Renal Endpoints Research Articles

P1839GLOMERULAR HYPERFILTRATION: THEORY AND APPLICATIONS

Abstract Background and Aims The role of glomerular hyperfiltration in the development and progression of diabetic and non-diabetic chronic kidney disease (CKD) was established during the 80’s of the last century and represented a paradigm shift in current nephrology practice. Method A web-based review of relevant bibliography: articles and textbooks, reporting the development of hyperfiltration theory and its clinical applications was conducted. Results In 1982, after a series of animal studies, Brenner and colleagues proposed that glomerular hyperfiltration, in diabetic and other glomerulopathies, contributes to intrarenal hypertension and predispose to progressive glomerular sclerosis and deterioration of renal function. Clinical trials during late 80’s and early 90’s then focused on inhibition of Renin Angiotensin Aldosteron system (RAAS) to reverse glomerular hyperfiltration, and suggested that ACE inhibitors can be anti-proteinuric independent of their blood pressure-lowering effect in non-diabetic and diabetic nephropathies. In 1993, a randomized controlled trial (RCT) by Lewis and colleagues proved a beneficial effect of captopril in patients with nephropathy caused by type 1 diabetes. Few years later, the results of Ramipril Efficacy in Nephropathy (REIN) study proved the renoprotective role of ACE inhibition in patients with non-diabetic nephropathies with nephrotic and non-nephrotic proteinuria in 2 Lancet articles in 1997 and 1999 respectively. The renoprotective role of RAAS inhibition with ARBs in patients with type 2 diabetes was proven in 3 RCTs published in the New England Journal of Medicine in 2001: Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA) Study, Irbesartan Diabetic Nephropathy Trial (IDNT), and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Dual blockade with an ACE inhibitor and an ARB was then attempted to further ameliorate glomerular hyperfiltration. Yet this approach was faced by an increased risk of hyperkalemia and acute kidney injury in 2 RCTs: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) in 2008 and The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) study in 2013. It was until 2014 when evidence appeared for a potential role of SGLT2 inhibition in attenuating glomerular hyperfiltration. The 1st clinical evidence of renoprotective effect of SGLT2i appeared in 2016 when the results of the EMPA-REG OUTCOME study found that empagliflozin was associated with lower rates of renal events. Subsequently, the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program trials and the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial found similar reductions in composite renal endpoints. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial published in 2019 was the first study designed to assess the effects of a SGLT2i, canagliflozin, on renal outcomes in patients with type 2 diabetes and albuminuric CKD, and proved significant reduction in the composite renal outcome with canagliflozin. The potentiality for renoprotective role of SGLT2i in patients with non-diabetic CKD has stimulated a number of ongoing clinical trials: DIAMOND and Dapa-CKD using Dapagliflozin and EMPATHY and EMPA-KIDNEY using Empagliflozin. Conclusion The hyperfiltration theory represents the basis for current therapeutic interventions in diabetic and non-diabetic CKD. Current guidelines recommend using RAAS blockers in diabetic and non-diabetic proteinuric CKD and SGLT2i in patients with type 2 diabetes and CKD. Whether SGLT2i could be considered in patients with CKD independent of the diabetic state awaits the results of ongoing studies which might change the management practice of CKD.

SO091URINE-TO-PLASMA UREA RATIO, AS SURROGATE MARKER FOR URINE CONCENTRATING CAPACITY, IS ASSOCIATED WITH DISEASE PROGRESSION IN ADPKD

Abstract Introduction Predicting disease progression in autosomal dominant polycystic kidney disease (ADPKD) patients poses a challenge, especially in early stage disease when renal function is not yet affected. The ongoing formation and growth of cysts causes the urine concentrating capacity to decrease from early on in the disease. We therefore hypothesized that the easy and inexpensive to measure urine-to-plasma urea ratio (UPU ratio), which is assumed to be surrogate for maximal urine concentrating capacity, can be used as marker to predict disease progression in ADPKD. Methods The UPU ratio was calculated by dividing urea concentration in a fasting morning spot urine sample by plasma urea concentration adjusted for plasma creatinine concentration. First, we validated the UPU ratio in 30 ADPKD patients who underwent a prolonged water deprivation test to measure the maximal urine concentrating capacity. Thereafter, the association of the UPU ratio with renal outcome was evaluated in 583 ADPKD patients participating in the DIPAK observational cohort (inclusion criteria: age>18 years, eGFR >15 mL/min/1.73m2, no concomitant diseases affecting eGFR, without V2 receptor antagonist prescription). Kidney function was assessed as eGFR by the creatinine based CKD-EPI formula, height adjusted total kidney volume (htTKV) by MRI and copeptin (surrogate for vasopressin) by ELISA. Results In the water deprivation test participants (n=30), the UPU ratio was strongly correlated with maximal urine concentrating capacity (R = 0.67, p<0.001). This association remained significant after correcting for sex, age, htTKV and eGFR (st. β = 0.53, p = 0.007). In these subjects maximal urine concentrating capacity as well as UPU ratio were associated with the rate of eGFR decline during a median follow-up of 6.3 yr (12 eGFR assessments per patient) assessed using linear mixed modeling, also when corrected for sex, baseline age and eGFR (β = 0.009, p = 0.04, and β = 5.56, p<0.001, resp.). We subsequently corroborated in the larger DIPAK observational cohort (n=583, 58% female, mean age 47 yr median eGFR 60 mL/min/1.73m2 and htTKV 898 ml/m), that the UPU ratio was significantly associated with rate of eGFR decline during a median follow-up of 4.0 yr (6 eGFR assessments per patient): β = 0.23, p = 0.005. This association remained significant when corrected for sex, baseline age and eGFR (β = 0.32, p<0.001) and even when additionally corrected for Mayo class, PDK mutation and copeptin (β = 0.40, p <0.001). Stepwise backward multivariate regression analysis resulted in a final model including the UPU ratio, PKD mutation, Mayo Class and copeptin. Cox survival analysis showed that a lower baseline UPU ratio (indicating less urine concentrating capacity) was significantly associated with a higher risk to develop the combined renal endpoint of incidence of start of kidney replacement therapy, eGFR <15 mL/min/1.73m2 or eGFR decrease >40% during follow-up (adjusted Hazard Ratio per SD = 1.39, p = 0.007). Limiting the aforementioned analyses to the subgroup of patients with relative early stage disease (n=122, age <40 yr and eGFR >60 mL/min/1.73m2) rendered essentially similar results, with an adjusted β for UPU ratio in the final model of 0.33 (p = 0.04). In this subgroup with a limited number of events (n=10), Cox survival analysis did not reach formal significance (adjusted HR per SD: 2.67, p = 0.055). Conclusion The UPU ratio, which is calculated from routine laboratory measurements, predicts renal prognosis in ADPKD in addition to other, more laborious to measure and expensive risk markers. Notably, this marker of urine concentrating capacity also shows promise in early-stage disease.

Urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL) Predicts Renal Function Decline in Patients With Glomerular Diseases.

ObjectiveAvailable biomarkers for monitoring primary glomerulonephritides (GNs), often lack the ability to assess longitudinal changes and have great variability with poor sensitivity. Accruing evidence has demonstrated that Neutrophil Gelatinase-Associated Lipocalin (NGAL), holds promising capacities in predicting renal function worsening in various renal diseases. We aimed at analyzing urinary NGAL (uNGAL) levels in a cohort of individuals with biopsy-proven GNs in order to evaluate its ability to reflect the entity of renal damage and to predict disease evolution overtime.MethodsWe enrolled 61 consecutive GNs patients still naïve to pathogenic therapy. uNGAL levels were measured at baseline and patients prospectively followed until the manifestation of a combined outcome of doubling of baseline serum creatinine and/or end-stage kidney disease requiring permanent dialysis support.ResultsMedian uNGAL levels were 107[35–312] ng/mL. At univariate and multivariate analyses an inverse correlation was found between eGFR and uNGAL levels (p = 0.001). Progressor subjects showed exceedingly increased baseline uNGAL values as compared with non-progressors (p < 0.001). Twenty-one patients (34%) reached the composite renal endpoint. Subjects with uNGAL values above the optimal, ROC-derived, cut-off of 107 ng/mL experienced a more rapid progression to the renal endpoint (p < 0.001; HR: 5.47; 95% CI 2.31–12.95) with a mean follow-up time to progression of 73.4 vs 83.5 months.ConclusionIn patients affected by primary glomerulonephritides, uNGAL may represent a real-time indicator of renal damage and an independent predictor of renal disease progression. Further studies on larger populations are warranted to confirm these findings.

Hypertension in the elderly: recent developments and insights.

This article will summarize the effects of more intensive blood pressure (BP) control on cardiovascular, cognitive, and renal outcomes among elderly (age ≥75 years) individuals at high risk for cardiovascular events. Subsets of patients who may not benefit and obstacles to implementation will be addressed. The authors' insights will conclude the review. A burst of new research regarding the effects of lower BP targets on cardiovascular, cognitive, and renal endpoints among the elderly has been published. Achieved values of 123 mmHg systolic in those without diabetes or prior stroke revealed striking declines in all-cause mortality, heart failure, and stroke. Although there was no benefit on the incidence of dementia, mild cognitive impairment was reduced. A trend towards modest declines in renal function and higher adverse event rates with normalization of BP were noted. Whether those with poor functional status or diastolic hypotension realize comparable gains remains unknown. Intensive BP control (systolic goal 120-130 mmHg systolic) results in lower rates of all-cause mortality and major adverse cardiac events. Elderly individuals with a good functional status and no history of diabetes or stroke are suitable candidates.

Schistosomiasis-associated glomerulopathy: Clinical aspects, pathological characteristics, and renal outcomes .

In Brazil, schistosomiasis is caused only by Schistosoma mansoni, occurring in the northeastern and southeastern regions. Schistosomiasis primarily affects the liver and gastrointestinal tract, although the kidneys can also be affected, mainly in the form of glomerulopathies. Here, we describe the characteristics of patients with schistosomiasis-associated glomerulopathies, including treatment and renal outcomes. This was a retrospective analysis of patients diagnosed with schistosomiasis-associated glomerulopathy between 2002 and 2017. Clinical, biochemical, and histopathological (kidney biopsy) data were evaluated. Of the 24 patients evaluated, 19 (79.1%) were male and 16 (66.4%) were White. The mean age was 38.58±9.83 years. We observed the hepatosplenic form of schistosomiasis in 15 patients (68.1%), nephrotic-nephritic syndrome in 13 (54.1%), hematuria in 20 (83.3%), and hypertension in 18 (75.0%). Renal histology showed a predominance of membranoproliferative pattern (n=17/70.8%). On immunofluorescence, 19 patients (82.6%) showed immunoglobulin M (IgM) expression, 10 (43.4%) showed IgM+IgG expression, and 1 (4.3%) showed a "full house" pattern. The median follow-up time was 59.70 months, by the end of which 9 patients (37.5%) had developed end-stage renal disease (ESRD). Baseline serum creatinine was higher among the patients who developed ESRD than among those who did not (1.99 ± 1.08 vs. 1.34 ± 0.46 mg/dL, p = 0.05). Our study is one of the rare clinical studies on schistosomiasis-associated glomerulopathy with a long follow-up and renal endpoints, showing that one third of our patients, independent of their histological form, progress to dialysis. .

Long-term blood pressure behavior and progression to end-stage renal disease in patients with immunoglobulin A nephropathy: a single-center observational study in Italy.

Antihypertensive treatment by the use of RAAS inhibitors (RAAS-is) is of paramount importance in the management of slowly progressive IgA nephropathy (IgAN). With the aim of better understanding the relationship between BP behavior and progression, we looked at time-averaged SBP and time-averaged proteinuria and renal outcome in a single-center cohort of IgAN patients. Among 248 consecutive patients referred to the Clinic of Nephrology of San Martino Hospital from 1996 to 2018 for native renal biopsy with a diagnosis of IgAN, we retrospectively analyzed 145 with available data at baseline and during follow-up. All patients received Supportive Care, 39% were on RAAS-is alone, 45% plus steroids, and 16% plus steroids and immunosuppressors. Renal replacing treatment (RRT) was the primary endpoint. During a mean follow-up of 67 ± 6 months, 23% of study patients (n = 33) progressed to RRT and 6% (n = 9) died. Patients who reached the renal endpoint, had lower baseline eGFR and higher proteinuria and proteinuria indexed at baseline. Moreover, they had higher TA-SBP (139 ± 17 vs. 130 ± 13, P = 0.0016). The incidence of RRT was higher in IgAN patients in the highest time-averaged SBP tertile as compared with the others (32 vs. 23 vs. 9%, χ 6.8, P = 0.033). After adjusting for baseline SBP, baseline and time-averaged proteinuria indexed, MEST-C score, and treatment, the association between TA-SBP and RRT persisted. Time-averaged low BP values were independently associated to a decreased risk of renal progression in IgAN with no evidence of a J-curve relationship even at SBP levels below 125 mmHg.

Lipoprotein(a)and renal function decline, cardiovascular disease and mortality in type 2 diabetes and microalbuminuria

AimsLipoprotein(a)(Lp(a)) has emerged as an independent risk marker for cardiovascular disease (CVD) in the general population and among persons with existing CVD. We investigated associations between serum Lp(a)concentrations and renal function decline, incident CVD and all-cause mortality in individuals with type 2 diabetes (T2D) and microalbuminuria. MethodsProspective study including 198 individuals with T2D, microalbuminuria and no CVD. Yearly p-creatinine was measured after baseline in 176 of the participants. The renal endpoint was defined as decline in eGFR of >30% from baseline. CVD events and mortality were tracked from national registries. Cox regression analyses were applied both unadjusted and adjusted for traditional risk factors (sex, age, systolic blood pressure, LDL-cholesterol, smoking, HbA1c, creatinine and urinary albumin creatinine ratio (UAER)). ResultsBaseline mean (SD) age was 59 (9)years, eGFR 89 (17) mL/min/1.73 m2, 77% were male, and median [IQR] UAER was 103 [38–242] mg/24-h. Median Lp(a)was 8.04 [3.42–32.3] mg/dL. Median follow-up was 6.1 years; 38 CVD events, 26 deaths and 43 renal events were recorded. For each doubling of baseline Lp(a), the following hazard ratios (95% confidence intervals) were found before and after adjustment respectively: 0.98 (0.84–1.15) and 1.01 (0.87–1.18) for decline in eGFR > 30%, 0.96 (0.81–1.13) and 0.99 (0.82–1.18) for CVD events, 1.04 (0.85–1.27) and 1.06 (0.87–1.30) for all-cause mortality. ConclusionsIn this cohort of individuals with T2D and microalbuminuria, the baseline concentration of Lp(a)was not a risk marker for renal function decline, CVD events or all-cause mortality.

What have we learned about renal protection from the cardiovascular outcome trials and observational analyses with SGLT2 inhibitors?

Over the past 5 years, sodium-glucose cotransport 2 (SGLT2) inhibitors have been increasingly regarded as glycaemic agents with cardiovascular (CV) and renal protective effects. The CV benefits of SGLT2 inhibitors have been well established in patients with type 2 diabetes (T2D) and a range of CV comorbidities at baseline. Subsequently, the renal benefits of SGLT2 inhibitors were established in the CREDENCE trial, a dedicated renal outcome trial where canagliflozin reduced the primary composite renal outcome by 30%. In light of these trials, clinical practice guidelines have rapidly evolved, recommending the use of SGLT2 inhibitors as renal and cardioprotective agents in appropriate patient populations. Accordingly, it is important to have an in-depth understanding of the evidence underlying the use of SGLT2 inhibitors in patients with T2D based on published clinical trials and real-world evidence (RWE) studies, as well as information related to potential safety concerns. To accomplish this, we reviewed the evidence for renal protection and safety with SGLT2 inhibitors in the EMPA-REG OUTCOME, CANVAS Program and DECLARE-TIMI 58 CV safety trials, and in the growing body of evidence emerging from real-world studies. This body of work has shown that SGLT2 inhibitors reduce the risk of surrogate renal endpoints such as albuminuria and mitigate the risk of hard renal endpoints including doubling of serum creatinine and end-stage kidney disease in patients with T2D.

Second revolution in cardiovascular prevention.

Type 2 diabetes has become a major disease burden in twenty-first century. Both incidence and prevalence of type 2 diabetes have quadrupled between 1980 and 2004 in the whole world. Atherosclerotic cardiovascular disease (ASCVD) is the major complication of type 2 diabetes. The introduction of statins in clinical settings is the first revolution in our battle against ASCVD. Most ASCVDs could be prevented or treated with statins. However, statin failed to reduce chronic kidney diseases (CKD) and heart failure (HF). Owing to a mandate from US Food and Drug Administration in 2008 that every new antidiabetic drug should be tested in clinical trials to demonstrate its safety, we now have a good opportunity to look for better antidiabetic drugs not only to decrease blood sugar but also to decrease CVD or renal disease. Among them, glucagon-like peptide-1 receptor agonists and sodium-glucose transport protein 2 inhibitors (SGLT-2 i) are two most extensively studied ones. SGLT-2 i, in particular, prevent CKD and end-stage renal disease, and prevent HF. In the recent CREDENCE trial, canagliflozin reduced renal endpoints by 34% and end-stage renal disease by 32%. Furthermore, in the recent DAPA-HF trial, dapagliflozin decreased hospitalization for HF/cardiovascular death by 26%, and total death by 17%, in patients with HF with reduced ejection fraction, irrespective of diabetes or nondiabetes. The beneficial effects of SGLT-2 i in CKD and HF are complementary to the effects of statins. The introduction of SGLT-2 i in clinical practice is the second revolution in cardiovascular prevention.

The Effect of Glucagon-Like Peptide-1 Receptor Agonists on Renal Outcomes in Type 2 Diabetes.

This review examines the available literature on the effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on renal outcomes in type 2 diabetes mellitus. Diabetes is an important cause of end-stage renal disease requiring renal replacement therapy, and diabetic kidney disease is an independent risk factor for cardiovascular disease (CVD). GLP-1RAs are proven to be safe in terms of CVD, and some of them have been shown to have a beneficial effect on cardiovascular outcomes. The effect of GLP-1RAs on hard renal endpoints has yet to be established; to date, there have been no published GLP-1RA clinical trials with primary renal endpoints. In this review, we discuss the evidence for a renal protective role of GLP-1RAs, highlighting the secondary renal outcomes from recent cardiovascular outcome trials of this class of glucose-lowering therapies.

The long-acting C5 inhibitor, Ravulizumab, is effective and safe in adult patients with atypical hemolytic uremic syndrome naïve to complement inhibitor treatment

Ravulizumab is a long-acting C5 inhibitor engineered from eculizumab with increased elimination half-life, allowing an extended dosing interval from two to eight weeks. Here we evaluate the efficacy and safety of ravulizumab in adults with atypical hemolytic uremic syndrome presenting with thrombotic microangiopathy. In this global, phase 3, single arm study in complement inhibitor-naïve adults (18 years and older) who fulfilled diagnostic criteria for atypical hemolytic uremic syndrome, enrolled patients received ravulizumab through a 26-week initial evaluation period. The primary endpoint was complete thrombotic microangiopathy response defined as normalization of platelet count and lactate dehydrogenase and 25% or more improvement in serum creatinine. Secondary endpoints included changes in hematologic variables and renal function. Safety was also evaluated. Ravulizumab treatment resulted in an immediate, complete, and sustained C5 inhibition in all patients. Complete thrombotic microangiopathy response was achieved in 53.6% of patients. Normalization of platelet count, lactate dehydrogenase and 25% or more improvement in serum creatinine was achieved in 83.9%, 76.8% and 58.9% of patients, respectively. Improvement in estimated glomerular filtration rate by one or more stage was achieved in 68.1% of patients by day 183. No unexpected adverse events were reported across a safety analysis set of 58 patients. Four deaths occurred (three within one month of study initiation, including one in a patient excluded based on eligibility criteria after the first dose) with none considered treatment-related by the study investigator. Thus, treatment with ravulizumab once every eight weeks resulted in rapidly improved hematologic and renal endpoints with no unexpected adverse events in adults with atypical hemolytic uremic syndrome.

Sodium‐glucose linked transporter‐2 inhibitor renal outcome modification in type 2 diabetes: Evidence from studies in patients with high or low renal risk

Data from three completed cardiovascular outcome trials (CVOTs), EMPA-REG OUTCOME, CANVAS Program and DECLARE-TIMI 58, add to the evidence supporting the potential renoprotective effects of sodium-glucose linked transporter-2 (SGLT2) inhibitors in patients with type 2 diabetes. Despite recommendations in recent guidelines, it is difficult to support a view that definitive evidence for renoprotection exists from these SGLT2 inhibitor CVOT results. To date, the only dedicated trial to report definitive data on the renal impact of SGLT2 inhibition is CREDENCE. Notably, the total number of patient-relevant renal endpoint events (dialysis, transplant or renal death) observed in CREDENCE was significantly higher than the total for all three CVOTs collectively (183 events/4401 patients vs. 69 events/34 322 patients, respectively), which shows the increased statistical power of CREDENCE for these renal endpoints. Treatment with canagliflozin was associated with a 30% relative risk reduction (RRR) in the primary composite endpoint of end-stage kidney disease, doubling of serum creatinine, or death from renal or cardiovascular causes and a 34% RRR for the renal-specific elements of this primary endpoint (P <0.001). Canagliflozin has therefore become the first US-approved SGLT2 inhibitor to include an indication for RRR, in addition to type 2 diabetes glycaemic control and cardiovascular risk reduction. While confirmatory of the exploratory data from CVOTs, CREDENCE provides the first robust data on the effects of canagliflozin on patient-relevant renal endpoints. Extrapolation to a conclusion of a SGLT2 inhibitor class effect cannot be made until additional renal trials with other SGLT2 inhibitors are reported.

Renal outcomes with the newer antidiabetes drugs: the era before and after CREDENCE.

In 2008, the US Food and Drug Administration provided guidance for the evaluation of the cardiovascular safety of antidiabetes drugs. The newer antidiabetes drugs, approved after 2008, were therefore evaluated in long-term cardiovascular outcome trials, designed and powered for the assessment of cardiovascular safety. Accordingly, the primary endpoint of these trials was a cardiac composite endpoint. Since 2008, the data from various cardiovascular outcome trials have been reported, including SAVOR-TIMI 53 (saxagliptin), EXAMINE (alogliptin), TECOS (sitagliptin), CARMELINA (linagliptin), CAROLINA (linagliptin), ELIXA (lixisenatide), LEADER (liraglutide), EXSCEL (exenatide once-weekly), SUSTAIN-6 (injectable semaglutide), HARMONY Outcomes (albiglutide), REWIND (dulaglutide), PIONEER-6 (oral semaglutide), EMPA-REG OUTCOME (empagliflozin), the CANVAS Program (canagliflozin) and DECLARE-TIMI 53 (dapagliflozin). Some of these trials subsequently also published data on renal outcomes, although these were secondary or exploratory analyses. Dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists had beneficial effects on albuminuria, while sodium-glucose co-transporter-2 inhibitors additionally showed a positive effect on 'hard' renal outcomes. In contrast to the cardiovascular outcome trials, the renal outcome trial of canagliflozin, CREDENCE, assessed a hard renal endpoint as its primary endpoint and showed positive effects on these hard renal outcomes. In this review, we aim to highlight the renal outcome data from the cardiovascular outcome trials and the CREDENCE trial and understand the differences between their results. The post CREDENCE era would appear to reinforce the position of sodium-glucose co-transporter-2 inhibitors as drugs providing cardiorenal protection, in addition to their anti-glycaemic effects.

Comparative Effectiveness of Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Classes of Glucose-Lowering Medications on Renal Outcome in Type 2 Diabetes

ObjectiveTo assess whether sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapy is associated with a favorable renal prognosis for patients with type 2 diabetes melllitus (T2DM) outside the clinical trials setting. Participants and MethodsThis retrospective study analyzed routinely collected health care records of ∼160 medical institutions in Japan from April 1, 2014, to December 31, 2017/2018 (varying at the institutional level). Adults with T2DM but without end-stage renal disease who initiated either SGLT2i or other classes of glucose-lowering medications (o-GLM) were matched using propensity score. The primary outcome was the time course of estimated glomerular filtration rate (eGFR) displayed in spline curve. The composite of renal worsening (>40% decline in eGFR) and the development of eGFR<30 mL/1.73 m2 per minute was evaluated as a secondary outcome. Two sensitivity analyses were conducted to determine the robustness of results. ResultsWe compared a matched cohort of 1433 SGLT2i users and 2739 o-GLM users (mean age: 61 years). The eGFR declined over time in both groups during the observation period (median: 17 months; maximum: 54 months), with a slower eGFR slope observed in SGLT2i users. This slower decline was consistently observed across different SGLT2i agents and different baseline eGFR groups. The cumulative incidence of composite renal endpoints was lower in the SGLT2i group with a hazard ratio of 0.70 (95% CI, 0.50-0.98; P=.039). Those findings were consistent in sensitivity analyses limited to the period adherent to the initial drug regimen and with a different approach for propensity score calculation. ConclusionIn a matched cohort of T2DM patients, SGLT2i use was associated with preserved renal function relative to o-GLM use over 2 to 4 years.

Association of blood glucose and renal end points in advanced diabetic kidney disease

AimsThe association of blood glucose in advanced diabetic kidney disease (DKD) is unclear. This study investigated the association between blood glucose and renal endpoints in DKD patients. MethodsThis retrospective cohort study enrolled type 2 diabetic patients with advanced DKD with an estimated glomerular filtration rate (eGFR) between 30 and 90 ml/min/1.73 m2 and urine albumin-to-creatinine ratio (UACR) of 300–5000 mg/g. We classified patients into 2 groups according to their 1-year average HbA1c: <7% and >7%. We followed up the patients until the occurrence of primary renal endpoints. ResultsA total of 345 patients were included in the analysis for the period 2012–2018. Mean baseline eGFR was 58 ml/min/1.73 m2 and mean albuminuria levels were 1146 and 1313 mg/g, respectively. Median study duration was 3 years. The risk of primary renal endpoints was not decreased in patients with HbA1c less than 7% with an adjusted hazard ratio (aHR) of 0.62, 95% CI 0.26–1.45. The risks of persistent eGFR lower than 15 ml/min/1.73 m2 and doubling of serum creatinine level were similar between 2 group with aHR of 0.58 (95% CI 0.19–1.83) and 0.61 (95% CI 0.26–1.44), respectively. ConclusionsIntensive blood sugar control did not prevent renal failure in advanced DKD.

Sodium-Glucose Cotransporter-2 Inhibitors in Nephrology Practice: A Narrative Review.

Purpose of the review:Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are recommended for eligible patients with type 2 diabetes for the secondary prevention of adverse cardiovascular and kidney disease outcomes. Patients with type 2 diabetes and albuminuric chronic kidney disease, a history of atherosclerotic cardiovascular disease, and/or heart failure with reduced ejection fraction should be assessed for the use of these therapies.Sources of information:The sources include published clinical trials with SGLT2is, with a focus on cardiovascular safety studies and kidney protection trials.Methods:Information was gathered via a review of relevant literature and clinical practice guidelines, incorporated with real-life clinical experience.Key findings:Clinicians prescribing these agents must be familiar with the benefits of SGLT2is on cardiovascular and renal endpoints, and with adverse effects of SGLT2is, including mycotic genital infections and diabetic ketoacidosis. Primary care physicians and specialists should know how to adjust antihypertensive, antiglycemic, and diuretic agents. With the results of completed cardiovascular outcome trials and the Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy trial, nephrologists specifically have a unique opportunity to impact the safe, effective, and equitable implementation of SGLT2is into clinical practice.Limitations:Further work is needed in specific patient subgroups, including patients with chronic kidney disease stages IV and V, patients with kidney disease but lower levels of albuminuria, and in patients without diabetes.

Extraglycemic Effects of SGLT2 Inhibitors: A Review of the Evidence.

Patients with type 2 diabetes (T2D) are often overweight/obese and affected by arterial hypertension, dyslipidaemia, and have high serum levels of uric acid. Moreover, T2D patient have a higher risk of developing cardiovascular or renal complications, which are leading causes of morbidity and mortality in this population. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a new class of glucose-lowering medications that block the reabsorption of glucose in the kidney, thereby increasing urinary glucose excretion, and lowering blood glucose levels. The beneficial effects of SGLT2 inhibition extend beyond glycaemic control, and include improvement in blood pressure, body weight, uric acid concentrations, liver steatosis, oxidative stress, and inflammation. In dedicated cardiovascular outcome trials, SGLT2i treatment was associated with a significant reduction in the rate of cardiovascular events and renal endpoints. In this review, we summarize the evidence for extra-glycemic effects of SGLT2i and the potential mechanisms driving cardiorenal protection exerted by this class of medications.

Renoprotective effects of sodium-glucose cotransporter-2 inhibitors and underlying mechanisms.

Emerging data have demonstrated that sodium-glucose cotransporter-2 (SGLT2) inhibitors prevent cardiovascular events, especially heart failure-associated endpoints. Cardiovascular outcome trials have also suggested their renoprotective effects. One large clinical trial investigated renal primary endpoints and demonstrated that SGLT2 inhibitors slowed the progression of diabetic kidney disease (DKD). This review summarizes clinical trial data on renal outcomes and discusses potential underlying mechanisms. The EMPA-REG, CANVAS, and DECLARE-TIMI 58 studies revealed that SGLT2 inhibitors reduce the risk of cardiovascular events and concomitantly suggested that these drugs slow the progression of kidney disease in type 2 diabetes. The CREDENCE trial on patients with high-risk type 2 diabetes and chronic kidney disease demonstrated that canagliflozin treatment reduced the relative risk of a composite outcome, including end-stage kidney disease, serum creatinine doubling, and renal/cardiovascular death, by 30% in these patients. Animal experiments revealed that oxidative stress, inflammation, fibrosis, and tubuloglomerular feedback are underlying renoprotective mechanisms behind SGLT2 inhibitors. Recent clinical trials have established the renoprotective effects of SGLT2 inhibitors. Further investigations on mechanisms of these renoprotective effects will provide deeper insights and understanding of pathogenetic properties of DKD.

Renal physiology of glucose handling and therapeutic implications.

The rationale for using sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes (T2D) has evolved over the last decade. Due to the effects on glucosuria and body weight loss, SGLT2 inhibitors were originally approved for glycemic control in T2D. Since glucosuria is attenuated in chronic kidney disease (CKD) Stages 3–5, initial regulatory approval for SGLT2 inhibitor use was limited to patients with T2D and preserved estimated glomerular filtration rate. Over time, however, it has become increasingly apparent that these therapies have a variety of important pharmacodynamic and clinical effects beyond glycemic lowering, including antihypertensive and antialbuminuric properties, and the ability to reduce glomerular hypertension. Importantly, these sodium-related effects are preserved across CKD stages, despite attenuated glycemic effects, which are lost at CKD Stage 4. With the completion of cardiovascular (CV) outcome safety trials—EMPA-REG OUTCOME, CANVAS Program and DECLARE TIMI-58—in addition to reductions in CV events, SGLT2 inhibition consistently reduces hard renal endpoints. Importantly, these CV and renal effects are independent of glycemic control. Subsequent data from the recent CREDENCE trial—the first dedicated renal protection trial with SGLT-2 inhibition—demonstrated renal and CV benefits in albuminuric T2D patients, pivotal results that have expanded the clinical importance of these therapies. Ongoing trials will ultimately determine whether SGLT2 inhibition will have a role in renal protection in other clinical settings, including nondiabetic CKD and type 1 diabetes.

Poor Renal and Cardiovascular Outcomes in Patients with Biopsy-Proven Diabetic Nephropathy

Background: Despite the high mortality of cardiovascular disease (CVD) in diabetic patients with renal injury, few studies have compared cardiovascular characteristics and outcomes between patients with diabetic nephropathy (DN) and non-diabetic renal disease (NDRD). Methods: A total of 326 type 2 diabetes mellitus patients with renal biopsy were assigned to DN and NDRD groups. Echocardiography and Doppler ultrasound were performed to evaluate left ventricular hypertrophy (LVH) and peripheral atherosclerosis disease (PAD). Renal and cardiovascular survival rates were compared between the DN and NDRD groups by Kaplan-Meier analysis. Risk factors for renal and cardiovascular events in DN patients were identified by a Cox proportional hazards model. Results: In total, 179 patients entered the DN group (54.9%) and 147 made up the NDRD group (45.1%). The presence of diabetic retinopathy, family history of diabetes, and dependence on insulin therapy were associated with the presence of DN. DN patients had more CVD with more severe LVH and PAD. Poorer renal (log-rank χ² = 26.534, p < 0.001) and cardiovascular (log-rank χ² = 16.257, p < 0.001) prognoses were seen in the DN group. DR (HR 1.539, 95% CI 1.332–1.842), eGFR (HR 0.943, 95% CI 0.919–0.961), and 24-h proteinuria (HR 1.211, 95% CI 1.132–1.387) were identified as risk factors for renal endpoints. Age (HR 1.672, 95% CI 1.487–1.821), HbA1C (HR 1.398, 95% CI 1.197–1.876), and 24-h proteinuria (HR 1.453, 95% CI 1.289–1.672) were associated with cardiovascular endpoints. Conclusion: Patients with DN had more severe CVD along with poorer renal and cardiovascular prognoses than those with NDRD.