSCEL),<a class="elsevierStyleCrossRef" href="#bib0510">44</a> exenatide LAR was not inferior to placebo in the cardiovascular objective. The study did not prespecify the renal prognosis, and the normoalbuminuria, macroalbuminuria and microalbuminuria results were similar in the 2 branches. Compared with glimepiride, which has no effect on microalbuminuria, treatment with exenatide LAR in 31 patients with diabetes and microalbuminuria resulted in a 38% reduction in ACR.<a class="elsevierStyleCrossRef" href="#bib0515">45</a>DulaglutideDulaglutide does not require a dosage adjustment in renal failure. The AWARD-7 study is currently underway and seeks to assess the safety and efficacy of dulaglutide versus insulin glargine in glycemic control and renal protection in patients with stage 3 and 4 CKD.<a class="elsevierStyleCrossRef" href="#bib0520">46</a>Sodium-glucose cotransporter-2 inhibitors (SGLT2Is)Dapagliflozin, empagliflozin and canagliflozin are currently approved in Europe.In conditions of hyperglycemia, there is an overexpression (36%) of SGLT2 receptors, which involves increased glucose reabsorption in the proximal convoluted tubule. With its block, renal hyperfiltration and intraglomerular hypertension decrease (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B). This mechanism of action results in an initial reduction of eGFR, with ad integrum recovery in 12 weeks. Attenuation of the glycosuric effects and weight loss is expected in patients with eGFR <60mL/min/1.73m2. In contrast, albuminuric effects and reduced blood pressure are preserved and perhaps exaggerated in CKD.<a class="elsevierStyleCrossRef" href="#bib0525">47</a> The reduction in HbA1c levels (−0.5% to −0.7%) is reduced in patients with eGFR of 30–60mL/min/1.73m2 (−0.4%). SGLT2Is are not recommended for concomitant use with loop diuretics or for patients with diseases that entail volume depletion.DapagliflozinThis was the first DPP4I marketed in Spain. There are two cardiovascular safety studies currently underway: the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI58),<a class="elsevierStyleCrossRef" href="#bib0530">48</a> whose results will be published sometime in 2018, and A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients with Chronic Kidney Disease (DAPA-CKD). Starting dapagliflozin when the eGFR is <60mL/min/1.73m2 is not recommended, starting it when eGFR is between 30 and 60mL/min/1.73m2 is not indicated, and starting it when the eGFR is <30mL/min/1.73m2 is contraindicated.EmpagliflozinThis was the second DPP4I marketed in Spain. In the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME),<a class="elsevierStyleCrossRef" href="#bib0535">49</a> empagliflozin significantly lowered the risk of the onset or worsening of kidney disease by 39% in patients with established cardiovascular disease, results that were maintained in a post hoc analysis in the patient subgroup with eGFR <60mL/min/1.73m2 and/or macroalbuminuria (ACR >300mg/g). The other results were a 55% reduction in the onset of RRT, a 44% reduction in the doubling of creatinine combined with an eGFR≤45mL/min/1.73m2 and a 38% reduction in the progression to macroalbuminuria.<a class="elsevierStyleCrossRefs" href="#bib0540">50,51</a> Dosage adjustments are not required if the eGFR is ≥45mL/min/1.73m2. The use of empagliflozin should be avoided or discontinued in patients with eGFR <45mL/min/1.73m2.CanagliflozinThis was the third drug of the DPP4I family to be marketed. The results of the Canagliflozin Cardiovascular Assessment Study (CANVAS) and CANVAS–R (Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes) study<a class="elsevierStyleCrossRef" href="#bib0550">52</a> showed a beneficial effect for canagliflozin in terms of progression to albuminuria (HR, 0.73; 95% CI 0.67–0.79) and in the composite objective of a 40% reduction in eGFR, need for RRT and death due to renal causes (HR, 0.73; 95% CI 0.47–0.77). As with empagliflozin, this result shows a protective effect on the kidneys for this therapeutic family of drugs. The currently underway Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy (CREDENCE) study is evaluating the potential protective effect of canagliflozin on the progression of kidney disease in patients with diabetes.<a class="elsevierStyleCrossRef" href="#bib0555">53</a> Dosage adjustments are not required if the eGFR is ≥60mL/min/1.73m2; adjustments are required for eGFR of 45–59mL/min/1.73m2. The use of canagliflozin should be avoided or discontinued for patients with eGFR persistently <45mL/min/1.73m2.InsulinEndogenous insulin is degraded in the liver; however, exogenous insulin is degraded in the kidneys, filtered in the glomerulus and reabsorbed in the proximal convoluted tubule. Its clearance decreases in parallel with the eGFR, which means that as the kidney disease progresses the need for insulin decreases.Insulin is the treatment of choice for patients with CKD and on dialysis. The treatment should be individualized, adjusting the dosage according to the patient's needs and even discontinued in the event of burnt-out diabetes.<a class="elsevierStyleCrossRef" href="#bib0560">54</a> A recently published consensus document on the insulinization of patients with CKD<a class="elsevierStyleCrossRef" href="#bib0565">55</a> recommended reducing the dosage by 25% up to an eGFR of 15–60mL/min/1.73m2 and reducing it 50% if the eGFR drops below this value. Depending on body weight, the initial dosage should 0.5IU/kg/d for an eGFR >60mL/min/1.73m2, 0.3–0.4IU/kg/d for an eGFR of 15–60mL/min/1.73m2 and 0.25IU/kg/d for an eGFR <15mL/min/1.73m2. Basal (glargine, detemir, degludec) and rapid-acting insulin analogs (aspart, lispro, glulisine) induce less hypoglycemia than human insulins (neutral protamine Hagedorn or regular insulin). There are no significant differences in the insulin aspart dosages for all eGFR levels. However, a small reduction for insulin lispro is recommended for eGFR <60mL/min/1.73m2. Among the basal insulins, insulin glargine is safe and effective and has a stable half-life in patients with CKD. Kulozik and Hasslacher reported the need for adjusting the dosage by 27–30% for insulin glargine and insulin detemir for eGFR levels <60mL/min/1.73m2.<a class="elsevierStyleCrossRef" href="#bib0570">56</a> Insulin degludec presents no differences in either absorption or clearance in patients with CKD.<a class="elsevierStyleCrossRef" href="#bib0575">57</a><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> lists the recommended dosages for the various antidiabetic drugs in CKD.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Conflicts of interestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:22 [ 0 => array:3 [ "identificador" => "xres1066227" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1014102" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1066228" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1014103" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Methodology" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Epidemiology and prevalence" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Classification of chronic kidney disease" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Etiopathogenesis and pathophysiology of diabetic kidney disease" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Glycemic control for patients with chronic kidney disease. The importance of the new oral diabetes drugs" ] 10 => array:3 [ "identificador" => "sec0035" "titulo" => "Alpha-glucosidase inhibitors" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Miglitol and acarbose" ] ] ] 11 => array:2 [ "identificador" => "sec0045" "titulo" => "Sulfonylureas" ] 12 => array:3 [ "identificador" => "sec0050" "titulo" => "Meglitinides" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Repaglinide and nateglinide" ] ] ] 13 => array:3 [ "identificador" => "sec0060" "titulo" => "Thiazolidinediones" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0065" "titulo" => "Pioglitazone" ] ] ] 14 => array:3 [ "identificador" => "sec0070" "titulo" => "Biguanides" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0075" "titulo" => "Metformin" ] ] ] 15 => array:3 [ "identificador" => "sec0080" "titulo" => "Dipeptidyl peptidase-4 inhibitors" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0085" "titulo" => "Sitagliptin" ] 1 => array:2 [ "identificador" => "sec0090" "titulo" => "Linagliptin" ] 2 => array:2 [ "identificador" => "sec0095" "titulo" => "Saxagliptin" ] 3 => array:2 [ "identificador" => "sec0100" "titulo" => "Alogliptin" ] 4 => array:2 [ "identificador" => "sec0105" "titulo" => "Vildagliptin" ] ] ] 16 => array:3 [ "identificador" => "sec0110" "titulo" => "Glucagon-like peptide-1 agonists (GLP-1 RA)" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0115" "titulo" => "Lixisenatide" ] 1 => array:2 [ "identificador" => "sec0120" "titulo" => "Liraglutide" ] 2 => array:2 [ "identificador" => "sec0125" "titulo" => "Exenatide – LAR" ] 3 => array:2 [ "identificador" => "sec0130" "titulo" => "Dulaglutide" ] ] ] 17 => array:3 [ "identificador" => "sec0135" "titulo" => "Sodium-glucose cotransporter-2 inhibitors (SGLT2Is)" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0140" "titulo" => "Dapagliflozin" ] 1 => array:2 [ "identificador" => "sec0145" "titulo" => "Empagliflozin" ] 2 => array:2 [ "identificador" => "sec0150" "titulo" => "Canagliflozin" ] ] ] 18 => array:2 [ "identificador" => "sec0155" "titulo" => "Insulin" ] 19 => array:2 [ "identificador" => "sec0160" "titulo" => "Conflicts of interest" ] 20 => array:2 [ "identificador" => "xack360883" "titulo" => "Acknowledgments" ] 21 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-03-04" "fechaAceptado" => "2018-03-19" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1014102" "palabras" => array:7 [ 0 => "Diabetes" 1 => "Chronic kidney disease" 2 => "Diabetic nephropathy" 3 => "Diabetic kidney disease" 4 => "SGLT2-i" 5 => "GLP-1RA" 6 => "DPP4-i" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1014103" "palabras" => array:7 [ 0 => "Diabetes" 1 => "Enfermedad renal crónica" 2 => "Nefropatía diabética" 3 => "Enfermedad renal del diabético" 4 => "iSGLT2" 5 => "arGLP1" 6 => "iDPP4" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Diabetes mellitus type 2 is the main cause of chronic kidney disease. Patients with this disease have higher morbidity and mortality and risk of hypoglycaemia than those without this disease. In 2010, type 2 diabetes was the reason for starting renal replacement therapy in 24.7% of patients. The prevalence of microalbuminuria, proteinuria and a reduced glomerular filtration rate is 36%, 8% and 22%, respectively. The presence of albuminuria is a predictor of chronic kidney disease. Diabetic kidney disease, previously known as diabetic nephropathy, refers to kidney disease caused by diabetes. Renal hyperfiltration is a marker of intraglomerular hypertension and a risk factor for onset and progression. The new antidiabetic drugs, mainly dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter inhibitors and glucagon-like peptide-1 agonists, have been shown to prevent or slow the progression of kidney disease." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La diabetes mellitus tipo2 es la principal causa de enfermedad renal crónica. Estos pacientes presentan mayor morbimortalidad y riesgo de hipoglucemias que el resto. En 2010, la diabetes tipo2 fue causa del inicio de terapia renal sustitutiva en el 24,7% de los pacientes. La prevalencia de microalbuminuria, proteinuria y disminución del filtrado glomerular es del 36, 8, y 22%, respectivamente. La presencia de albuminuria es un factor predictivo de enfermedad renal crónica. La enfermedad renal diabética, previamente conocida como nefropatía diabética, hace referencia a la enfermedad renal causada por la diabetes. La hiperfiltración renal es marcador de hipertensión intraglomerular y factor de riesgo tanto de inicio como de progresión. Los nuevos antidiabéticos, fundamentalmente los inhibidores del enzima dipeptidil peptidasa-4, los inhibidores del cotransportador de sodio/glucosa y los agonistas del péptido similar al glucagón tipo1, han demostrado prevenir o enlentecer la progresión de la enfermedad renal." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Carretero Gómez J, Arévalo Lorido JC. Evaluación clínica y tratamiento de la diabetes en pacientes con enfermedad renal crónica. Rev Clin Esp. 2018;218:305–315." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1243 "Ancho" => 2500 "Tamanyo" => 254535 ] ] "descripcion" => array:1 [ "en" => "Staging of chronic kidney disease according to the 2012 KDIGO guidelines. Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; KDIGO, Kidney Disease Global Outcomes. Albumin/creatinine ratio 1mg/g=0.113mg/mmol; 30mg/g (3.4mg/mmol). The colors show the adjusted relative risk for 5 events: overall mortality, cardiovascular mortality, renal failure treated with dialysis or transplantation, acute renal failure and progression of the kidney disease. Green indicates the lowest risk, followed by yellow (“moderately increased” risk), orange (“high risk”) and red (“very high risk”)." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1275 "Ancho" => 3249 "Tamanyo" => 251519 ] ] "descripcion" => array:1 [ "en" => "The kidneys in diabetes. Panel (A) In the early phases of DKD, the reduced release of Na+ to the macula densa is erroneously interpreted by the juxtaglomerular apparatus as a reduction in effective circulating volume, resulting in compensatory vasodilation of the afferent arteriole and an increase in intraglomerular pressure. This mechanism has been called “tubuloglumerular feedback” and is the pathophysiological basis of DKD. Panel (B) SGLT2I receptors are overexpressed in hyperglycemic conditions (36%), increasing the renal reabsorption of Na+ and Cl− by at least 14%. Inhibition of SGLT2I receptors in the proximal tubule reverses the previous hemodynamic condition, resulting in vasoconstriction of the afferent arteriole and eGFR normalization. Overall, they induce a reduction in hyperfiltration, proteinuria, glomerular hypertrophy and mesangial expansion. DPP4 receptors are widely expressed in the brush border in segments S1-S3 of the proximal convoluted tubule and to a lesser extent in other segments at the tubulointerstitial level. Through the reduction in NHE3 activity (Na/H-exchanger), the tyrosine kinase pathway decreases sodium reabsorption in the proximal convoluted tubule. GLP-1 is expressed exclusively in the smooth muscle cells of the vessels, both preglomerular and juxtaglomerular. Through the reduction in NHE3 activity via PKA (unlike DPP4Is that inhibit through TKA), they increase natriuresis and osmotic diuresis. Globally, they reduce the resistance of the afferent arteriole and increase the resistance of the efferent arteriole, decreasing the hydrostatic pressure in the Bowman capsule and increasing it on the glomerular level, either through the GLP-1 receptor, nitric oxide or other vascular factors that mediate renal hyperfiltration, such as angiotensin I and II, atrial natriuretic peptide, endothelin1 and oxygen reactive species (ROS). Abbreviations: Ang-I, angiotensinI; Ang-II, angiotensinII; ANP, atrial natriuretic peptide; GLP-1RA, glucagon-like peptide-1 receptor agonists; DKD, diabetic kidney disease; DPP4, enzyme dipeptidyl peptidase-4; ET1, endothelin1; NHE3, isoform 3 of the sodium/hydrogen exchanger; PKA, protein kinase A; ROS, reactive oxygen species; SGLT2i, sodium-dependent glucose cotransporter 2 inhibitor; TGF, tubuloglomerular feedback; TKA, tyrosine kinase A." ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: FDA, Food and Drug Administration; eGFR, glomerular filtration rate." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">eGFR, mL/min/1.73m2 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">FDA recommendations \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">>45 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No contraindications Annual eGFR \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">30–45 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No recommendation start treatment Risk/benefit for continuing treatment \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Contraindicated \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Withdraw treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Liver disease, alcoholism, heart failure The patient will undergo an imaging test with iodinated contrast and eGFR 30–60mL/min \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1818488.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Review of the 2016 Food and Drug Administration for the use of metformin in chronic kidney disease." ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: CKD, chronic kidney disease; DPP4, dipeptidyl peptidase-4 enzyme; eGFR, estimated glomerular filtration rate; GLP-1, glucagon-like peptide-1; SGLT2i, sodium-glucose cotransporter." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Recommended dosage for renal failure eGFR (mL/min/1.73m2) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Biguanides</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Metformin</td><td class="td" title="table-entry " align="left" valign="top">No dosage adjustment needed if eGFR >45mL/min/1.73m2. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Do not start or assess risk-benefit if eGFR is 30–45mL/min/1.73m2. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Discontinue if eGFR <30mL/min/1.73m2. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Second generation sulfonylureas</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Glipizide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No dosage adjustment required. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Glimepiride \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Start conservatively at a dosage of 1mg per day. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Glyburide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Avoid its use. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Meglitinides</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Repaglinide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Start conservatively at a dosage of 0.5mg at each meal if eGFR <30mL/min/1.73m2. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nateglinide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Start conservatively at a dosage of 60mg at each meal if eGFR <30mL/min/1.73m2. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Thiazolidinediones</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pioglitazone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No dosage adjustment required. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rosiglitazone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No dosage adjustment required. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Alfa-glucosidase inhibitors</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Acarbose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Avoid if eGFR <30mL/min/1.73m2. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Miglitol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Avoid if eGFR <25mL/min/1.73m2. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Partial GLP-1 receptor agonists</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LAR exenatide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not recommended with eGFR <30mL/min/1.73m2. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Liraglutide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No dosage adjustment required. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lixisenatide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No dosage adjustment required for eGFR=60–89mL/min/1.73m2. No dosage adjustment required if eGFR is 30–59mL/min/1.73m2; however, patients should be monitored if adverse effects occur or if there is renal function impairment. There is little clinical experience with eGFR of 15–29mL/min/1.73m2; however, patients should be monitored if adverse effects occur or if there is renal function impairment. Avoid if eGFR <15mL/min/1.73m2. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Albiglutide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No dosage adjustment required for eGFR=15–89mL/min/1.73m2. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Dulaglutide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No dosage adjustment required. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">DPP4 inhibitors</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sitagliptin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100mg/day if eGFR>50mL/min/1.73m2. 50mg/day if eGFR=30–50mL/min/1.73m2. 25mg/day if eGFR<30mL/min/1.73m2. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Saxagliptin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5mg/day if eGFR>50mL/min/1.73m2. 2.5mg/day if eGFR≤50mL/min/1.73m2. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Vildagliptin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100mg every 24h if eGFR>60mL/min/1.73m2. 50mg every 24h if eGFR is 30–60mL/min/1.73m2. 25mg every 24h if eGFR<30mL/min/1.73m2. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Linagliptin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No dosage adjustment required. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Alogliptin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25mg/day if eGFR>60mL/min/1.73m2. 12.5mg/day if eGFR is 30–60mL/min/1.73m2. 6.25mg/day if eGFR<30mL/min/1.73m2. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">SGLT2 inhibitors</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Canagliflozin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No dosage adjustment required if eGFR≥60mL/min/1.73m2. 100mg/day if eGFR is 45–59mL/min/1.73m2. Avoid its use and discontinue in patients with eGFR persistently <45. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Dapagliflozin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Avoid starting if eGFR<60mL/min/1.73m2. Not recommended with an eGFRof30–60mL/min/1.73m2. Contraindicated for eGFR<30mL/min/1.73m2. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Empagliflozin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No dosage adjustment required if eGFR≥45mL/min/1.73m2. Avoid its use and discontinue in patients with eGFR persistently <45mL/min/1.73m2. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Insulin</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Basal: glargine, detemir, degludec \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduce 25% if eGFR is 15–60mL/min/1.73m2. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Prandial: lispro, aspart, glulisine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduce 50% if eGFR <15mL/min/1.73m2. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1818489.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Summary of recommended antidiabetic dosages for chronic kidney disease." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:57 [ 0 => array:3 [ "identificador" => "bib0295" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prevalence of diabetes mellitus and impaired glucose regulation in Spain: The Di@bet.es Study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. 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Clinical assessment and treatment of diabetes in patients with chronic kidney disease

Evaluación clínica y tratamiento de la diabetes en pacientes con enfermedad renal crónica

J. Carretero Gómez

Corresponding author

juanicarretero@gmail.com

Corresponding author.

, J.C. Arévalo Lorido

Servicio de Medicina Interna, Hospital Comarcal de Zafra, Badajoz, Spain

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heart failure&#44; diabetes&#44; hospitalization&#44; mortality&#46; We assessed experimental studies with control groups and observational studies&#46; An individualized search was also conducted for each antidiabetic drug&#44; adding the term &#8220;diabetic nephropathy&#8221;&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Epidemiology and prevalence</span><p id="par0015" class="elsevierStylePara elsevierViewall">The prevalence of DM2 in Spain has been estimated according to the Diabet&#64;s study at 14&#37; of the adult population&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">1</span></a> Worldwide&#44; the prevalence of diabetes is estimated at 3&#8211;4&#37; of the population&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">2</span></a> In parallel with the increase in the incidence of diabetes&#44; there has been an increase in terminal CKD associated with diabetes&#46; According to the Spanish Society of Nephrology&#44; DM2 was the reason for starting renal replacement therapy &#40;RRT&#41; in 24&#46;7&#37; of patients in 2010&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Some 25&#8211;40&#37; of patients with diabetes will present some degree of kidney disease&#46; The prevalence of microalbuminuria&#44; proteinuria and reduced glomerular filtration can reach 36&#37;&#44; 8&#37; and 22&#37; respectively&#44; starting 20&#8211;25 years after the diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">4</span></a> The presence of albuminuria is a predictor of CKD&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">5</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Classification of chronic kidney disease</span><p id="par0025" class="elsevierStylePara elsevierViewall">An annual screening of renal function using the estimated glomerular filtration rate &#40;eGFR&#41; and albumin&#47;creatinine ratio &#40;ACR&#41;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">6</span></a> is recommended&#46; The 2012 Kidney Disease Improving Global Outcomes &#40;KDIGO&#41; guidelines<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">7</span></a> recommend the use of the Chronic Kidney Disease Epidemiology Collaboration equation &#40;CKD-EPI&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The Kidney Disease Outcomes Quality Initiative &#40;KDOQI&#41; guidelines<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">9</span></a> define CKD as the presence for at least 3 months of an eGFR &#8804;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> structural renal lesions &#40;histological abnormalities in the renal biopsy&#41; or functional renal lesions &#40;albuminuria&#44; urinary sediment abnormalities&#41; that might cause a reduction in eGFR&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The new CKD prognostic classification proposed by KDIGO<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">7</span></a> and based on eGFR stages and albuminuria is shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Etiopathogenesis and pathophysiology of diabetic kidney disease</span><p id="par0040" class="elsevierStylePara elsevierViewall">Diabetic kidney disease &#40;DKD&#41;&#44; previously known as diabetic nephropathy&#44; refers to kidney disease caused by diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">10</span></a> Chronic hyperglycemia&#44; through tissue glycosylation &#40;including glomerular and mesangial cells&#41;&#44; is the determining factor&#46; Three hypotheses have been proposed for this condition&#58; nonenzymatic glycosylation and advanced glycosylation end products&#44; protein kinase C activation and aldose reductase pathway acceleration&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">11</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">This condition occurs 5&#8211;10 years after the DM2 diagnosis&#44; and its progression is influenced by factors such as the activity of the renin-angiotensin-aldosterone system &#40;RAAS&#41;&#44; race&#44; microalbuminuria&#44; arterial hypertension &#40;AHT&#41;&#44; obesity&#44;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">12</span></a> dyslipidemia and nicotine addiction&#46; Renal hyperfiltration &#40;eGFR<span class="elsevierStyleHsp" style=""></span>&#8805;135<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#41; is a marker of intraglomerular hypertension and a risk factor for onset and progression&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">13</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">With time&#44; functional and structural changes in the nephron lead to hemodynamic changes&#44; cell proliferation and hypertrophy&#44; onset of albuminuria and proteinuria in intermediate phases up to CKD&#44; as we can see in the following diagram&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0055" class="elsevierStylePara elsevierViewall">Stage 1&#46; Renal hypertrophy and hyperfiltration<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0060" class="elsevierStylePara elsevierViewall">Increased kidney size</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0065" class="elsevierStylePara elsevierViewall">Increased eGFR</p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0070" class="elsevierStylePara elsevierViewall">Stage 2&#46; Kidney injury with no clinical evidence<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0075" class="elsevierStylePara elsevierViewall">Thickening of the basal membranes and increased mesangial volume</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0080" class="elsevierStylePara elsevierViewall">Various histological patterns in DM2</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8226;</span><p id="par0085" class="elsevierStylePara elsevierViewall">Intermittent microalbuminuria</p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">-</span><p id="par0090" class="elsevierStylePara elsevierViewall">Stage 3&#46; Intermittent diabetic kidney disease<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#8226;</span><p id="par0095" class="elsevierStylePara elsevierViewall">Persistent microalbuminuria</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#8226;</span><p id="par0100" class="elsevierStylePara elsevierViewall">Start of AHT</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#8226;</span><p id="par0105" class="elsevierStylePara elsevierViewall">No reduction in eGFR</p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">-</span><p id="par0110" class="elsevierStylePara elsevierViewall">Stage 4&#46; Established diabetic kidney disease<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">&#8226;</span><p id="par0115" class="elsevierStylePara elsevierViewall">Presence of proteinuria or macroalbuminuria</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">&#8226;</span><p id="par0120" class="elsevierStylePara elsevierViewall">AHT in most cases</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">&#8226;</span><p id="par0125" class="elsevierStylePara elsevierViewall">Loss of eGFR starts</p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">&#8226;</span><p id="par0130" class="elsevierStylePara elsevierViewall">Characteristic histological lesions&#58; diabetic glomerulosclerosis&#44; interstitial fibrosis&#44; tubular atrophy&#44; arteriolar hyalinosis</p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">-</span><p id="par0135" class="elsevierStylePara elsevierViewall">Stage 5&#46; Renal failure<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">&#8226;</span><p id="par0140" class="elsevierStylePara elsevierViewall">Progressive loss of eGFR</p></li><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">&#8226;</span><p id="par0145" class="elsevierStylePara elsevierViewall">AHT and diabetic retinopathy present almost continuously</p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">&#8226;</span><p id="par0150" class="elsevierStylePara elsevierViewall">Onset of uremic symptoms and associated complications</p></li></ul></p></li></ul></p><p id="par0155" class="elsevierStylePara elsevierViewall">In <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#44; we can observe the changes in the nephron that are produced in DKD&#44; both at the intraglomerular and vascular level &#40;afferent and efferent arterioles&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0160" class="elsevierStylePara elsevierViewall">In recent years&#44; the &#8220;nonproteinuric phenotype&#8221; has become frequent&#44; that is&#44; progression to CKD without developing proteinuria&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">14&#44;15</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Glycemic control for patients with chronic kidney disease&#46; The importance of the new oral diabetes drugs</span><p id="par0165" class="elsevierStylePara elsevierViewall">The main guidelines recommend individualized glycemic control for patients with CKD&#46; For example&#44; the American Diabetes Association recommended in its last revision an HbA1c objective &#60;8&#37; for patients with comorbidities including CKD&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">16</span></a> The National Kidney Foundation guidelines &#40;KDOQI guidelines&#41; recommend an HbA1c control objective &#62;7&#37; for patients with a high risk of hypoglycemia&#44; short life expectancy and comorbidities including CKD&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">17</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Other than glycemic control and AHT control&#44; only RAAS inhibition has been shown to have a renoprotective effect&#46; In recent years&#44; the emergence of new oral antidiabetic drugs &#40;ODAs&#41;&#44; such as dipeptidyl peptidase-4 inhibitors &#40;DPP4Is&#41;&#44; glucagon-like peptide-1 &#40;GLP-1&#41; agonists and sodium-glucose cotransporter inhibitors &#40;SGLT2Is&#41;&#44; with effects beyond glycemic control &#40;weight control&#44; antihypertensive and hypouricemic effect&#41;&#44; has represented a benefit both for macrovascular and microvascular disease in patients with DM2&#46; The 3 drug groups have a high safety profile&#44; making them drugs of choice for DKD&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">17</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">It is important to understand the definitions and outcomes at the renal level of the main studies with ADOs in DKD&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">11</span></a><ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">-</span><p id="par0180" class="elsevierStylePara elsevierViewall">Normal renal function&#58; eGFR &#62;90<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#44; albumin excretion &#60;30<span class="elsevierStyleHsp" style=""></span>mg&#47;d or ACR &#60;30<span class="elsevierStyleHsp" style=""></span>mg&#47;g confirmed in 3 measurements&#46;</p></li><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">-</span><p id="par0185" class="elsevierStylePara elsevierViewall">With kidney disease&#58;</p></li><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">-</span><p id="par0190" class="elsevierStylePara elsevierViewall">eGFR &#62;90<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> with microalbuminuria &#40;30&#8211;300<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41; or ACR 30&#8211;300<span class="elsevierStyleHsp" style=""></span>mg&#47;g&#46;</p></li><li class="elsevierStyleListItem" id="lsti0120"><span class="elsevierStyleLabel">-</span><p id="par0195" class="elsevierStylePara elsevierViewall">Macroalbuminuria defined as an albumin excretion &#8805;300<span class="elsevierStyleHsp" style=""></span>mg&#47;d or ACR<span class="elsevierStyleHsp" style=""></span>&#8805;300<span class="elsevierStyleHsp" style=""></span>mg&#47;g confirmed in 3 measurements&#46;</p></li></ul></p><p id="par0200" class="elsevierStylePara elsevierViewall">Similarly&#44; the primary outcomes in clinical trials refer to&#46;&#46;&#46;<ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0125"><span class="elsevierStyleLabel">-</span><p id="par0205" class="elsevierStylePara elsevierViewall">Doubling of baseline creatinine levels&#46;</p></li><li class="elsevierStyleListItem" id="lsti0130"><span class="elsevierStyleLabel">-</span><p id="par0210" class="elsevierStylePara elsevierViewall">CKD&#58; eGFR &#60;15<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> for 3 months or more&#44; need for RRT or kidney transplantation&#46;</p></li><li class="elsevierStyleListItem" id="lsti0135"><span class="elsevierStyleLabel">-</span><p id="par0215" class="elsevierStylePara elsevierViewall">Death &#40;all-cause&#44; cardiovascular&#44; sudden death&#41;&#44; nonfatal infarction or stroke&#46;</p></li></ul></p><p id="par0220" class="elsevierStylePara elsevierViewall">The secondary outcomes are&#46;&#46;&#46;<ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0140"><span class="elsevierStyleLabel">-</span><p id="par0225" class="elsevierStylePara elsevierViewall">Onset&#44; progression or regression of microalbuminuria&#46;</p></li><li class="elsevierStyleListItem" id="lsti0145"><span class="elsevierStyleLabel">-</span><p id="par0230" class="elsevierStylePara elsevierViewall">ACR value at the end of treatment or change between the start and end of treatment&#46;</p></li><li class="elsevierStyleListItem" id="lsti0150"><span class="elsevierStyleLabel">-</span><p id="par0235" class="elsevierStylePara elsevierViewall">Creatinine clearance or eGFR at the end of treatment or change between the start and end of treatment and change in eGFR at 1 year of follow-up&#46;</p></li></ul></p><p id="par0240" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B shows the various action levels of the new ODAs that have shown renal protection&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Alpha-glucosidase inhibitors</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Miglitol and acarbose</span><p id="par0245" class="elsevierStylePara elsevierViewall">These drugs delay the absorption of complex carbohydrates in the intestines&#44; decreasing the postprandial glucose peak&#46; These drugs are contraindicated in stage 4 CKD&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Sulfonylureas</span><p id="par0250" class="elsevierStylePara elsevierViewall">Sulfonylureas are contraindicated in cases of severe renal failure&#46; Their main adverse effects are hypoglycemia&#44; which can be severe&#44; and weight gain&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">18</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Meglitinides</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Repaglinide and nateglinide</span><p id="par0255" class="elsevierStylePara elsevierViewall">Both have a short half-life&#46; Repaglinide is more potent and is eliminated by the bile duct and can therefore be used in any grade of CKD and in dialysis&#46; Despite having hepatic metabolism&#44; nateglinide forms active metabolites that are cleared by the kidneys and is therefore not recommended in CKD&#46; The main secondary effect of both drugs is hypoglycemia&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">19</span></a></p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Thiazolidinediones</span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Pioglitazone</span><p id="par0260" class="elsevierStylePara elsevierViewall">An insulin sensitizer that stimulates glucose uptake by the muscle and adipose tissue&#46; Reduces gluconeogenesis and fatty acid synthesis at the hepatic level&#46; The drug is metabolized in the liver and excreted in feces and is therefore not contraindicated in CKD&#46; Its main adverse effects are water retention &#40;its use is not recommended in heart and hepatic failure&#41;&#44; distal bone fractures in women and a debatable increase in the incidence of bladder cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">20</span></a></p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Biguanides</span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Metformin</span><p id="par0265" class="elsevierStylePara elsevierViewall">Approved by the FDA in 1973&#46; It was not until 2016 that the warnings were revised on its use in CKD&#44; concluding that it is safe in patients with mild to moderate CKD&#44; adjusted to eGFR &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">21</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0270" class="elsevierStylePara elsevierViewall">A recent systematic review on the use of metformin in patients with moderate to severe CKD and heart failure or chronic liver disease showed a reduction in all-cause mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">22</span></a> The data regarding the risk of lactic acidosis in patients with CKD are limited&#44; but the overall risk is low&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">23</span></a></p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Dipeptidyl peptidase-4 inhibitors</span><p id="par0275" class="elsevierStylePara elsevierViewall">DPP4Is are a safe and effective treatment option&#44; with a low risk of hypoglycemia and few adverse effects&#46; The DPP4 receptor is expressed in several segments of the nephron and in the interstitial tubule &#40;segments S1-S3&#41;&#44; with anti-inflammatory effects&#44; immune system activation&#44; sodium regulation and kidney fibrosis regulation &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">24</span></a> The 5 compounds reduce HbA1c levels by approximately 0&#46;5&#37; in patients with stage 3&#8211;4 CKD<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">25</span></a> and decrease urinary albumin excretion&#44; regardless of the blood pressure or blood glucose control&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">26</span></a></p><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Sitagliptin</span><p id="par0280" class="elsevierStylePara elsevierViewall">This was the first DPP4I marketed in 2006&#46; With an 80&#37; renal elimination rate&#44; dosage adjustments of up to 5<span class="elsevierStyleHsp" style=""></span>mg&#47;d are needed for eGFRs of 30&#8211;50<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;m<span class="elsevierStyleSup">2</span> and 25<span class="elsevierStyleHsp" style=""></span>mg&#47;d for eGFRs &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73 m<span class="elsevierStyleSup">2</span>&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">Data on the possible beneficial effect of sitagliptin on the kidneys mostly comes from uncontrolled observational studies&#46; Arjona Ferreira et al&#46; randomized 426 patients to sitagliptin &#40;50<span class="elsevierStyleHsp" style=""></span>mg for moderate renal failure or 25<span class="elsevierStyleHsp" style=""></span>mg for severe renal failure&#41; or 10-mg glipizide for 54 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">27</span></a> The reduction in HbA1c levels was 0&#46;8&#37; and 0&#46;6&#37; for sitagliptin and glipizide&#44; respectively&#46; The combined objective of an HbA1c reduction &#62;0&#46;5&#37; with no weight gain or hypoglycemia was achieved in 37&#46;5&#37; and 14&#46;2&#37; of cases&#44; respectively&#46; Both the reduction in eGFR &#40;3&#46;9 vs&#46; 3&#46;3<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#41; and the percentage of patients who developed renal failure &#40;18&#46;8&#37; vs&#46; 11&#46;0&#37;&#41; were similar in the 2 groups&#46; In another small study with 36 patients lasting 6 months&#44; sitagliptin &#40;50<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41; decreased HbA1c levels 0&#46;7&#37; and the ACR&#44; in normoalbuminuria&#44; microalbuminuria and macroalbuminuria&#44; with no changes in eGFR&#46; In another randomized study with 85 patients assigned to 50-mg sitagliptin versus other ODAs&#44; only sitagliptin lowered the ACR in patients with normoalbuminuria&#44; revealing a potential preventive and protective effect in the initial stages of DKD&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">26</span></a> In the Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin &#40;TECOS&#41;&#44; designed to assess the effect of sitagliptin on the cardiovascular prognosis of patients with diabetes and cardiovascular disease&#44; sitagliptin was not inferior to placebo in the primary objective &#40;hazard ratio &#91;HR&#93;&#44; 0&#46;98&#59; 95&#37; confidence interval &#91;95&#37; CI&#93; 0&#46;88&#8211;1&#46;09&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">28</span></a> After stratifying the patients by renal function&#44; the rate of cardiovascular events increased as the eGFR decreased&#44; with an adjusted HR for stages 2&#44; 3a and 3b compared with stage 1 of 0&#46;93 &#40;95&#37; CI 0&#46;82&#8211;1&#46;06&#41;&#44; 1&#46;28 &#40;95&#37; CI 1&#46;10&#8211;1&#46;49&#41; and 1&#46;39 &#40;95&#37; CI 1&#46;13&#8211;1&#46;72&#41;&#44; respectively&#46; The reduction in renal function was similar in both groups&#44; with a marginal but constant reduction &#40;-1&#46;3<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#41; in the treatment group&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">29</span></a></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Linagliptin</span><p id="par0290" class="elsevierStylePara elsevierViewall">This drug has the lowest renal elimination and does not require dosage adjustments in CKD&#46; The drug is currently being analyzed in 2 studies&#58; the Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus &#40;CARMELINA&#41; versus placebo<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">30</span></a> and the Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Early Type 2 Diabetes &#40;CAROLINA&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">31</span></a> whose results will be published between 2018 and 2020&#46; Sixty percent of the included patients have an eGFR &#60;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#44; and 15&#37; have an eGFR &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46; In a meta-analysis of three 24-week&#44; placebo-controlled studies&#44; linagliptin consistently lowered HbA1c levels at all stages of renal function&#58; 0&#46;63&#37; for normal eGFR &#40;&#62;90<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#41;&#44; 0&#46;67&#37; for an eGFR of 60&#8211;90<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> and 0&#46;53&#37; for an eGFR of 30&#8211;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#44; with renal function remaining stable&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">32</span></a> In a phase-III study by Groop et al&#46; that added linagliptin to the conventional treatment of patients with diabetes treated with RAAS inhibitors&#44; the percentage change in the ACR curve was 32&#37; with linagliptin compared with 6&#37; with placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">33</span></a> These results were not confirmed in the Modification of Albuminuria in Type 2 Diabetes Subjects with Renal Disease with Linagliptin &#40;MARLINA T2D&#41; study&#44;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">34</span></a> where the change was &#8722;11&#46;0&#37; &#40;95&#37; CI &#8722;16&#46;8 to &#8722;4&#46;7&#41; with linagliptin and &#8722;5&#46;1&#37; &#40;95&#37; CI&#44; &#8722;11&#46;4 to 1&#46;6&#41; with placebo&#44; an overall difference of &#8722;6&#46;0&#37; &#40;95&#37; CI&#44; &#8722;15&#46;0 to 3&#46;0&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;1954&#41;&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Saxagliptin</span><p id="par0295" class="elsevierStylePara elsevierViewall">For saxagliptin&#44; the dosage needs to be reduced for patients with moderate to severe renal failure &#40;2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&#46; This dosage is approved in the US for patients on hemodialysis but not in Europe&#46; The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus trial &#40;SAVOR-TIMI<span class="elsevierStyleHsp" style=""></span>53&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">34</span></a> designed to assess the cardiovascular safety of saxagliptin&#44; showed noninferiority versus placebo in the primary objective &#40;HR&#44; 1&#46;00&#59; 95&#37; CI 0&#46;89&#8211;1&#46;12&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; In a post hoc analysis&#44; saxagliptin showed an improvement in ACR for all categories&#44; for normoalbuminuria&#44; microalbuminuria and macroalbuminuria &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;02&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;05&#44; respectively&#41;&#44; with no variations in the eGFR&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">35</span></a></p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Alogliptin</span><p id="par0300" class="elsevierStylePara elsevierViewall">For alogliptin&#44; the dosage should be adjusted according to renal function&#58; 12&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;d for stage 3 CKD and 6&#46;25<span class="elsevierStyleHsp" style=""></span>mg&#47;d for stages 4&#8211;5&#46; In the Cardiovascular Mortality in Patients With Type 2 Diabetes and Recent Acute Coronary Syndromes &#40;EXAMINE&#41; study&#44;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">36</span></a> designed as a noninferiority study for patients with diabetes and a cardiac ischemic event in the previous 15&#8211;90 days&#44; alogliptin was not inferior to placebo for the primary objective &#40;HR&#44; 0&#46;96&#59; 95&#37; CI 0&#46;96&#8211;1&#46;16&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#44; with similar changes in eGFR and the need for dialysis&#46; Twenty-nine percent of the patients had eGFR &#60;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Vildagliptin</span><p id="par0305" class="elsevierStylePara elsevierViewall">Vildagliptin requires a dosage adjustment with eGFR &#60;50<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46; No cardiovascular safety studies have been performed for vildagliptin&#46; However&#44; the Galvus in Addition to Metformin vs&#46; TZD&#47;metformin in T2DM &#40;GALIANT&#41; retrospective analysis showed that the safety and efficacy of vildagliptin versus metformin for patients with eGFR between 50 and 80<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> was similar to that for patients with preserved renal function&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">37</span></a> Lukashevich et al&#46; randomized 515 patients with moderate &#40;eGFR of 30&#8211;50<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#41; or severe CKD &#40;eGFR &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#41; to vildagliptin or placebo and observed a similar reduction in HbA1c &#40;&#8722;0&#46;5&#37; vs&#46; &#8722;0&#46;6&#37;&#41;&#44; with no increase in hypoglycemia or greater eGFR deterioration&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">38</span></a></p></span></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Glucagon-like peptide-1 agonists &#40;GLP-1 RA&#41;</span><p id="par0310" class="elsevierStylePara elsevierViewall">GLP-1 RAs act by increasing insulin secretion&#44; inhibiting glucagon secretion by alpha-pancreatic cells&#44; slowing gastric emptying and inducing satiety&#46; Their use was initially associated with worsening renal function&#44; due to adverse gastrointestinal effects or in patients with heart failure&#44; pancreatitis&#44; infections or the concomitant use of diuretics&#44; angiotensin-converting enzyme inhibitors or nonsteroidal anti-inflammatory drugs&#46;</p><p id="par0415" class="elsevierStylePara elsevierViewall">The GLP-1 receptor is expressed almost exclusively in the vascular tree of the kidneys&#46; Through the reduction in NHE3 &#40;sodium&#47;hydrogen exchanger&#41; activity via the protein kinase A &#40;PKA&#41; pathway&#44; DPP4Is inhibit the tyrosine kinase A &#40;TKA&#41; pathway&#44; increasing natriuresis and osmotic diuresis&#46; Through the GLP-1 receptor pathway&#44; DPP4Is reduce the resistance of the afferent arteriole and increase the resistance of the efferent arteriole&#44; decreasing the hydrostatic pressure in the Bowman capsule and increasing it on the glomerular level&#46; They also act through nitric oxide and other vascular factors that mediate renal hyperfiltration &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">39</span></a></p><p id="par0320" class="elsevierStylePara elsevierViewall">The GLP-1 RAs currently approved by the FDA&#47;EMA are liraglutide&#44; lixisenatide&#44; exenatide LAR&#44; albiglutide and dulaglutide&#46; The first 3 have completed their cardiovascular safety studies&#46;</p><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Lixisenatide</span><p id="par0325" class="elsevierStylePara elsevierViewall">Lixisenatide does not require dosage adjustment for eGFR of 60&#8211;90<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46; Monitoring is recommended for eGFR of 30&#8211;59<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46; This drug is contraindicated for eGFR of 15<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;</p><p id="par0330" class="elsevierStylePara elsevierViewall">In the Evaluation of Lixisenatide in Acute Coronary Syndrome &#40;ELIXA&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">40</span></a> lixisenatide did not increase the incidence of cardiovascular events compared with standard treatment &#40;13&#46;4&#37; vs&#46; 13&#46;2&#37;&#59; HR&#44; 1&#46;02&#59; 95&#37; CI 0&#46;89&#8211;1&#46;17&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; In a subanalysis of the ELIXA study&#44; lixisenatide did not significantly improve the microalbuminuria or eGFR levels&#46; Although a benefit was initially observed in the treatment branch &#40;34&#37; vs&#46; 34&#37;&#41;&#44; mainly in patients undergoing treatment with drugs that inhibit RAAS&#44; after adjusting for baseline and at 3 months of HbA1c&#44; the reduction was not statistically significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;07&#41;&#46; The Effect of Lixisenatide on the Renal System &#40;ELIXIRS&#41; study is currently underway to assess the behavior of this drug on renal function and on biomarkers&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">41</span></a></p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Liraglutide</span><p id="par0335" class="elsevierStylePara elsevierViewall">Liraglutide does not require dosage adjustments in any stage of CKD&#46;</p><p id="par0340" class="elsevierStylePara elsevierViewall">In the Liraglutide Effect and Action in Diabetes&#58; Evaluation of Cardiovascular Outcome Results &#40;LEADER&#41; study&#44; liraglutide was superior to placebo in the primary endpoint &#40;HR&#44; 0&#46;87&#59; 95&#37; CI 0&#46;78&#8211;0&#46;97&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;01&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">42</span></a> In a secondary analysis to assess the renal prognosis&#44; the combined outcome of persistent or new onset macroalbuminuria&#44; doubling of serum creatinine values&#44; terminal CKD or death due to renal causes clearly favored liraglutide &#40;HR&#44; 0&#46;78&#59; 95&#37; CI 0&#46;67&#8211;0&#46;92&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;003&#41;&#46; The benefit was mainly observed at the expense of a reduction in macroalbuminuria &#40;HR&#44; 0&#46;74&#59; 95&#37; CI 0&#46;60&#8211;0&#46;91&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;004&#41;&#46; The eGFR readings improved&#44; mainly for baseline eGFR &#60;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#44; with no increase in adverse events&#46; The renal protective mechanism appears to be multifactorial&#44; involving glycemic control&#44; blood pressure control and weight loss&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">43</span></a></p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Exenatide &#8211; LAR</span><p id="par0345" class="elsevierStylePara elsevierViewall">Exenatide LAR is not indicated for eGFR &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;</p><p id="par0350" class="elsevierStylePara elsevierViewall">In the Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in T2D &#40;EXSCEL&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">44</span></a> exenatide LAR was not inferior to placebo in the cardiovascular objective&#46; The study did not prespecify the renal prognosis&#44; and the normoalbuminuria&#44; macroalbuminuria and microalbuminuria results were similar in the 2 branches&#46; Compared with glimepiride&#44; which has no effect on microalbuminuria&#44; treatment with exenatide LAR in 31 patients with diabetes and microalbuminuria resulted in a 38&#37; reduction in ACR&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">45</span></a></p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Dulaglutide</span><p id="par0420" class="elsevierStylePara elsevierViewall">Dulaglutide does not require a dosage adjustment in renal failure&#46; The AWARD-7 study is currently underway and seeks to assess the safety and efficacy of dulaglutide versus insulin glargine in glycemic control and renal protection in patients with stage 3 and 4 CKD&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">46</span></a></p></span></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Sodium-glucose cotransporter-2 inhibitors &#40;SGLT2Is&#41;</span><p id="par0360" class="elsevierStylePara elsevierViewall">Dapagliflozin&#44; empagliflozin and canagliflozin are currently approved in Europe&#46;</p><p id="par0365" class="elsevierStylePara elsevierViewall">In conditions of hyperglycemia&#44; there is an overexpression &#40;36&#37;&#41; of SGLT2 receptors&#44; which involves increased glucose reabsorption in the proximal convoluted tubule&#46; With its block&#44; renal hyperfiltration and intraglomerular hypertension decrease &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#41;&#46; This mechanism of action results in an initial reduction of eGFR&#44; with <span class="elsevierStyleItalic">ad integrum</span> recovery in 12 weeks&#46; Attenuation of the glycosuric effects and weight loss is expected in patients with eGFR &#60;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46; In contrast&#44; albuminuric effects and reduced blood pressure are preserved and perhaps exaggerated in CKD&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">47</span></a> The reduction in HbA1c levels &#40;&#8722;0&#46;5&#37; to &#8722;0&#46;7&#37;&#41; is reduced in patients with eGFR of 30&#8211;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> &#40;&#8722;0&#46;4&#37;&#41;&#46; SGLT2Is are not recommended for concomitant use with loop diuretics or for patients with diseases that entail volume depletion&#46;</p><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Dapagliflozin</span><p id="par0370" class="elsevierStylePara elsevierViewall">This was the first DPP4I marketed in Spain&#46; There are two cardiovascular safety studies currently underway&#58; the Dapagliflozin Effect on Cardiovascular Events &#40;DECLARE-TIMI<span class="elsevierStyleHsp" style=""></span>58&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">48</span></a> whose results will be published sometime in 2018&#44; and A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients with Chronic Kidney Disease &#40;DAPA-CKD&#41;&#46; Starting dapagliflozin when the eGFR is &#60;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> is not recommended&#44; starting it when eGFR is between 30 and 60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> is not indicated&#44; and starting it when the eGFR is &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> is contraindicated&#46;</p></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Empagliflozin</span><p id="par0375" class="elsevierStylePara elsevierViewall">This was the second DPP4I marketed in Spain&#46; In the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose &#40;EMPA-REG OUTCOME&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">49</span></a> empagliflozin significantly lowered the risk of the onset or worsening of kidney disease by 39&#37; in patients with established cardiovascular disease&#44; results that were maintained in a post hoc analysis in the patient subgroup with eGFR &#60;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> and&#47;or macroalbuminuria &#40;ACR &#62;300<span class="elsevierStyleHsp" style=""></span>mg&#47;g&#41;&#46; The other results were a 55&#37; reduction in the onset of RRT&#44; a 44&#37; reduction in the doubling of creatinine combined with an eGFR<span class="elsevierStyleHsp" style=""></span>&#8804;45<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> and a 38&#37; reduction in the progression to macroalbuminuria&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">50&#44;51</span></a> Dosage adjustments are not required if the eGFR is &#8805;45<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46; The use of empagliflozin should be avoided or discontinued in patients with eGFR &#60;45<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;</p></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Canagliflozin</span><p id="par0380" class="elsevierStylePara elsevierViewall">This was the third drug of the DPP4I family to be marketed&#46; The results of the Canagliflozin Cardiovascular Assessment Study &#40;CANVAS&#41; and CANVAS&#8211;R &#40;Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes&#41; study<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">52</span></a> showed a beneficial effect for canagliflozin in terms of progression to albuminuria &#40;HR&#44; 0&#46;73&#59; 95&#37; CI 0&#46;67&#8211;0&#46;79&#41; and in the composite objective of a 40&#37; reduction in eGFR&#44; need for RRT and death due to renal causes &#40;HR&#44; 0&#46;73&#59; 95&#37; CI 0&#46;47&#8211;0&#46;77&#41;&#46; As with empagliflozin&#44; this result shows a protective effect on the kidneys for this therapeutic family of drugs&#46; The currently underway Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy &#40;CREDENCE&#41; study is evaluating the potential protective effect of canagliflozin on the progression of kidney disease in patients with diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">53</span></a> Dosage adjustments are not required if the eGFR is &#8805;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#59; adjustments are required for eGFR of 45&#8211;59<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46; The use of canagliflozin should be avoided or discontinued for patients with eGFR persistently &#60;45<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;</p></span></span><span id="sec0155" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Insulin</span><p id="par0385" class="elsevierStylePara elsevierViewall">Endogenous insulin is degraded in the liver&#59; however&#44; exogenous insulin is degraded in the kidneys&#44; filtered in the glomerulus and reabsorbed in the proximal convoluted tubule&#46; Its clearance decreases in parallel with the eGFR&#44; which means that as the kidney disease progresses the need for insulin decreases&#46;</p><p id="par0390" class="elsevierStylePara elsevierViewall">Insulin is the treatment of choice for patients with CKD and on dialysis&#46; The treatment should be individualized&#44; adjusting the dosage according to the patient&#39;s needs and even discontinued in the event of burnt-out diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">54</span></a> A recently published consensus document on the insulinization of patients with CKD<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">55</span></a> recommended reducing the dosage by 25&#37; up to an eGFR of 15&#8211;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> and reducing it 50&#37; if the eGFR drops below this value&#46; Depending on body weight&#44; the initial dosage should 0&#46;5<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#47;d for an eGFR &#62;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#44; 0&#46;3&#8211;0&#46;4<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#47;d for an eGFR of 15&#8211;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> and 0&#46;25<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#47;d for an eGFR &#60;15<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46; Basal &#40;glargine&#44; detemir&#44; degludec&#41; and rapid-acting insulin analogs &#40;aspart&#44; lispro&#44; glulisine&#41; induce less hypoglycemia than human insulins &#40;neutral protamine Hagedorn or regular insulin&#41;&#46; There are no significant differences in the insulin aspart dosages for all eGFR levels&#46; However&#44; a small reduction for insulin lispro is recommended for eGFR &#60;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46; Among the basal insulins&#44; insulin glargine is safe and effective and has a stable half-life in patients with CKD&#46; Kulozik and Hasslacher reported the need for adjusting the dosage by 27&#8211;30&#37; for insulin glargine and insulin detemir for eGFR levels &#60;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">56</span></a> Insulin degludec presents no differences in either absorption or clearance in patients with CKD&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">57</span></a></p><p id="par0395" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> lists the recommended dosages for the various antidiabetic drugs in CKD&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Conflicts of interest</span><p id="par0400" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Classification of chronic kidney disease"
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          "titulo" => "Etiopathogenesis and pathophysiology of diabetic kidney disease"
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          "titulo" => "Glycemic control for patients with chronic kidney disease&#46; The importance of the new oral diabetes drugs"
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          "titulo" => "Alpha-glucosidase inhibitors"
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              "titulo" => "Miglitol and acarbose"
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          "titulo" => "Sulfonylureas"
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          "titulo" => "Meglitinides"
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          "titulo" => "Thiazolidinediones"
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          "titulo" => "Dipeptidyl peptidase-4 inhibitors"
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              "titulo" => "Sitagliptin"
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              "titulo" => "Linagliptin"
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              "titulo" => "Saxagliptin"
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              "titulo" => "Alogliptin"
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              "titulo" => "Vildagliptin"
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          "titulo" => "Glucagon-like peptide-1 agonists &#40;GLP-1 RA&#41;"
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              "identificador" => "sec0115"
              "titulo" => "Lixisenatide"
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              "titulo" => "Liraglutide"
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            2 => array:2 [
              "identificador" => "sec0125"
              "titulo" => "Exenatide &#8211; LAR"
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              "titulo" => "Dulaglutide"
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          "titulo" => "Sodium-glucose cotransporter-2 inhibitors &#40;SGLT2Is&#41;"
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            0 => array:2 [
              "identificador" => "sec0140"
              "titulo" => "Dapagliflozin"
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              "identificador" => "sec0145"
              "titulo" => "Empagliflozin"
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            2 => array:2 [
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              "titulo" => "Canagliflozin"
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          ]
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          "titulo" => "Insulin"
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          "titulo" => "Conflicts of interest"
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          "identificador" => "xack360883"
          "titulo" => "Acknowledgments"
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          "titulo" => "References"
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    "fechaRecibido" => "2018-03-04"
    "fechaAceptado" => "2018-03-19"
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          "clase" => "keyword"
          "titulo" => "Keywords"
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          "palabras" => array:7 [
            0 => "Diabetes"
            1 => "Chronic kidney disease"
            2 => "Diabetic nephropathy"
            3 => "Diabetic kidney disease"
            4 => "SGLT2-i"
            5 => "GLP-1RA"
            6 => "DPP4-i"
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            0 => "Diabetes"
            1 => "Enfermedad renal cr&#243;nica"
            2 => "Nefropat&#237;a diab&#233;tica"
            3 => "Enfermedad renal del diab&#233;tico"
            4 => "iSGLT2"
            5 => "arGLP1"
            6 => "iDPP4"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Diabetes mellitus type 2 is the main cause of chronic kidney disease&#46; Patients with this disease have higher morbidity and mortality and risk of hypoglycaemia than those without this disease&#46; In 2010&#44; type 2 diabetes was the reason for starting renal replacement therapy in 24&#46;7&#37; of patients&#46; The prevalence of microalbuminuria&#44; proteinuria and a reduced glomerular filtration rate is 36&#37;&#44; 8&#37; and 22&#37;&#44; respectively&#46; The presence of albuminuria is a predictor of chronic kidney disease&#46; Diabetic kidney disease&#44; previously known as diabetic nephropathy&#44; refers to kidney disease caused by diabetes&#46; Renal hyperfiltration is a marker of intraglomerular hypertension and a risk factor for onset and progression&#46; The new antidiabetic drugs&#44; mainly dipeptidyl peptidase-4 inhibitors&#44; sodium-glucose cotransporter inhibitors and glucagon-like peptide-1 agonists&#44; have been shown to prevent or slow the progression of kidney disease&#46;</p></span>"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La diabetes mellitus tipo<span class="elsevierStyleHsp" style=""></span>2 es la principal causa de enfermedad renal cr&#243;nica&#46; Estos pacientes presentan mayor morbimortalidad y riesgo de hipoglucemias que el resto&#46; En 2010&#44; la diabetes tipo<span class="elsevierStyleHsp" style=""></span>2 fue causa del inicio de terapia renal sustitutiva en el 24&#44;7&#37; de los pacientes&#46; La prevalencia de microalbuminuria&#44; proteinuria y disminuci&#243;n del filtrado glomerular es del 36&#44; 8&#44; y 22&#37;&#44; respectivamente&#46; La presencia de albuminuria es un factor predictivo de enfermedad renal cr&#243;nica&#46; La enfermedad renal diab&#233;tica&#44; previamente conocida como nefropat&#237;a diab&#233;tica&#44; hace referencia a la enfermedad renal causada por la diabetes&#46; La hiperfiltraci&#243;n renal es marcador de hipertensi&#243;n intraglomerular y factor de riesgo tanto de inicio como de progresi&#243;n&#46; Los nuevos antidiab&#233;ticos&#44; fundamentalmente los inhibidores del enzima dipeptidil peptidasa-4&#44; los inhibidores del cotransportador de sodio&#47;glucosa y los agonistas del p&#233;ptido similar al glucag&#243;n tipo<span class="elsevierStyleHsp" style=""></span>1&#44; han demostrado prevenir o enlentecer la progresi&#243;n de la enfermedad renal&#46;</p></span>"
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Carretero G&#243;mez J&#44; Ar&#233;valo Lorido JC&#46; Evaluaci&#243;n cl&#237;nica y tratamiento de la diabetes en pacientes con enfermedad renal cr&#243;nica&#46; Rev Clin Esp&#46; 2018&#59;218&#58;305&#8211;315&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Staging of chronic kidney disease according to the 2012 KDIGO guidelines&#46; <span class="elsevierStyleItalic">Abbreviations</span>&#58; CKD&#44; chronic kidney disease&#59; eGFR&#44; estimated glomerular filtration rate&#59; KDIGO&#44; Kidney Disease Global Outcomes&#46; Albumin&#47;creatinine ratio 1<span class="elsevierStyleHsp" style=""></span>mg&#47;g<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;113<span class="elsevierStyleHsp" style=""></span>mg&#47;mmol&#59; 30<span class="elsevierStyleHsp" style=""></span>mg&#47;g &#40;3&#46;4<span class="elsevierStyleHsp" style=""></span>mg&#47;mmol&#41;&#46; The colors show the adjusted relative risk for 5 events&#58; overall mortality&#44; cardiovascular mortality&#44; renal failure treated with dialysis or transplantation&#44; acute renal failure and progression of the kidney disease&#46; Green indicates the lowest risk&#44; followed by yellow &#40;&#8220;moderately increased&#8221; risk&#41;&#44; orange &#40;&#8220;high risk&#8221;&#41; and red &#40;&#8220;very high risk&#8221;&#41;&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The kidneys in diabetes&#46; Panel &#40;A&#41; In the early phases of DKD&#44; the reduced release of Na<span class="elsevierStyleSup">&#43;</span> to the macula densa is erroneously interpreted by the juxtaglomerular apparatus as a reduction in effective circulating volume&#44; resulting in compensatory vasodilation of the afferent arteriole and an increase in intraglomerular pressure&#46; This mechanism has been called &#8220;tubuloglumerular feedback&#8221; and is the pathophysiological basis of DKD&#46; Panel &#40;B&#41; SGLT2I receptors are overexpressed in hyperglycemic conditions &#40;36&#37;&#41;&#44; increasing the renal reabsorption of Na<span class="elsevierStyleSup">&#43;</span> and Cl<span class="elsevierStyleSup">&#8722;</span> by at least 14&#37;&#46; Inhibition of SGLT2I receptors in the proximal tubule reverses the previous hemodynamic condition&#44; resulting in vasoconstriction of the afferent arteriole and eGFR normalization&#46; Overall&#44; they induce a reduction in hyperfiltration&#44; proteinuria&#44; glomerular hypertrophy and mesangial expansion&#46; DPP4 receptors are widely expressed in the brush border in segments S1-S3 of the proximal convoluted tubule and to a lesser extent in other segments at the tubulointerstitial level&#46; Through the reduction in NHE3 activity &#40;Na&#47;H-exchanger&#41;&#44; the tyrosine kinase pathway decreases sodium reabsorption in the proximal convoluted tubule&#46; GLP-1 is expressed exclusively in the smooth muscle cells of the vessels&#44; both preglomerular and juxtaglomerular&#46; Through the reduction in NHE3 activity via PKA &#40;unlike DPP4Is that inhibit through TKA&#41;&#44; they increase natriuresis and osmotic diuresis&#46; Globally&#44; they reduce the resistance of the afferent arteriole and increase the resistance of the efferent arteriole&#44; decreasing the hydrostatic pressure in the Bowman capsule and increasing it on the glomerular level&#44; either through the GLP-1 receptor&#44; nitric oxide or other vascular factors that mediate renal hyperfiltration&#44; such as angiotensin I and II&#44; atrial natriuretic peptide&#44; endothelin<span class="elsevierStyleHsp" style=""></span>1 and oxygen reactive species &#40;ROS&#41;&#46;</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; Ang-I&#44; angiotensin<span class="elsevierStyleHsp" style=""></span>I&#59; Ang-II&#44; angiotensin<span class="elsevierStyleHsp" style=""></span>II&#59; ANP&#44; atrial natriuretic peptide&#59; GLP-1RA&#44; glucagon-like peptide-1 receptor agonists&#59; DKD&#44; diabetic kidney disease&#59; DPP4&#44; enzyme dipeptidyl peptidase-4&#59; ET1&#44; endothelin<span class="elsevierStyleHsp" style=""></span>1&#59; NHE3&#44; isoform 3 of the sodium&#47;hydrogen exchanger&#59; PKA&#44; protein kinase A&#59; ROS&#44; reactive oxygen species&#59; SGLT2i&#44; sodium-dependent glucose cotransporter 2 inhibitor&#59; TGF&#44; tubuloglomerular feedback&#59; TKA&#44; tyrosine kinase A&#46;</p>"
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; FDA&#44; Food and Drug Administration&#59; eGFR&#44; glomerular filtration rate&#46;</p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">eGFR&#44; mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">FDA recommendations&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No contraindications<br>Annual eGFR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">30&#8211;45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No recommendation start treatment<br>Risk&#47;benefit for continuing treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#60;30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Contraindicated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Withdraw treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Liver disease&#44; alcoholism&#44; heart failure<br>The patient will undergo an imaging test with iodinated contrast and eGFR 30&#8211;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Review of the 2016 Food and Drug Administration for the use of metformin in chronic kidney disease&#46;</p>"
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; CKD&#44; chronic kidney disease&#59; DPP4&#44; dipeptidyl peptidase-4 enzyme&#59; eGFR&#44; estimated glomerular filtration rate&#59; GLP-1&#44; glucagon-like peptide-1&#59; SGLT2i&#44; sodium-glucose cotransporter&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Recommended dosage for renal failure<br>eGFR &#40;mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Biguanides</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Metformin</td><td class="td" title="table-entry  " align="left" valign="top">No dosage adjustment needed if eGFR &#62;45<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Do not start or assess risk-benefit if eGFR is 30&#8211;45<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Discontinue if eGFR &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Second generation sulfonylureas</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Glipizide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No dosage adjustment required&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Glimepiride&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Start conservatively at a dosage of 1<span class="elsevierStyleHsp" style=""></span>mg per day&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Glyburide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Avoid its use&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Meglitinides</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Repaglinide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Start conservatively at a dosage of 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg at each meal if eGFR &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Nateglinide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Start conservatively at a dosage of 60<span class="elsevierStyleHsp" style=""></span>mg at each meal if eGFR &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Thiazolidinediones</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Pioglitazone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No dosage adjustment required&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Rosiglitazone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No dosage adjustment required&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Alfa-glucosidase inhibitors</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Acarbose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Avoid if eGFR &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Miglitol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Avoid if eGFR &#60;25<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Partial GLP-1 receptor agonists</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LAR exenatide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not recommended with eGFR &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Liraglutide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No dosage adjustment required&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Lixisenatide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No dosage adjustment required for eGFR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>60&#8211;89<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;<br>No dosage adjustment required if eGFR is 30&#8211;59<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#59; however&#44; patients should be monitored if adverse effects occur or if there is renal function impairment&#46;<br>There is little clinical experience with eGFR of 15&#8211;29<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#59; however&#44; patients should be monitored if adverse effects occur or if there is renal function impairment&#46;<br>Avoid if eGFR &#60;15<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Albiglutide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No dosage adjustment required for eGFR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>15&#8211;89<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Dulaglutide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No dosage adjustment required&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">DPP4 inhibitors</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Sitagliptin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100<span class="elsevierStyleHsp" style=""></span>mg&#47;day if eGFR<span class="elsevierStyleHsp" style=""></span>&#62;50<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;<br>50<span class="elsevierStyleHsp" style=""></span>mg&#47;day if eGFR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>30&#8211;50<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;<br>25<span class="elsevierStyleHsp" style=""></span>mg&#47;day if eGFR<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Saxagliptin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5<span class="elsevierStyleHsp" style=""></span>mg&#47;day if eGFR<span class="elsevierStyleHsp" style=""></span>&#62;50<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;<br>2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;day if eGFR<span class="elsevierStyleHsp" style=""></span>&#8804;50<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Vildagliptin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100<span class="elsevierStyleHsp" style=""></span>mg every 24<span class="elsevierStyleHsp" style=""></span>h if eGFR<span class="elsevierStyleHsp" style=""></span>&#62;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;<br>50<span class="elsevierStyleHsp" style=""></span>mg every 24<span class="elsevierStyleHsp" style=""></span>h if eGFR is 30&#8211;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;<br>25<span class="elsevierStyleHsp" style=""></span>mg every 24<span class="elsevierStyleHsp" style=""></span>h if eGFR<span class="elsevierStyleHsp" style=""></span>&#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Linagliptin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No dosage adjustment required&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Alogliptin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25<span class="elsevierStyleHsp" style=""></span>mg&#47;day if eGFR<span class="elsevierStyleHsp" style=""></span>&#62;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;<br>12&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;day if eGFR is 30&#8211;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;<br>6&#46;25<span class="elsevierStyleHsp" style=""></span>mg&#47;day if eGFR<span class="elsevierStyleHsp" style=""></span>&#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">SGLT2 inhibitors</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Canagliflozin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No dosage adjustment required if eGFR<span class="elsevierStyleHsp" style=""></span>&#8805;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;<br>100<span class="elsevierStyleHsp" style=""></span>mg&#47;day if eGFR is 45&#8211;59<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;<br>Avoid its use and discontinue in patients with eGFR persistently &#60;45&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Dapagliflozin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Avoid starting if eGFR<span class="elsevierStyleHsp" style=""></span>&#60;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;<br>Not recommended with an eGFR<span class="elsevierStyleHsp" style=""></span>of<span class="elsevierStyleHsp" style=""></span>30&#8211;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;<br>Contraindicated for eGFR<span class="elsevierStyleHsp" style=""></span>&#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Empagliflozin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No dosage adjustment required if eGFR<span class="elsevierStyleHsp" style=""></span>&#8805;45<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;<br>Avoid its use and discontinue in patients with eGFR persistently &#60;45<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Insulin</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Basal&#58; glargine&#44; detemir&#44; degludec&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduce 25&#37; if eGFR is 15&#8211;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Prandial&#58; lispro&#44; aspart&#44; glulisine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduce 50&#37; if eGFR &#60;15<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Summary of recommended antidiabetic dosages for chronic kidney disease&#46;</p>"
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    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:57 [
            0 => array:3 [
              "identificador" => "bib0295"
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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2018.03.010

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