Renal Endpoints Research Articles

Neues zu Hypertonie und Diabetes

Hypertonie und Diabetes treten oft gemeinsam auf und erhöhen die kardiovaskuläre Mortalität. Beide Erkrankungen sind bei COVID-19-Patienten (COVID-19: „coronavirus disease 2019“) mit schweren Verläufen gehäuft anzutreffen. Hinsichtlich der Kausalität für COVID-19 ist die Datenlage widersprüchlich. Sicher ist ein Surrogateffekt, da meiste ältere COVID-19-Patienten einen schweren Verlauf aufgrund der Vorschäden aufweisen. Hemmer des Renin-Angiotensin-Aldosteron-Systems (RAAS-Blocker) erhöhen nicht die Wahrscheinlichkeit der positiven SARS-CoV-2-Testung (SARS-CoV-2: „severe acute respiratory syndrome coronavirus 2“). Sie haben keinen Einfluss auf die Schwere des Verlaufs und die Mortalität und sollten daher unter COVID-19 nicht pausiert/abgesetzt werden. Die renale Denervierung erfreut sich einer Renaissance, nachdem sich die Studiendesigns und Technologien stark weiterentwickelt haben. Bei den SGLT-2-Hemmern (SGLT-2: „sodium glucose linked transporter 2“) ist der Wissenszuwachs enorm. In den ersten beiden großen randomisierten kontrollierten Studien mit primären renalen Endpunkten verzögerten sie die Progression der chronischen Niereninsuffizienz (CKD) bis zum Dialysebeginn deutlich um zusätzliche ca. 12–13 Jahre. Sie sind prinzipiell bei Typ‑2- sowie Typ-1-Diabetes und auch bei herzinsuffizienten Patienten mit und ohne Diabetes einsetzbar und reduzieren den systolischen Blutdruck. Der nichtsteroidale Mineralokortikoidrezeptorantagonist (MRA) Finerenon wirkt bei Typ‑2-Diabetes reno- und kardioprotektiv bezüglich kardiovaskulärer Mortalität und Niereninsuffizienz. Wie bei den klassischen MRA kann es auch hier zur Hyperkaliämie in höheren CKD-Bereichen kommen. Größere Vergleichsstudien zu den klassischen MRA liegen nicht vor. Die Zulassung in Deutschland steht noch aus.

How to Assess Diabetic Kidney Disease Progression? From Albuminuria to GFR.

Diabetic kidney disease (DKD) is one of the most relevant complications of type 2 diabetes and dramatically increases the cardiovascular risk in these patients. Currently, DKD is severely infra-diagnosed, or its diagnosis is usually made at advanced stages of the disease. During the last decade, new drugs have demonstrated a beneficial effect in terms of cardiovascular and renal protection in type 2 diabetes, supporting the crucial role of an early DKD diagnosis to permit the use of new available therapeutic strategies. Moreover, cardiovascular and renal outcome trials, developed to study these new drugs, are based on diverse cardiovascular and renal simple and composite endpoints, which makes difficult their interpretation and the comparison between them. In this article, DKD diagnosis is reviewed, focusing on albuminuria and the recommendations for glomerular filtration rate measurement. Furthermore, cardiovascular and renal endpoints used in classical and recent cardiovascular outcome trials are assessed in a pragmatic way.

773-P: The Association between the Estimated GFR Trajectory and Cardiovascular/Renal Outcomes in SGLT2i Users

Purpose: To evaluate the association between the eGFR trajectory and cardiovascular/renal outcomes in SGLT2i users. Methods: Cardiovascular and Renal Outcome Trials of SGLT2i with reports of eGFR change were included. Random-effect model was used. Results: In all, 7 RCTs were included. Meta-analysis showed that the risk of all-cause mortality was only reduced in SGLT2i users with eGFR change rate >-1ml/min/1.73m2 per year (RR=0.87, 95%CI, 0.77 to 0.99). Consistent risk reductions were observed in SGLT2i users in terms of heart failure, 3P-MACE (MI, stroke, CV death), 4P-MACE (3P-MACE and heart failure) and composite renal endpoints (sustained decline in eGFR, renal replacement treatment and renal death), regardless of eGFR change rate. Conclusions: The preserved eGFR decline may confer reduced risk of all-cause mortality but did not influence the benefits in cardiovascular and renal outcomes in SGLT2i users. Disclosure C. Lin: None. X. Cai: None. L. Ji: None. Funding Beijing Natural Science Foundation (7202216); National Natural Science Foundation of China (81970698, 81970708)

MO514CARDIORENAL OUTCOMES AND MORTALITY IN PATIENTS WITH TYPE 2 DIABETES MELLITUS: A MULTINATIONAL PROSPECTIVE COHORT STUDY (PROVALID)

Abstract Background and Aims PROVALID is a prospective, observational, multinational cohort study in 4000 patients with type 2 diabetes mellitus. Our aim was to determine the incidence rate of renal and cardiovascular endpoints, as well as all-cause-mortality in different European countries and to identify risk factors associated with the investigated outcomes. Method Potential risk factors associated with the investigated outcomes were identified by calculation of the incidence rate ratio. Crude and adjusted incidence rates for every country were estimated using generalized linear (poisson) regression models and corresponding 95 % confidence intervals were computed. Incidence rates were adjusted for different risk factors including age, sex, estimated GFR, albuminuria, HbA1c, LDL, HDL, total cholesterol, systolic blood pressure, BMI and cardiovascular and renal comorbidities; among these several show significant impact on outcomes. The renal outcome was a composite of a sustained decline in the estimated GFR of at least 40%, a sustained increase in albuminuria of at least 30 % including the progression from normo- to micro- or macroalbuminuria, end-stage kidney disease, or death from renal causes. The cardiovascular composite endpoint was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results 3461 participants of four European countries (Austria 18 %, Hungary 41 %, Netherlands 26 % and Scotland 15 %) with a mean follow up time of 3.9 years were included into this study. Participants from Poland were excluded due to missing follow-up data. In total, 9.2 % and 6.4 % participants reached the renal and cardiovascular composite endpoint, respectively. 7.0 % of the participants died within this timeframe. The adjusted incidence rate for the renal endpoint ranged from 14.5 to 25.3 (per 1000 patient-years) with no significant differences between countries. On average, the incidence rate was lower in Scotland (IR, 14.5; 95 % CI, 8.7 to 22.5) and in the Netherlands (IR, 15.7; 95 % CI, 10.9 to 21.8) compared to Hungary (IR, 25.3; 95 % CI, 20.7 to 30.6) and Austria (IR 21.3; 95 % CI, 16.2 to 27.5). The adjusted incidence rate for the cardiovascular endpoint ranged from 7.0 to 20.3 and was significantly lower in Hungary (IR, 7.0; 95 % CI, 5.1 to 9.3) and the Netherlands (IR, 7.6; 95 % CI, 4.4 to 12.2) compared to Austria (IR, 16.7; 95 % CI, 12.4 to 22.1) and Scotland (IR, 20.3; 95 % CI, 13.8 to 28.9). The adjusted incidence rate for all-cause-mortality ranged from 4.2 to 15.9 and was significantly lower in the Netherlands (IR, 4.2; 95 % CI, 2.2 to 7.6) compared to Scotland (IR, 15.9; 95 % CI, 10.9 to 22.6). No significant difference in the incidence rates between Austria (IR, 9.8; 95 % CI, 7.0 to 13.4) and Hungary (IR, 9.3; 95 % CI, 6.8 to 12.4) was found. Conclusion After adjustment for known risk factors, incidence rates of cardiovascular endpoints, as well as all-cause-mortality still vary significantly between four European countries. This may be due to manifold reasons. Further analysis of the national therapeutic practice pattern within the PROVALID cohort may provide additional information.

MO413EFFECTS OF CHRONIC, LONG-TERM ACE-INHIBITOR TREATMENT ON CYTOKINE STORM AND RENAL FUNCTION AFTER CARDIO-PULMONARY BYPASS: A PROSPECTIVE OBSERVATIONAL STUDY

Abstract Background and Aims Cardiopulmonary bypass (CPB) may trigger organs damage, including kidney injury, due to a massive cytokine release. In this observational, prospective study, we have analyzed the possible impact of chronic treatment with ACE-Inhibitors (ACE-I) on the inflammatory response and renal function after CPB. Method Sixty-nine patients undergoing major cardiac surgery with CPB were enrolled. Patients were stratified according to long-term (>6 mo.) ACE-I use (n=38) or not (n=31). The primary endpoint was to analyze the changes in their IL-1 alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, TNF alpha, EGF and VEGF plasma levels. Secondary (renal) endpoints were: postoperative acute kidney injury (AKI), recovery of baseline GFR values and the absolute changes in renal function indexes. Results After CPB, IL-1alpha, IL-1beta, IL-4 and TNF-alpha remained stable overtime, while a significant decrease in IL-2 plasma levels was noticed in the ACE-I group (p=0.01). IL-6 and IL-8 plasma levels increased after surgery and tended to decrease after 48h. IL-10 plasma levels showed a similar variation, but both their rise and decrease were more pronounced in patients under ACE-I treatment (p=0.007). Finally, VEGF and EGF showed a marked initial decrease with a tendency to normalization 10 days after surgery (p for trend ranging from 0.01 to 0.001) (Figure 1-2). The occurrence of AKI within 2 days after surgery, the rate of GFR recovery and the absolute changes in renal function indexes were not statistically different between groups (Figure 3). Conclusion Chronic, long-term ACE-I treatment may influence the inflammatory response following CPB. On the other hand, this drug class apparently has neutral impact on perioperative renal outcomes.

Effect of empagliflozin on albuminuria, eGFR and serum creatinine: updated results from the ABCD nationwide empagliflozin audit

Introduction: Evidence from phase III and the EMPA-REG OUTCOME trials have demonstrated improvements in renal endpoints with empagliflozin use. The EMPA-KIDNEY trial is currently underway and is assessing whether there are benefits of empagliflozin in improving renal outcomes in people both with and without diabetes, and the mechanism has been suggested to be similar to that of ACE inhibitors with the haemodynamic effects of sodium-glucose co-transporter-2 inhibition reducing intraglomerular pressure.Aim: To assess the impacts of empagliflozin use on albuminuria and estimated glomerular filtration rate (eGFR) in a real-world UK-based audit.Methods: Data were collated via the ABCD nationwide audit programme, with analyses performed using either t-tests/ ANOVA or Wilcoxon signed rank/Kruskal–Wallis tests. Pre-specified stratified subgroup analyses by baseline eGFR and baseline albuminuria levels were also performed.Results: Our results demonstrated significant reductions in albuminuria across the population as a whole. When stratified by baseline albuminuria levels, those with microalbuminuria (30–300 μg/mg) or macroalbuminuria (>300 μg/mg) had significant improvements in urine albumin levels at 6-month (3–9-month) follow-up, with median changes of −17.7 μg/mg (p<0.0001; 95% CI −17.4 to −23.7) and 379.4 μg/mg (p=0.03; 95% CI −269.9 to −725.4), respectively. Across the population as a whole, eGFR reduced initially (at 6 months, −1.26 mL/min/1.73 m3; p<0.0001; 95% CI −0.87 to −1.64) before recovering to baseline by 24 months. When stratified by baseline eGFR, those with reduced renal function (eGFR <90) recovered quickest, with improvements in eGFR noted from baseline by 24 months.Conclusion: In this real-world analysis, the results are comparable to those in randomised controlled trials and are likely more generalisable to UK clinical practice. Unfortunately, we do not have clinical endpoints such as end-stage renal failure, renal death or dialysis as part of our dataset. Future audits could consider including these data to establish clinical as well as biochemical outcomes.

In-depth review: is hepcidin a marker for the heart and the kidney?

Iron is an essential trace element involved in oxidation-reduction reactions, oxygen transport and storage, and energy metabolism. Iron in excess can be toxic for cells, since iron produces reactive oxygen species and is important for survival of pathogenic microbes. There is a fine-tuning in the regulation of serum iron levels, determined by intestinal absorption, macrophage iron recycling, and mobilization of hepatocyte stores versus iron utilization, primarily by erythroid cells in the bone marrow. Hepcidin is the major regulatory hormone of systemic iron homeostasis and is upregulated during inflammation. Hepcidin metabolism is altered in chronic kidney disease. Ferroportin is an iron export protein and mediates iron release into the circulation from duodenal enterocytes, splenic reticuloendothelial macrophages, and hepatocytes. Systemic iron homeostasis is controlled by the hepcidin-ferroportin axis at the sites of iron entry into the circulation. Hepcidin binds to ferroportin, induces its internalization and intracellular degradation, and thus inhibits iron absorption from enterocytes, and iron release from macrophages and hepatocytes. Recent data suggest that hepcidin, by slowing or preventing the mobilization of iron from macrophages, may promote atherosclerosis and may be associated with increased cardiovascular disease risk. This article reviews the current data regarding the molecular and cellular pathways of systemic and autocrine hepcidin production and seeks the answer to the question whether changes in hepcidin translate into clinical outcomes of all-cause and cardiovascular mortality, and cardiovascular and renal end-points.

Sodium-Glucose Cotransporter2 Inhibitors in Patients with Non-Diabetic Chronic Kidney Disease.

Sodium-glucose cotransporter2 (SGLT2) inhibitors can reduce cardiovascular morbidity and mortality in patients with type2 diabetes. Furthermore, recent clinical studies have revealed that SGLT2 inhibitors decrease the risk of renal function impairment in patients with type2 diabetes. However, the effects of SGLT2 inhibitors on non-diabetic chronic kidney disease (CKD) remains unclear. Regarding long-term clinical outcomes, the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial explicitly showed improvements in cardiovascular outcomes in patients presenting with heart failure, even in the absence of diabetes. The reduction in heart failure in patients without diabetes was confirmed following empagliflozin administration in the EMPagliflozin outcomE tRial in patients with chrOnic heart failure with Reduced ejection fraction (EMPEROR-Reduced) trial. A recent systematic review and meta-analysis of DAPA-HF and EMPEROR-Reduced showed improvements in the composite renal endpoint regardless of the presence of diabetes or baseline estimated glomerular filtration rate. The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) trial evaluated patients with CKD with or without type2 diabetes, irrespective of whether SGLT2 inhibitor dapagliflozin was added for renin-angiotensin system blockade as background renoprotective therapy. In this trial, dapagliflozin reduced the hazard ratio for a composite renal and cardiovascular death endpoint in patients with CKD attributed to various causes, with or without type2 diabetes.

Blood pressure monitoring in kidney transplantation: a systematic review on hypertension and target organ damage.

Sparse studies show that ambulatory blood pressure monitoring (ABPM) is superior to office BP (oBP) measurements to predict target organ damage and cardiovascular (CV) events in kidney transplant recipients (KTRs). We performed a systematic review aimed at determining the potential associations between BP recordings by different methods and renal and CV outcomes in this population. Major medical databases were searched for studies enrolling adult KTRs undergoing 24h ABPM compared to office or home BP measurements. Main outcomes were: associations between different BP recordings and renal and CV outcomes. Additionally, any association between the circadian BP pattern (dipping/non-dipping status) and outcomes was assessed. Twenty-two studies (2078 participants) were reviewed. Amongst 12 studies collecting data on renal endpoints, ten studies found that BP assessed by ABPM was a stronger predictor of renal function decline, assessed by serum creatinine (SCr) and/or creatinine clearance (CrCl) or estimated glomerular filtration rate (eGFR), than traditional office measurements. Twelve studies analyzed the relation between different BP recordings and CV target organ damages and reported robust correlations between echocardiographic abnormalities [i.e. left ventricular mass index (LVM/LVMI)] and 24h ABPM, but not with office BPs. Furthermore, 24h ABPM correlated better than oBP with markers of vascular damage, such as carotid intima-media thickness (IMT), diffuse thickening, and endothelial dysfunction. Additionally, abnormal circadian BP pattern (non-dippers and reverse dippers) identified a group of kidney recipients at risk for kidney function loss and CV abnormalities. In our systematic review, ABPM reflected target organ damage more closely than oBP in KTRs. Furthermore, altered circadian BP profile associated with renal and CV target organ damages.

Effects of ertugliflozin on kidney composite outcomes, renal function and albuminuria in patients with type 2 diabetes mellitus: an analysis from the randomised VERTIS CV trial

Aims/hypothesisIn previous work, we reported the HR for the risk (95% CI) of the secondary kidney composite endpoint (time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death) with ertugliflozin compared with placebo as 0.81 (0.63, 1.04). The effect of ertugliflozin on exploratory kidney-related outcomes was evaluated using data from the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial (NCT01986881).MethodsIndividuals with type 2 diabetes mellitus and established atherosclerotic CVD were randomised to receive ertugliflozin 5 mg or 15 mg (observations from both doses were pooled), or matching placebo, added on to existing treatment. The kidney composite outcome in VERTIS CV (reported previously) was time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death. The pre-specified exploratory composite outcome replaced doubling of serum creatinine with sustained 40% decrease from baseline in eGFR. In addition, the impact of ertugliflozin on urinary albumin/creatinine ratio (UACR) and eGFR over time was assessed.ResultsA total of 8246 individuals were randomised and followed for a mean of 3.5 years. The exploratory kidney composite outcome of sustained 40% reduction from baseline in eGFR, chronic kidney dialysis/transplant or renal death occurred at a lower event rate (events per 1000 person-years) in the ertugliflozin group than with the placebo group (6.0 vs 9.0); the HR (95% CI) was 0.66 (0.50, 0.88). At 60 months, in the ertugliflozin group, placebo-corrected changes from baseline (95% CIs) in UACR and eGFR were −16.2% (−23.9, −7.6) and 2.6 ml min−1 [1.73 m]−2 (1.5, 3.6), respectively. Ertugliflozin was associated with a consistent decrease in UACR and attenuation of eGFR decline across subgroups, with a suggested larger effect observed in the macroalbuminuria and Kidney Disease: Improving Global Outcomes in Chronic Kidney Disease (KDIGO CKD) high/very high-risk subgroups.Conclusions/interpretationAmong individuals with type 2 diabetes and atherosclerotic CVD, ertugliflozin reduced the risk for the pre-specified exploratory composite renal endpoint and was associated with preservation of eGFR and reduced UACR.Trial registrationClinicalTrials.gov NCT01986881Graphical abstract

Plasma trimethylamine N-oxide and its metabolic precursors and risk of mortality, cardiovascular and renal disease in individuals with type 2-diabetes and albuminuria.

The trimethylamine N-oxide (TMAO) pathway is related to intestinal microbiota and has been associated to risk of cardiovascular disease (CVD). We investigated associations between four plasma metabolites in the TMAO pathway and risk of all-cause mortality, CVD and deterioration in renal function in individuals with type 2-diabetes (T2D) and albuminuria. Plasma concentrations of TMAO, choline, carnitine, and betaine were measured by liquid chromatography-tandem mass spectrometry at baseline in 311 individuals with T2D and albuminuria. Information on all-cause mortality and fatal/non-fatal CVD during follow-up was obtained from registries. The association of each metabolite, and a weighted sum score of all four metabolites, with the endpoints were examined. Serum creatinine was measured at follow-up visits and the renal endpoint was defined as eGFR-decline of ≥30%. Associations were analysed using proportional hazards models adjusted for traditional risk factors. Baseline mean(SD) age was 57.2(8.2) years and 75% were males. Follow-up was up to 21.9 years (median (IQR) follow-up 6.8 (6.1-15.5) years for mortality and 6.5 (5.5-8.1) years for CVD events). The individual metabolites and the weighted sum score were not associated with all-cause mortality (n = 106) or CVD (n = 116) (adjusted p≥0.09). Higher choline, carnitine and the weighted sum score of the four metabolites were associated with higher risk of decline in eGFR (n = 106) (adjusted p = 0.001, p = 0.03 and p<0.001, respectively). In individuals with T2D and albuminuria, higher choline, carnitine and a weighted sum of four metabolites from the TMAO pathway were risk markers for deterioration in renal function during long-term follow-up. Metabolites from the TMAO pathway were not independently related to risk of all-cause mortality or CVD.

Gliflozins for the Treatment of Congestive Heart Failure and Renal Failure in Type 2 Diabetes.

Gliflozins are effective drugs for the treatment of type 2 diabetes. They inhibit sodium glucose cotransporter 2 in the proximal renal tubule, leading to increased glucose excretion. On the basis of findings from relevant studies, gliflozins are also increasingly used in clinical practice to treat congestive heart failure and renal failure. This review is based on pertinent publications retrieved from a selective literature search in PubMed and GoogleScholar. Cardiovascular safety studies revealed early on that gliflozins can lower the hospitalization rate of patients suffering from congestive heart failure with a reduced leftventricular ejection fraction (HFrEF). They also showed favorable effects on multiple renal endpoints. In recent years, studies such as DAPA-HF and CREDENCE have further documented the benefit of gliflozins in the treatment of congestive heart failure and renal failure in patients with type 2 diabetes, and gliflozins have accordingly been incorporated into the pertinent guidelines. In the recently published EMPEROR-Reduced trial, empagliflozin was found to significantly lower the frequency of a combined cardiovascular endpoint in patients with HFrEF (19.4 % versus 24.7%; hazard ratio [HR] 0.75; 95% confidence interval [0.65; 0.86]; number needed to treat [NNT] 19, p <0.001). In the DAPA-CKD trial, which was also recently published, dapagliflozin was found to significantly lower the frequency of a combined renal endpoint (9.2% versus 14.5%; HR 0.61 [0.51; 0.72]; NNT 19; p <0.001). On the basis of findings from specific studies, gliflozins will henceforth be a major class of drug for the treatment of HFrEF and renal failure, independently of the presence of type 2 diabetes.

Overhydration: A cause or an effect of kidney damage and how to treat it.

Volume overload can be both the cause and effect of chronic kidney disease (CKD). Overhydration often accompanies renal insufficiency. In cardiovascular disease (CVD), fluid overload can also be the cause of renal function impairment. Beside salt restriction, loop diuretics are the first-line therapy. Frequently developed resistance can be overcome by switching to intravenous administration, adding albumin alone or in combination with other diuretics. Transient factors like infection or contrast media can impair diuretic response and contribute to congestion. Apart from conservative management, ultrafiltration (UF) and peritoneal dialysis (PD) are used. In huge congestion with inadequate diuretic effect, hemodialysis with UF plays an important role as a temporary or permanent remedy. An increasing amount of data indicates that sodium-glucose co-transporter-2 inhibitors (SGLT2i) have allowed for a breakthrough in controlling fluid volume in diabetic and non-diabetic patients with CKD. Sodium-glucose cotransporter 2 inhibitors show cardioand renoprotective effects and have a positive impact on hard cardiovascular and renal endpoints.

Efficacy and safety of immunosuppressive therapies in the treatment of high-risk IgA nephropathy: A network meta-analysis.

Background:IgA nephropathy (IgAN) is one of the significant contributing factors of end-stage renal disease (ESRD). It is reported that over half of patients with IgAN accompany multiple high-risk factors, which increase the risk of ESRD progression. Studies have shown that immunosuppressive agents were beneficial in high-risk IgAN, but the efficacy and safety have not been fully demonstrated yet. The present study aims to elucidate the efficacy of commonly used immunosuppressants in high-risk IgAN and their relative safety profiles via a network meta-analysis strategy.Methods:Randomized controlled trials (RCTs) eligible for this network meta-analysis were included to evaluate the efficacy and safety of different immunosuppressants for high-risk IgAN. Main outcomes and measures include incidence of renal composite end point, the rate of total remission, adverse events, and proteinuria. Besides, subgroup analysis and cluster analysis were carried out.Results:This network meta-analysis of 37 RCTs involving 3012 participants found that Mycophenolate mofetil (MMF) combined with corticosteroids (CS) was superior to other interventions in end point events and proteinuria. Cyclosporine A (CsA) plus CS was the best option for clinical remission rate, and supportive care (SC) was the safest treatment. Cluster analysis showed that MMF+CS and Leflunomide (LEF)+CS were best protocols in efficacy and safety. Subgroup analysis indicated the best benefits of MMF were presented among the Asian population, and the benefits increased with the increase of follow-up duration. The effect of Cyclophosphamide (CTX) +CS on crescent IgAN was better than that of other risk factors. Moreover, the increasing follow-up duration was negatively associated with the effect.Conclusions:MMF+CS and LEF+CS appear to serve as the best choice for treating high-risk IgAN than other immunosuppressive therapies.

Kidney, Cardiovascular, and Safety Outcomes of Canagliflozin according to Baseline Albuminuria: A CREDENCE Secondary Analysis.

The kidney protective effects of renin-angiotensin system inhibitors are greater in people with higher levels of albuminuria at treatment initiation. Whether this applies to sodium-glucose cotransporter 2 (SGLT2) inhibitors is uncertain, particularly in patients with a very high urine albumin-to-creatinine ratio (UACR; ≥3000 mg/g). We examined the association between baseline UACR and the effects of the SGLT2 inhibitor, canagliflozin, on efficacy and safety outcomes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) randomized controlled trial. The study enrolled 4401 participants with type 2 diabetes, an eGFR of 30 to <90 ml/min per 1.73 m2, and UACR of >300 to 5000 mg/g. Using Cox proportional hazards regression, we examined the relative and absolute effects of canagliflozin on kidney, cardiovascular, and safety outcomes according to a baseline UACR of ≤1000 mg/g (n=2348), >1000 to <3000 mg/g (n=1547), and ≥3000 mg/g (n=506). In addition, we examined the effects of canagliflozin on UACR itself, eGFR slope, and the intermediate outcomes of glycated hemoglobin, body weight, and systolic BP. Overall, higher UACR was associated with higher rates of kidney and cardiovascular events. Canagliflozin reduced efficacy outcomes for all UACR levels, with no evidence that relative benefits varied between levels. For example, canagliflozin reduced the primary composite outcome by 24% (hazard ratio [HR], 0.76; 95% confidence interval [95% CI], 0.56 to 1.04) in the lowest UACR subgroup, 28% (HR, 0.72; 95% CI, 0.56 to 0.93) in the UACR subgroup >1000 to <3000 mg/g, and 37% (HR, 0.63; 95% CI, 0.47 to 0.84) in the highest subgroup (Pheterogeneity=0.55). Absolute risk reductions for kidney outcomes were greater in participants with higher baseline albuminuria; the number of primary composite events prevented across ascending UACR categories were 17 (95% CI, 3 to 38), 45 (95% CI, 9 to 81), and 119 (95% CI, 35 to 202) per 1000 treated participants over 2.6 years (Pheterogeneity=0.02). Rates of kidney-related adverse events were lower with canagliflozin, with a greater relative reduction in higher UACR categories. Canagliflozin safely reduces kidney and cardiovascular events in people with type 2 diabetes and severely increased albuminuria. In this population, the relative kidney benefits were consistent over a range of albuminuria levels, with greatest absolute kidney benefit in those with an UACR ≥3000 mg/g. ClinicalTrials.gov: CREDENCE, NCT02065791. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_02_22_CJN15260920_final.mp3.

Endothelial Dysfunction Is Associated with Cerebrovascular Events in Pre-Dialysis CKD Patients: A Prospective Study.

Background: Patients with chronic kidney disease (CKD) have markedly increased rates of end stage renal disease, major adverse cardiovascular/cerebrovascular events (MACCEs), and mortality. Endothelial dysfunction (ED) is an early marker of atherosclerosis that is emerging as an increasingly important non-traditional cardiovascular risk factor in CKD. There is a lack of clinical studies examining the association between ED and both cardiovascular and renal endpoints in patients with CKD. Aims: We examined the association between reactive hyperemia index (RHI), a validated measure of endothelial function measured by peripheral arterial tonometry (PAT), with traditional cardiovascular risk factors in pre-dialysis CKD patients and prospectively evaluated the role of RHI as predictor of renal and cardiovascular outcomes in this population. Methods: One hundred and twenty pre-dialysis patients with CKD stages 1 to 5 (CKD group) and 18 healthy kidney donor candidates (control group) were recruited and had a successful RHI measurement by PAT. General demographic and clinical information including traditional cardiovascular risk factors were registered from all participants. Thereafter, patients were prospectively followed-up for a median time of 47 (IQR 19–66) months to determine associations of RHI with renal outcomes, MACCEs, hospitalizations or mortality. Results: In the CKD patient population, the mean age was 57.7 ± 15.5 years, the mean eGFR was 54.9 ± 36.7 mL/min/1.73 m2 (CKD-EPI) and 57 were males (47.5%). At baseline, in univariate analysis, RHI in the CKD group correlated positively with eGFR (r = 0.332, p < 0.0001) and correlated negatively with age (r = −0.469, p < 0.0001), Charlson index (r = −0.399, p < 0.0001), systolic blood pressure (r = −0.256, p = 0.005), and proteinuria (r = 0.211, p = 0.027). Reactive hyperemia index in the control group did not significantly differ from RHI observed in patients with CKD stages 1 to 5 (2.09 ± 0.40 vs. 2.01 ± 0.06, p = 0.493). In adjusted analysis, only age (β = −0.014, p = 0.003) remained independently associated with RHI at baseline. During follow-up, 8 patients suffered a MACCEs, 33 patients experienced renal function deterioration, 17 patients were hospitalized for medical reasons and 6 patients died. RHI at baseline was not significantly associated with CKD progression (1.94 vs. 2.02, p = 0.584), hospitalizations (1.90 vs. 2.04, p = 0.334), and all-cause mortality (1.65 vs. 2.01, p = 0.208) or MACCEs (1.77 vs. 2.01, p = 0.356), but was significantly associated with cerebrovascular events (1.27 vs. 2.02, p = 0.004) and with a composite cardiovascular outcome (MACCEs, hospital admissions and death; 1.73 vs. 2.07, p = 0.035). Conclusion: Our results suggest that RHI may be a predictor for the development of cerebrovascular events in pre-dialysis CKD patients who may benefit from more aggressive preventive measures.

Heterogeneity in renal endpoints of cardiovascular outcomes trials in Type 2 diabetes.

Composite renal end points and end stage renal disease (ESRD) are frequently included as prespecified secondary end points in the cardiovascular outcomes trials (CVOTs) of diabetes medications. We examined the heterogeneity in the definitions of composite renal end point and ESRD in CVOTs. Five criteria (macroalbuminuria, doubling of serum creatinine, estimated glomerular filtration rate [GFR], ESRDand renal death), were considered for the renal composite end point across the trials. Only three of the 12 trials included all five criteria, whereas the other trials included different combinations of four, three and two criteria. ESRD definition also showed considerable heterogeneity across the trials. Heterogeneity exists in the definitions of renal composite and ESRD end points in CVOTs making it challenging to assess comparative efficacy of the active treatments for reimbursement purposes.

The association of echocardiographic parameters on renal outcomes in chronic kidney disease

Background Patients with chronic kidney disease (CKD) often have structural abnormalities of the heart due to pressure and volume overload. The aim of this study was to evaluate associations between echocardiographic parameters and renal outcomes (estimated glomerular filtration rate [eGFR] slope and progression to dialysis) in patients with stage 3–5 CKD. Methods This longitudinal study enrolled 419 patients. Changes in renal function were assessed using the eGFR slope. Rapid renal progression was defined as an eGFR slope < −3 mL/min/1.73 m2/year, and the renal endpoint was defined as commencing dialysis. Results Increased left atrial diameter (LAD), ratio of left ventricular mass to body surface area (LVM/BSA), ratio of LVM to height2.7 (LVM/ht2.7), and ratio of observed to predicted LVM (o/p LVM) were associated with eGFR slope in an adjusted model, but left ventricular ejection fraction (LVEF) was not. Furthermore, LAD ≥ 4.7 cm, LVM/BSA > 115 g/m2 in males and > 95 g/m2 in females, and LVM/ht2.7 > 48 g/ht2.7 in males and > 44 g/ht2.7 in females were correlated with progression to dialysis, but o/p LVM and LVEF were not. The maximum change in χ2 change to predict renal outcomes was observed for LAD, followed by LVM/BSA and LVM/ht2.7. Conclusions A large LAD and increased LVM, regardless of how it was measured (LVM/BSA, LVM/ht2.7 and o/p LVM), were correlated with adverse renal outcomes in patients with CKD stage 3–5. LAD had superior prognostic value to LVM and LVEF.

Antecedent ACE-inhibition, inflammatory response, and cardiac surgery associated acute kidney injury

Cardiopulmonary bypass (CPB) may trigger organs damage, including kidney injury, due to a massive cytokine release. In this observational, prospective study, we analyzed the possible impact of chronic treatment with ACE-Inhibitors (ACE-I) on the inflammatory response and renal function after CPB. Sixty-nine patients undergoing major cardiac surgery with CPB were enrolled. Patients were stratified according to long-term (> 6 mo.) ACE-I use (n = 38) or not (n = 31). The primary endpoint was the change in IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, TNF alpha, EGF and VEGF plasma levels. Secondary (renal) endpoints were postoperative acute kidney injury (AKI), recovery of baseline GFR values and the absolute changes in renal function indexes. After CPB, IL-1alpha, IL-1beta, IL-4 and TNF-alpha remained stable over time while a significant decrease in IL-2 levels was noticed in the ACE-I group (p = 0.01). IL-6 and IL-8 increased after surgery and tended to decrease after 48 h. IL-10 levels showed a similar variation, but both their rise and decrease were more pronounced in patients under ACE-I treatment (p = 0.007). Finally, VEGF and EGF showed a marked initial decrease with a tendency to normalization 10 days after surgery (p for trend ranging from 0.01 to 0.001). The occurrence of AKI within 2 days after surgery, the rate of GFR recovery and the absolute changes in renal function indexes were not statistically different between groups. Chronic, long-term ACE-I treatment may influence the inflammatory response following CPB. On the other hand, this drug class apparently has neutral impact on perioperative renal outcomes.

Acute kidney injury in idiopathic membranous nephropathy with nephrotic syndrome

Background and objectives The impact of acute kidney injury (AKI) on the progression of renal function in idiopathic membranous nephropathy (iMN) with nephrotic syndrome (NS) patients have not yet been reported, we sought to investigate the incidence, clinical features and prognosis of AKI in iMN with NS patients and determine clinical predictors for progression from AKI to advanced chronic kidney disease (CKD) stage. Methods We analyzed clinical and pathological data of iMN with NS patients retrospectively collected from Jan 2012 to Dec 2018. The primary renal endpoint was defined as persistent eGFR <45ml/min per 1.73 m2 more than 3 months. Comparisons of survival without primary renal endpoint were performed by Kaplan-Meier curves and log-rank test. Univariate and multivariate Cox proportional hazard models were constructed to determine independent variables associated with primary renal endpoint . Results 434 iMN with NS patients were enrolled. The incidence of AKI 1 stage, AKI 2 stage and AKI 3 stage was 23.1, 4.8 and 0.7% respectively. 66 (53.2%) patients with AKI had complete renal function recovery and 42 (33.9%) patients with AKI reached primary renal endpoint. Survival without primary renal endpoint was worse in AKI patients than No AKI patients (67.1 ± 5.3 and 43.7 ± 7.3% vs 99.5 ± 0.5 and 92.5 ± 4.2% at 2 and 4 years,p < 0.001). AKI was independently associated with primary renal endpoint, with an adjusted hazard ratio(HR) of 25.1 (95%CI 7.7–82.1, p < 0.001). Conclusions AKI was usually mild and overlooked in iMN patients with NS, but it had a strong association with poor clinical outcomes and was an independent risk factor for CKD progression.