Renal Endpoints Research Articles

Impact of Empagliflozin in Heart Failure With Reduced Ejection Fraction in Patients With Ischemic Versus Nonischemic Cause.

Background Outcomes and treatment effects of therapy may vary according to the cause of heart failure (HF). Methods and Results In this post hoc analysis of the EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction) trial, the effect of empagliflozin on cardiovascular and renal outcomes was assessed according to the cause of HF. The cause of HF was investigator reported and stratified as ischemic or nonischemic. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% CIs. Of the 3730 patients enrolled, 1929 (51.7%) had ischemic cause. In the placebo arm, patients with ischemic cause of HF did not have a significantly higher risk of cardiovascular mortality (HR, 1.21 [95% CI, 0.90-1.63]) and hospitalization for HF (HR, 0.90 [95% CI, 0.72-1.12]) compared with nonischemic cause. Empagliflozin compared with placebo significantly reduced the risk of cardiovascular death or hospitalization for HF in patients with ischemic and nonischemic cause (HR, 0.82 [95% CI, 0.68-0.99] for ischemic and HR, 0.67 [95% CI, 0.55-0.82] for nonischemic cause; P interaction=0.15). The benefit of empagliflozin on HF hospitalization, the renal composite end point, estimated glomerular filtration slope changes, and health status scores were also consistent in both groups without treatment by cause modification. Conclusions Empagliflozin offers cardiovascular and renal benefits in patients with heart failure with reduced ejection fraction regardless of the cause of HF. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Association of single and joint metals with albuminuria and estimated glomerular filtration longitudinal change in middle-aged adults from Spain: The Aragon workers health study

The nephrotoxicity of low-chronic metal exposures is unclear, especially considering several metals simultaneously. We assessed the individual and joint association of metals with longitudinal change in renal endpoints in Aragon Workers Health Study participants with available measures of essential (cobalt [Co], copper [Cu], molybdenum [Mo] and zinc [Zn]) and non-essential (As, barium [Ba], Cd, chromium [Cr], antimony [Sb], titanium [Ti], uranium [U], vanadium [V] and tungsten [W]) urine metals and albumin-to-creatinine ratio (ACR) (N = 707) and estimated glomerular filtration rate (eGFR) (N = 1493) change. Median levels were 0.24, 7.0, 18.6, 295, 3.1, 1.9, 0.28, 1.16, 9.7, 0.66, 0.22 μg/g for Co, Cu, Mo, Zn, As, Ba, Cd, Cr, Sb, Ti, V and W, respectively, and 52.5 and 27.2 ng/g for Sb and U, respectively. In single metal analysis, higher As, Cr and W concentrations were associated with increasing ACR annual change. Higher Zn, As and Cr concentrations were associated with decreasing eGFR annual change. The shape of the longitudinal dose-responses, however, was compatible with a nephrotoxic role for all metals, both in ACR and eGFR models. In joint metal analysis, both higher mixtures of Cu–Zn–As–Ba–Ti–U–V–W and Co–Cd–Cr–Sb–V–W showed associations with increasing ACR and decreasing eGFR annual change. As and Cr were main drivers of the ACR change joint metal association. For the eGFR change joint metal association, while Zn and Cr were main drivers, other metals also contributed substantially. We identified potential interactions for As, Zn and W by other metals with ACR change, but not with eGFR change. Our findings support that Zn, As, Cr and W and suggestively other metals, are nephrotoxic at relatively low exposure levels. Metal exposure reduction and mitigation interventions may improve prevention and decrease the burden of renal disease in the population.

Time-Averaged Hematuria as a Prognostic Indicator of Renal Outcome in Patients with IgA Nephropathy.

We aim to investigate the association of time-averaged hematuria (TA-hematuria) with the progression of IgA nephropathy (IgAN). Based on TA-hematuria during follow-up, 152 patients with IgAN were divided into a hematuria remission group (≤28 red blood cells [RBCs]/μL) and a persistent hematuria group (>28 RBCs/μL). The persistent hematuria group had a higher percentage of patients with macroscopic hematuria, lower levels of hemoglobin and TA-serum albumin, and more severe renal pathologic lesions. The composite endpoint is defined as a doubling of the baseline SCr level (D-SCr), or the presence of ESRD. During the mean follow-up of 58.08 ± 23.51 months, 15 patients (9.9%) reached the primary outcome of ESRD and 19 patients (12.5%) reached the combined renal endpoint. Kaplan-Meier analysis showed that the persistent hematuria group had a lower renal survival rate. The persistent hematuria patients who were incorporated with proteinuria (≥1.0 g/day) and low TA-serum albumin (<40 g/L) had the worst renal outcomes. Multivariate Cox regression indicated that TA-hematuria (hazard ratio [HR] = 0.004, 95% CI: 0.001, 0.008; p = 0.010) was independently associated with the progression of IgAN. Receiver operating characteristic analysis indicated the optimal TA-hematuria cutoff value for predicting the progression of IgAN was 201.21 RBCs/μL in females and 37.25 RBCs/μL in males.

Effect of angiotensin receptor neprilysin inhibitor in patients of heart failure with reduced ejection fraction with reduced ejection fraction with cardiorenal syndrome type-1

Background: Heart failure is recognized as one of the most common indications for hospitalization. The dysfunction of either the heart or the kidneys affect the functioning of each other and thus play an important role in the quality of life.Methods: This study is a Prospective interventional Cohort study over a period of 18 months in 125 patients. The patients were divided into two broad treatment groups. The primary end point of the study was to quantify the response of ARNI for renal recovery in patients of cardio-renal syndrome and improvement in cardiovascular parameters by measuring the change in urine output, estimated glomerular filtration rate, serum creatinine, change in weight of the patients, control of blood pressure and change in left ventricular ejection fraction. The secondary end-points were evaluated during the 60 days follow up period post admissions.Results: Cardio-renal syndrome was seen in 39% of the patients. On screening e-GFR was 91±14 and 49±8 for group 1and 2 respectively, the median age, UACR was 59 years ,1.0 mg/mmol respectively for both the groups and 19% had micro albuminuria. ACEIs had more reports of hyperkalemia (8/32, 25%), and greater deterioration of renal parameters (10/32, 34%) needing discontinuation of the drug in some patients. Patients also developed cough (6/32, 20%) needing replacement with ARBs. ARNI group developed more hypotension (6/31, 20%). In all cardiovascular and renal end points except UACR, ARNI showed better recovery profile in CRS-1patients including diabetics.Conclusions: This study showed beneficial effects of ARNI in heart failure patients with cardio-renal syndrome.

Cardiovascular Effects of Canagliflozin in Relation to Renal Function and Albuminuria

BackgroundPeople with type 2 diabetes mellitus (T2DM) have elevated cardiovascular (CV) risk, including for hospitalization for heart failure (HHF). Canagliflozin reduced CV and kidney events in patients with T2DM and high CV risk or nephropathy in the CANVAS (CANagliflozin cardioVascular Assessment Study) Program and the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial. ObjectivesThe aim of this study was to assess the effects of canagliflozin on CV outcomes according to baseline estimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio (UACR) in pooled patient-level data from the CANVAS Program and CREDENCE trial. MethodsCanagliflozin effects on CV death or HHF were assessed by baseline eGFR (<45, 45-60, and >60 mL/min/1.73 m2) and UACR (<30, 30-300, and >300 mg/g). HRs and 95% CIs were estimated by using Cox regression models overall and according to subgroups. ResultsA total of 14,543 participants from the CANVAS Program (N = 10,142) and the CREDENCE (N = 4,401) trial were included, with a mean age of 63 years, 35% female, 75% White, 13.2% with baseline eGFR <45 mL/min/1.73 m2, and 31.9% with UACR >300 mg/g. Rates of CV death or HHF increased as eGFR declined and/or UACR increased. Canagliflozin significantly reduced CV death or HHF compared with placebo (19.4 vs 28.0 events per 1,000 patient-years; HR: 0.70; 95% CI: 0.62-0.79), with consistent results across eGFR and UACR categories (all P interaction >0.40). ConclusionsRisk of CV death or HHF was higher in those with lower baseline eGFR and/or higher UACR. Canagliflozin consistently reduced CV death or HHF in participants with T2DM and high CV risk or nephropathy regardless of baseline renal function or level of albuminuria. (Canagliflozin Cardiovascular Assessment Study [CANVAS], NCT01032629; A Study of the Effects of Canagliflozin [JNJ-24831754] on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus [CANVAS-R], NCT01989754; and Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy [CREDENCE], NCT02065791)

Effects of empagliflozin on cardiovascular and renal outcomes in heart failure with reduced ejection fraction according to age: a secondary analysis of EMPEROR-Reduced.

Empagliflozin improves cardiovascular and renal outcomes in patients with heart failure (HF) and reduced ejection fraction (HFrEF), but its efficacy and safety across patient's age is not well established. We assessed the effects of empagliflozin (10mg daily) versus placebo, on top of standard HF therapy, in symptomatic HFrEF patients with a left ventricular ejection fraction ≤40% and increased natriuretic peptides stratified by age (<65, 65-74, ≥75 years). The primary endpoint was a composite of cardiovascular death or HF hospitalization. Key secondary endpoints included first and recurrent HF hospitalizations and slope of change in estimated glomerular filtration rate (eGFR); the latter was supported by an analysis of a renal composite endpoint (chronic dialysis or renal transplantation or profound and sustained reduction in eGFR). Of 3730 patients, 38% were <65 years, 35% were 65-74 years and 27% were ≥75 years. Compared with placebo, empagliflozin reduced the primary endpoint consistently across the three age groups (hazard ratio 0.71 [95% confidence interval 0.57-0.89] for <65 years, 0.72 [0.57-0.93] for 65-74 years, 0.86 [0.67-1.10] for ≥75 years, interaction p-trend test=0.24). The effects of empagliflozin were also consistent across age groups for key secondary endpoints of first and recurrent HF hospitalization (p-trend=0.30), the rate of decline in eGFR (p-trend=0.78) and the renal composite (p-trend=0.94). Adverse events (AEs), serious AEs and AEs leading to drug discontinuation increased with age in both treatment arms, but empagliflozin did not increase their incidence over placebo within each age group. The efficacy and safety of empagliflozin in improving cardiovascular and renal outcomes in HFrEF was consistent across the spectrum of age, including older patients (aged ≥75).

Value of SGLT-2 inhibitors in the treatment of chronic kidney disease : Clinical and practical implications.

Chronic kidney disease (CKD) drastically increases the risk for cardiovascular morbidity and mortality and its worldwide prevalence is still rising. Effective treatment slows CKD progression, prevents development of end-stage kidney disease and cardiovascular disease thereby prolonging survival of patients. Recently, several large-scale studies with sodium-glucose cotransport‑2 inhibitors (SGLT-2i) have demonstrated profound nephroprotective and cardioprotective properties in patients with type2diabetes mellitus with both CKD and heart failure. Recently, the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial demonstrated that the selective SGLT-2i dapagliflozin reduced the hazard ratio for acomposite renal and cardiovascular death endpoint in patients with CKD with or without type2diabetes. Furthermore, dapagliflozin exerted strong nephroprotection in CKD patients with diverse etiologies like IgA nephropathy. Furthermore, other promising CKD trials such as with empagliflozin are underway. Hence, individualized treatment with SGLT2i represents apromising therapeutic option for patients with both diabetic and non-diabetic CKD. Here we summarize the current knowledge on the treatment with SGLT-2i in CKD patients underscoring astrong rationale for SGLT2 inhibition to be incorporated into standard of care for most CKD patients also with non-diabetic kidney disease. Finally, we aim to translate the current evidence into recommendations for the clinical practice in the management of patients with CKD.

Prognostic value of the albumin-to-fibrinogen ratio (AFR) in IgA nephropathy patients

BackgroundThe albumin-to-fibrinogen ratio (AFR), a novel inflammatory marker, has been studied in various diseases. However, whether AFR could act as a prognostic factor for IgAN patients remains unclear. We aimed to investigate the prognostic value of AFR in IgAN. MethodsA total of 1289 biopsy-confirmed primary IgAN patients from 2008 to 2018 in West China Hospital, Sichuan University, were studied retrospectively. Receiver operating characteristic curve analysis was generated to assess and compare the ability of indicators to predict survival. Based on the cut-off value of AFR, IgAN patients were classified into the low AFR group and the high AFR group. The demographic and clinical-histopathological data were collected. Renal endpoints included eGFR decreased ≥50 % of the baseline level, ESRD, renal transplantation and/or death. Patients were followed up until a composite endpoint. Kaplan–Meier survival curves and Cox proportional hazards models were used to determine independent predictors. ResultsThe area under the curve (AUC) of AFR was 0.677, with an optimal cut-off value of 12.44. IgAN patients were classified into two groups (low AFR group: AFR < 12.44, n = 541; high AFR group: AFR ≥ 12.44, n = 748) with a median follow-up of 55.3 (36.4–78.6) months. A higher composition of hypertension, worse renal function, higher proteinuria, and more severe pathological lesions were significantly shown in the low AFR group. Further multivariable Cox regression analyses showed that a low AFR was an independent risk factor for renal survival (HR 1.90, 95 % CI 1.29–2.81, p = 0.001). Kaplan–Meier curves showed that the cumulative incidences of both ESRD and composite end point were significantly higher in patients with AFR < 12.44 (both p < 0.001). ConclusionsOur study demonstrated that a low AFR (<12.44) is an independent prognostic factor of poor renal prognosis in Chinese IgAN patients.

Incidence of heart failure and renal endpoints in heart failure patients with and without severe chronic kidney disease: a nationwide real-life study of 21,959 patients

Abstract Background Renal endpoints like end stage renal disease (ESRD) and a 50% decline in estimated glomerular filtration rate (eGFR) have been used in recent randomized clinical trials in heart failure (HF). However, the distribution of these events in larger real-life HF cohorts is unknown Purpose We examined the risk of traditional HF endpoints like death and worsening HF and the risk of these new renal endpoints in HF with and without severe chronic kidney disease (+/−eGFR 30 ml/min/1.73 m2) at the time of diagnosis of HF. Methods From nationwide registries, we identified patients receiving a diagnosis of HF from 2014–2018. Patients were included if they had creatinine available in proximity of the diagnosis (90 days before inclusion). Outcomes comprised of: (i) all-cause mortality, (ii) HF worsening, (iii) end stage renal disease and (iv) sustained 50% eGFR decline. 4-year rates of the primary outcomes were estimated using cumulative incidence function adjusted for competing risk of death, and multivariable Cox proportional hazards models were used to examine the association of covariates with a combined endpoint of the primary outcomes. Results We included 21,959 patients with HF and known CKD status. Median age was 73.9 years, and 7% had an eGFR &amp;lt;30 mL/min/1.73 m2. There were few differences in baseline characteristics for patients with and without eGFR below 30. Patients with eGFR below 30 were elder and had more comorbidities. The mortality rate was 33.9% for patients with eGFR≥30 and 70.4% for patients with eGFR &amp;lt;30. For patients with eGFR &amp;lt;30 at the time of HF diagnosis renal outcomes were more pronounced as the first event as compared to patients with eGFR ≥30. The risk of all-cause mortality and HF hospitalization as first event was comparable between eGFR ≥30 and eGFR&amp;lt;30 (22.7% vs 22.5% and 25.8% vs 22.5%, respectively). The risk of end-stage renal disease as first event was significantly higher for patients with eGFR &amp;lt;30 (0.03% vs. 33.8%). The risk of a sustained 50% decline in eGFR was 4.6% for patients with eGFR ≥30 and 1.0% for patients with eGFR&amp;lt;30 (figure 1). Across all important subgroups an eGFR &amp;lt;30 ml/min/1.73 m2 was associated with an increased rate of the composite endpoint of death, worsening HF or a renal endpoint, and no interactions were observed (P&amp;gt;0.01 for all) (figure 2). Conclusion The risks of newly introduced renal trial-endpoints in a large real-life cohort of HF patients was low compared to the risks of death or worsening HF if eGFR ≥30 ml/min/1.73 m2 at the time of diagnosis of HF. However, this pattern changed in HF patients with a eGFR &amp;lt;30 ml/min/1.73 m2 at the time of diagnosis time of HF. The present study provides important insights into cardiorenal epidemiology in HF and have implications for planning of future trials. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Herlev/Gentofte Hospital

Comparison between outcomes of IgA nephropathy with nephrotic-range proteinuria and nephrotic syndrome: do podocytes play a role?

Background Nephrotic syndrome (NS) and nephrotic-range proteinuria (NRP) are uncommon in IgA nephropathy (IgAN), and their clinicopathology and prognosis have not been discussed. Podocytes may play an important role in both clinical phenotypes. Methods We investigated 119 biopsy-proven IgAN patients with proteinuria over 2 g/d. The patients were divided into three groups according to proteinuria level: the overt proteinuria (OP) group, NS group, and NRP group. In addition, according to the severity of foot process effacement (FPE), the patients were divided into three groups: the segmental FPE (SFPE) group, moderate FPE (MFPE) group, and diffuse FPE (DFPE) group. The outcome was survival from a combined event defined by a doubling of the baseline serum creatinine and a 50% reduction in eGFR or ESRD. Results Compared with the NRP group, patients in the NS group had more severe microscopic hematuria, presented with more severe endocapillary hypercellularity and had a higher percentage of DFPE. The Kaplan–Meier curve showed that MFPE patients had a better outcome in the NRP group <50% of tubular atrophy/interstitial fibrosis. In the multivariate model, the NRP group (HR = 17.098, 95% CI = 3.835–76.224) was associated with an increased risk of the combined event, while MFPE (HR = 0.260, 95% CI = 0.078–0.864; p = 0.028) was associated with a reduced risk of the combined event. After the addition of renin-angiotensin system inhibitors (RASi), the incidence of the combined event in the MFPE group (HR = 0.179, 95% CI = 0.047–0.689; p = 0.012) was further reduced. Conclusions NS presented more active lesions and more severe FPE in IgAN. NRP was an independent risk factor for progression to the renal endpoint, while MFPE indicated a better prognosis in NRP without obvious chronic renal lesions, which may benefit from RASi.

Association between hemoglobin and chronic kidney disease progression: a secondary analysis of a prospective cohort study in Japanese patients

ObjectiveAnemia has been reported as a risk factor for chronic kidney disease (CKD) progression. However, there are still few studies examining the relationship between specific hemoglobin (Hb) levels and renal prognosis and renal function decline simultaneously. Meanwhile, the possible non-linear relationship between Hb and CKD progression also deserves further exploration. On that account, our primary goal is to explore the link of Hb on renal prognosis and renal function decline in patients with CKD.MethodsThis study was a secondary analysis of a prospective cohort study, which consecutively and non-selectively collected 962 participants from the research of CKD-ROUTE in Japan from November 2010 to December 2011. We used the Cox proportional-hazards and linear regression models to evaluate the independent association between baseline Hb and renal prognosis (renal composite endpoint, initiation of dialysis during follow-up or 50% decline in eGFR from baseline) and renal function decline(annual eGFR decline), respectively. A multivariate Cox proportional hazards regression analysis with cubic spline functions model and smooth curve fitting (penalized spline method) were conducted to address Hb and CKD prognosis's non-linearity. At the same time, a generalized additive model (GAM) and smooth curve fitting (penalized spline method) was conducted to explore the exact shape of the curve between Hb and renal function decline. Additionally, we did a series of sensitivity analyses to ensure the robustness of the results. Moreover, we conducted subgroup analyses.ResultsThe mean age of the included patients was 67.35 ± 13.56 years old, and 69.65% were male. The mean baseline Hb and estimated glomerular filtration rate (eGFR) was 12.06 ± 2.21 g/dL and 33.04 ± 18.01 ml/min per 1.73 m2. The annual decline in eGFR was 2.09 mL/min/1.73 m2/year. During a median follow-up time of 33.5 months, 252(26.2%) people experienced renal composite endpoint. After adjusting covariates, the results showed that Hb was negatively associated with renal composite endpoint (HR = 0.836, 95%CI: 0.770, 0.907) and renal function decline (β = -0.436, 95%CI: -0.778, -0.093). There was also a non-linear relationship between Hb and renal composite endpoint, and the inflection point of Hb was 8.6 g/dL. The effect sizes(HR) on the left and right sides of the inflection point were 1.257 (0.841, 1.878) and 0.789 (0.715, 0.870), respectively. And the sensitive analysis demonstrated the robustness of the results. Subgroup analysis showed that Hb was more strongly associated with the renal composite endpoint in non-hypertensive, SBP < 140 mmHg, urine protein-to-creatinine ratio (UPCR) < 0.5 g/gCr, and diuretic use patients. In contrast, the weaker association was probed in hypertensive and non-diuretic use patients and the patients with SBP ≥ 140 mmHg, and UPCR ≥ 0.5 g/gCr.ConclusionThis study demonstrates a negative and non-linear relationship between Hb and renal prognosis and renal function decline in Japanese CKD patients. Hb is strongly related to renal prognosis when Hb is above 8.6 g/dL.

Modelling kidney outcomes based on MELD eras - impact of MELD score in renal endpoints after liver transplantation

BackgroundAcute kidney injury is a common complication in solid organ transplants, notably liver transplantation. The MELD is a score validated to predict mortality of cirrhotic patients, which is also used for organ allocation, however the influence of this allocation criteria on AKI incidence and mortality after liver transplantation is still uncertain.MethodsThis is a retrospective single center study of a cohort of patients submitted to liver transplant in a tertiary Brazilian hospital: Jan/2002 to Dec/2013, divided in two groups, before and after MELD implementation (pre-MELD and post MELD). We evaluate the differences in AKI based on KDIGO stages and mortality rates between the two groups.ResultsEight hundred seventy-four patients were included, 408 in pre-MELD and 466 in the post MELD era. The proportion of patients that developed AKI was lower in the post MELD era (p 0.04), although renal replacement therapy requirement was more frequent in this group (p < 0.01). Overall mortality rate at 28, 90 and 365 days was respectively 7%, 11% and 15%. The 1-year mortality rate was lower in the post MELD era (20% vs. 11%, p < 0.01). AKI incidence was 50% lower in the post MELD era even when adjusted for clinically relevant covariates (p < 0.01).ConclusionLiver transplants performed in the post MELD era had a lower incidence of AKI, although there were more cases requiring dialysis. 1-year mortality was lower in the post MELD era, suggesting that patient care was improved during this period.

Left ventricular myocardial mass index associated with cardiovascular and renal prognosis in IgA nephropathy

IntroductionIn chronic kidney disease (CKD), like in IgA nephropathy (IgAN), cardiovascular (CV) mortality and morbidity are many times higher than in the general population, and left ventricular hypertrophy (LVH) is an independent risk factor for CV disease. This follow-up study investigated the association between left ventricular mass index (LVMI) and renal or cardiovascular outcomes.MethodsWe examined 118 IgAN patients prospectively. LVMI and LV geometry was investigated using echocardiography. The primary combined endpoints were total mortality, major CV events, and end-stage renal disease. Secondary endpoints, i.e.—cardiovascular or renal endpoints,—were also examined separately.ResultsSixty seven percent were males, mean age 53.5 ± 13.5. Mean follow-up time: 184 months. LVMI inversely correlated with eGFR (corr. coefficient: -0.365; p < 0.01). We divided the patients into two groups based on the LVMI cut-off suggested by the literature. The presence of LVH caused a worse prognosis in primary (p < 0.001), renal endpoints (p = 0.01), and also in CV endpoints (p = 0.001). The higher LVMI in men significantly worsened the prognosis in all endpoints. Concentric hypertrophy meant a worse prognosis. Independent predictors of LVMI were gender and eGFR in uni- and multivariate regression and hemoglobin levels only in logistic regression. Independent predictors of the primary endpoint were LVMI, eGFR, gender, obesity, HT, DM, and metabolic syndrome in Cox regression analysis.ConclusionIncreased LVMI may predict the progression to end-stage renal disease and CV events in IgAN. Determining LVMI may be a useful parameter not only in CV risk but also in the stratification of renal risk in CKD.

New Strategies for Volume Control in Patients with Diabetes Mellitus, a Narrative Review.

Sodium is reabsorbed all along the renal tubules. The positive impacts of sodium-glucose cotransporter-2 inhibitors (SGLT2i), angiotensin receptor neprilysin inhibitor (ARNI) and mineralocorticoid receptor antagonists (MRA) on hard renal and/or cardiac endpoints calls for the role of diuretics in nephroprotection and cardioprotection in patients with diabetes mellitus to be reviewed. Here, we review: (a) the mechanisms of action of the available natriuretics; (b) the physiological adaptations to chronic loop diuretic usage that lead to increased sodium reabsorption in the proximal and distal convoluted tubules; (c) the physiology of sodium retention in patients with diabetes mellitus; and (d) the mechanisms of aldosterone breakthrough. We show the rationale for combined diuretics to target not only the loop of Henle, but also the proximal and distal convoluted tubules. Indeed, higher residual proteinuria in patients treated with renin-angiotensin-aldosterone system (RAAS) blockers portends poorer renal and cardiovascular outcomes. Diuretics are known to optimize the reduction of proteinuria, in addition to RAAS blockers, but may favor aldosterone breakthrough in the absence of MRA. The aim of our study is to support a combined diuretics strategy to improve the management of patients with diabetes mellitus and chronic kidney disease or heart failure.

CKD-MBD biomarkers and CKD progression: an analysis by the joint model.

Biomarkers of chronic kidney disease-mineral and bone disorder (CKD-MBD) have been implicated in CKD progression in follow-up studies focusing on single measurements of individual biomarkers made at baseline only. The simultaneous relationship between the time trend of these biomarkers over the course of CKD and renal outcomes has never been tested. We applied the joint model (JM) to investigate the longitudinal relationship between repeated measurements of CKD-MBD biomarkers and a combined renal endpoint (estimated glomerular filtration rate reduction>30%, dialysis or transplantation) in 729 stage 2-5 CKD patients over a 36-month follow-up. In the survival submodel of the JM, the longitudinal series of parathyroid hormone (PTH) values was directly and independently related to the risk of renal events [hazard ratio (HR) (1 ln increase in parathyroid hormone (PTH) 2.0 (range 1.5-2.8), P<.001)] and this was also true for repeated measurements of serum phosphate [HR (1mg/dl) 1.3924 (range 1.1459-1.6918), P=.001], serum calcium [HR (1mg/dl) 0.7487 (range 0.5843-0.9593), P=.022], baseline fibroblast growth factor 23 [HR (1 pg/ml) 1.001 (range 1.00-1.002), P=.045] and 1,25-dihydroxyvitamin D [HR (1 pg/ml) 0.9796 (range 0.9652-0.9942), P=.006]. Repeated measurements of serum PTH, calcium and phosphate as well as baseline FGF23 and 1,25-dihydroxyvitamin D are independently related with the progression to kidney failure in a cohort of stage 2-5 CKD patients. This longitudinal study generates the hypothesis that interventions at multiple levels on MBD biomarkers can mitigate renal function loss in this population.

Sodium-glucose Cotransporter Type 2 Inhibitors: A New Insight into the Molecular Mechanisms of Diabetic Nephropathy.

Diabetic nephropathy is one of the chronic microvascular complications of diabetes and is a leading cause of end-stage renal disease. Fortunately, clinical trials have demonstrated that sodium-glucose cotransporter type 2 inhibitors could decrease proteinuria and improve renal endpoints and are promising agents for the treatment of diabetic nephropathy. The renoprotective effects of sodium-glucose cotransporter type 2 inhibitors cannot be simply attributed to their advantages in aspects of metabolic benefits, such as glycemic control, lowering blood pressure, and control of serum uric acid, or improving hemodynamics associated with decreased glomerular filtration pressure. Some preclinical evidence suggests that sodium-glucose cotransporter type 2 inhibitors exert their renoprotective effects by multiple mechanisms, including attenuation of oxidative and endoplasmic reticulum stresses, anti-fibrosis and anti-inflammation, protection of podocytes, suppression of megalin function, improvement of renal hypoxia, restored mitochondrial dysfunction and autophagy, as well as inhibition of sodium-hydrogen exchanger 3. In the present study, the detailed molecular mechanisms of sodium-glucose cotransporter type 2 inhibitors with the actions of diabetic nephropathy were reviewed, with the purpose of providing the basis for drug selection for the treatment of diabetic nephropathy.

The Significance of Crescents on the Clinical Features and Outcomes of Primary Immunoglobin A Nephropathy

BackgroundIt is still controversial whether the proportion of crescents below 50% can be an independent predictive risk factor for poor prognosis in IgAN patients. We reported the significance of different proportions of crescents on the clinical features and the cut-off value of crescents in predicting the occurrence of end-stage kidney disease (ESKD) in patients with IgAN.MethodsWe retrospectively analyzed biopsy-proven primary IgAN patients in Sichuan Provincial People’s Hospital from 2007 to 2019. The patients were divided into 5 groups on the basis of crescent proportion as follows: 0 (n = 647), < 10% (n = 221), 10 to 24% (n = 272), 25 to 49% (n = 80), and ≥50% (n = 22). The primary endpoint was defined as ESKD, and the secondary endpoint was the combined renal endpoint (≥50% reduction in eGFR or ESKD). A validation cohort of 346 patients were enrolled from Affiliated Hospital of Southwest Medical University. Cox regression model and Kaplan-Meier survival analysis were performed.ResultsA total of 1242 eligible patients with biopsy-proven IgAN were recorded in the database, compared with the non-crescent group, patients in the crescent group had lower levels of hemoglobin (Hb) and albumin (Alb), higher levels of blood urea nitrogen (BUN), 24h urinary protein and hematuria, a higher proportion of mesangial hypercellularity (M1), endocapillary hypercellularity (E1), segmental glomerulosclerosis (S1), and tubular atrophy/interstitial fibrosis (T1/T2) (p < 0.05). A higher crescent proportion was associated with lower levels of Hb, ALB, eGFR and serum IgG (p < 0.05), higher levels of SCr, BUN, increasing amounts of 24 h urinary protein, increasing proportion of M1 and E1, and increasing severity of interstitial inflammatory infiltration. During the median follow-up of 43 months (range 6-151), 63 individuals (7.0%) reached the primary outcome of ESKD and 99 patients (11.1%) reached the combined renal endpoint. 34(7.5%), 21 (13.3%), 24(12.2%), 14(21.5%) and 6(31.6%) patients reached the combined renal endpoint in the above five groups in crescents 0, <10%, 10∼24%, 25∼49% and ≥50%, respectively. A total of 274(62.6%) cases in the crescent group and 254 (55.7%) cases in the non-crescent group received immunosuppressive therapy. Multivariate Cox regression showed that crescents ≥50% was an independent risk factor for the progression of ESKD (p = 0.003) and crescents ≥25% was an independent risk factor for the combined renal endpoint(p < 0.001). The receiver operating characteristic curve showed that IgAN patients with crescents ≥43.7% had a higher risk of ESKD, even with immunosuppressants (Sensitivity = 75.7%,specificity = 89.6%,p < 0.001). This discovery cohort and the validation cohort further confirmed that patients with crescents <43.7% had better renal prognosis than those with crescents ≥43.7% in the whole group and those with immunosuppressants (p < 0.001).ConclusionIgAN patients with crescents had more severe clinicopathological features and poorer prognosis. Crescents ≥50% was an independent risk factor for the progression of ESKD and crescents ≥25% was an independent risk factor for ≥50% reduction in eGFR or ESKD in treated and untreated IgAN patients. Crescents ≥43.7% was an independent risk factor for ESKD in those with immunosuppressants.

A Narrative Review of Diabetic Kidney Disease: Previous and Current Evidence-Based Therapeutic Approaches.

Diabetic kidney disease (DKD) is one of the most important diabetic complications. DKD is also the most common cause of chronic kidney disease (CKD) and end-stage renal disease. This review focused on potential therapeutic drugs for which there is established evidence of treatment for DKD. The earliest evidence for DKD treatment was established with renin-angiotensin system (RAS) inhibitors; however, their efficacy was partial. Recently, the sodium-glucose co-transporter2 (SGLT2) inhibitors, including empagliflozin (EMPA-REG Outcome), canagliflozin (CREDENCE trial), and dapagliflozin (DAPA-CKD), demonstrated a significant and clinically relevant reduction in the risks of albuminuria and progression of nephropathy, doubling of serum creatinine levels, and initiation of renal replacement therapy. Additionally, incretin-based therapeutic agents, such as glucagon-like peptide1, liraglutide (LEADER), and dipeptidyl peptidase4 inhibitors, linagliptin (CARMERINA) have elicited vasotropic actions, suggesting a potential for reducing the risk of DKD. Until recently, mineralocorticoid receptor antagonists (MRAs) have not been suitable for DKD treatment because of their adverse effect of hyperkalemia. In contrast, finerenone, a non-steroidal MRA, significantly reduced renal composite endpoint without severe hyperkalemia that would force its discontinuation (FIDELIO-DKD). Thus, the mainstay treatments of DKD are RAS inhibitors, SGLT2 inhibitors, incretin-based therapeutic agents, and non-steroidal MRA, or in other words, the DKD "fantastic four".

Review of SGLT2i for the Treatment of Renal Complications: Experience in Patients with and Without T2D

The management of type 2 diabetes (T2D) involves decreasing plasma glucose levels and reducing cardiovascular and microvascular complications. Diabetic kidney disease (DKD), defined as presence of albuminuria, impaired glomerular filtration, or both, is an insidious microvascular complication of diabetes that generates a substantial personal and clinical burden. The progressive reduction in renal function and increased albuminuria results in an increase of cardiovascular events. Thus, patients with DKD require exhaustive control of the associated cardiovascular risk factors. People with diabetes and renal impairment have fewer options of antidiabetic drugs because of contraindications, adverse effects, or altered pharmacokinetics. Sodium–glucose cotransporter type 2 inhibitors (SGLT2i) reduce blood glucose concentrations by blocking the uptake of sodium and glucose in the proximal tubule and promoting glycosuria, and these agents now have an important role in the management of T2D. The results of several cardiovascular outcomes trials suggested that SGLT2i are associated with improvements in renal endpoints in addition to their reduction in cardiovascular events and mortality, which represents a major advance in the care of this population. The dedicated kidney outcomes trials have confirmed the renoprotective action of SGLT2i across different glomerular filtration and albuminuria values, even in patients with non-diabetic chronic kidney disease. Notably, this improvement in kidney function may indirectly benefit cardiac function through multifaceted interorgan cross talk, which can break the cardiorenal vicious circle linked to T2D. In this article, we briefly review the different mechanisms of action that may explain the renal beneficial effects of SGLT2i and disclose the results of the key renal outcome trials and the subsequent update of related clinical guidelines.

Initiating SGLT2 inhibitor therapy to improve renal outcomes for persons with diabetes eligible for an intensified glucose-lowering regimen: hypothetical intervention using parametric g-formula modeling

IntroductionSodium–glucose cotransporter 2 (SGLT2) inhibitors are now recommended in guidelines for persons with type 2 diabetes mellitus (T2DM) and at risk of advanced kidney disease as part of the glucose-lowering...