Greater Reduction In Albuminuria Research Articles

Graded Organ Response and Progression Criteria for Kidney Immunoglobulin Light Chain Amyloidosis

Kidney light chain (AL) amyloidosis is associated with a risk of progression to kidney replacement therapy (KRT) and death. Several studies have shown that a greater reduction in proteinuria following successful anticlonal therapy is associated with improved outcomes. To validate graded kidney response criteria and their association with kidney and overall survival (OS). This retrospective, multicenter cohort was conducted at 10 referral centers for amyloidosis from 2010 to 2015 and included patients with kidney AL amyloidosis that was evaluable for kidney response and who achieved at least hematologic partial response within 12 months of diagnosis. The median follow-up was 69 (54-88) months. Data analysis was conducted in 2023. Four kidney response categories based on the reduction in pretreatment 24-hour urine protein (24-hour UP) levels: complete response (kidCR, 24-hour UP ≤200 mg), very good partial response (kidVGPR, >60% reduction in 24-hour UP), partial response (kidPR, 31%-60% reduction), and no response (kidNR, ≤30% reduction). Kidney response was assessed at landmark points (6, 12, and 24 months) and best kidney response. Cumulative incidence of progression to KRT and OS. Seven-hundred and thirty-two patients (335 women [45.8%]) were included, with a median (IQR) age of 63 (55-69) years. The median (IQR) baseline 24-hour proteinuria and estimated glomerular filtration rate was 5.3 (2.8-8.5) g per 24 hours and 72 (48-92) mL/min/1.73m2, respectively. In a competing-risk analysis, the 5-year cumulative incidence rates of progression to KRT decreased with deeper kidney responses as early as 6 months from therapy initiation (11%, 12%, 2.1%, and 0% for kidNR, kidPR, kidVGPR, and kidCR, respectively; P = .002) and were maintained at 12 months and 24 months and best kidney response. Patients able to achieve kidCR/kidVGPR by 24 months and at best response had significantly better OS compared with kidPR/kidNR. Kidney progression, defined as a 25% or greater decrease in estimated glomerular filtration rate, was associated with cumulative incidence of progression to KRT and OS. The results of this cohort study suggest that graded kidney response criteria offers clinically and prognostically meaningful information for treating patients with kidney AL amyloidosis. The response criteria potentially inform kidney survival based on the depth of reduction in 24-hour proteinuria levels and demonstrate an OS advantage for those able to achieve kidCR/kidVGPR compared with kidPR/kidNR. Taken together, achievement of at least kidVGPR by 12 months is needed to ultimately improve kidney and patient survival.

Practical Considerations for the Use of Sparsentan in the Treatment of Patients with IgAN in Clinical Practice.

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. It is characterized by the mesangial deposition of IgA-containing immune complexes, triggering damage to the glomerular filtration barrier that is amplified by the tandem action of endothelin-1 and angiotensin II at their receptors. Proteinuria and progressive glomerular damage cause loss of kidney function in up to 50% of patients within 10-20 years. The risk of progression is strongly associated with persistent proteinuria (>0.75-1 g/day). Current standard of care involves interventions to decrease proteinuria and control blood pressure. Immunosuppressive agents, used in selected patients at high risk for progression, can be associated with significant side effects. Sparsentan, a novel non-immunosuppressive single-molecule Dual Endothelin Angiotensin Receptor Antagonist (DEARA), received FDA accelerated approval based on interim results from the PROTECT trial, which demonstrated that sparsentan-treated patients achieved a significantly greater reduction in proteinuria from baseline versus the active control irbesartan and that sparsentan was generally safe and well tolerated. Sparsentan is the first non-immunosuppressive treatment to be FDA-approved for the reduction of proteinuria in adults with IgAN at high risk of disease progression. We provide practical guidance for the clinical use of sparsentan in adults with IgAN.

Sparsentan versus Irbesartan in Focal Segmental Glomerulosclerosis

BackgroundAn unmet need exists for focal segmental glomerulosclerosis (FSGS) treatment. In an 8-week, phase 2 trial, sparsentan, a dual endothelin–angiotensin receptor antagonist, reduced proteinuria in patients with FSGS. The efficacy and safety of longer-term treatment with sparsentan for FSGS are unknown.MethodsIn this phase 3 trial, we enrolled patients with FSGS (without known secondary causes) who were 8 to 75 years of age; patients were randomly assigned to receive sparsentan or irbesartan (active control) for 108 weeks. The surrogate efficacy end point assessed at the prespecified interim analysis at 36 weeks was the FSGS partial remission of proteinuria end point (defined as a urinary protein-to-creatinine ratio of ≤1.5 [with protein and creatinine both measured in grams] and a >40% reduction in the ratio from baseline). The primary efficacy end point was the estimated glomerular filtration rate (eGFR) slope at the time of the final analysis. The change in eGFR from baseline to 4 weeks after the end of treatment (week 112) was a secondary end point. Safety was also evaluated.ResultsA total of 371 patients underwent randomization: 184 were assigned to receive sparsentan and 187 to receive irbesartan. At 36 weeks, the percentage of patients with partial remission of proteinuria was 42.0% in the sparsentan group and 26.0% in the irbesartan group (P=0.009), a response that was sustained through 108 weeks. At the time of the final analysis at week 108, there were no significant between-group differences in the eGFR slope; the between-group difference in total slope (day 1 to week 108) was 0.3 ml per minute per 1.73 m2 of body-surface area per year (95% confidence interval [CI], −1.7 to 2.4), and the between-group difference in the slope from week 6 to week 108 (i.e., chronic slope) was 0.9 ml per minute per 1.73 m2 per year (95% CI, −1.3 to 3.0). The mean change in eGFR from baseline to week 112 was −10.4 ml per minute per 1.73 m2 with sparsentan and −12.1 ml per minute per 1.73 m2 with irbesartan (difference, 1.8 ml per minute per 1.73 m2; 95% CI, −1.4 to 4.9). Sparsentan and irbesartan had similar safety profiles, and the frequency of adverse events was similar in the two groups.ConclusionsAmong patients with FSGS, there were no significant between-group differences in eGFR slope at 108 weeks, despite a greater reduction in proteinuria with sparsentan than with irbesartan. (Funded by Travere Therapeutics; DUPLEX ClinicalTrials.gov number, NCT03493685.)

#3649 EPIDEMIOLOGY OF IGA NEPHROPATHY AT A UK CENTRE OVER 2 DECADES – EFFECTS OF IMMUNOSUPPRESSION

Abstract Background and Aims IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide. The clinical course is heterogeneous. As such, determining which patients to treat with immunosuppression (IS) is often the key decision in management. Here, we present a 20-year retrospective study from a single centre with the following aims: to describe the epidemiology of our cohort, to assess outcomes (such as progression to end-stage kidney disease [ESKD] requiring renal replacement therapy [RRT] and mortality), and to determine the effect of IS. Method We collected all cases of IgAN from our biopsy database between January 2000 and December 2019. After exclusion, the total number for analysis was 401 patients. We collected demographic data for each patient, along with creatinine and proteinuria values over time, MEST-C histological scores, progression to ESKD, mortality, use of renin-angiotensin system blockade (RAS) blockade and IS treatment. CKD progression in the overall cohort was computed using the rate of change of estimated glomerular filtration rate [eGFR] (delta eGFR) from baseline to study end point, with the linear regression slope generated using all available eGFR measurements. Similarly, the rate of change of urine protein creatinine ratio [uPCR] (delta uPCR) from baseline to study endpoint was calculated using linear regression from serial uPCR measurements. Results Median age of the cohort was 45.0 years, with 69.6% male and 87.5% were Caucasian. Baseline laboratory values (median) included: creatinine 142µmol/L, eGFR 46.7ml/min/1.73 m2, uPCR 183mg/mmol. The median rate of decline of eGFR was -1.31ml/min/1.73 m2/yr and median change in uPCR was -4.46mg/mmol/yr. RAS blockade was used in 79.6% and IS in 20.4%. Progression to ESKD requiring RRT was seen in 29.7% and mortality in 19.7%. Median follow up duration was 51 months. Cox regression analysis revealed several factors associated with mortality, including increasing age, non-Caucasian ethnicity, diabetes, hypertension, cardiovascular disease, systolic blood pressure, creatinine, uPCR, ACEi/ARB use, and E and T score on biopsy. Several factors were associated with need for RRT including hypertension, various histological markers, creatinine, uPCR and ACEi/ ARB use. IS was not found to be a factor associated with all-cause mortality or RRT. Those treated with IS (table 1) had a higher uPCR (301.5mg/mol vs 141mg/mmol, p<0.001), were more likely to have a C score (37.7% vs 10.8%, p <0.001) or total MEST score >2 (42% vs 29.1%, p = 0.041). They showed greater reduction in proteinuria over time (−16.8mg/mmol/year vs −2.64mg/mmol/year, p = 0.003), but no difference in eGFR decline (−1.18 vs −1.32ml/min/1.7 3m2/yr, p = 0.703). Conclusion This is one of the largest retrospective observational studies assessing clinical and histological characteristics, along with outcomes, for IgAN. This provides important real-world data which will be useful for clinicians, particularly as the IgAN landscape changes with the introduction of novel therapies. Whilst IS was associated with a greater proteinuria reduction over time, this did not translate into an amelioration of eGFR decline. The study received grant support from CSL Vifor.

Graded Renal Response Criteria for Light Chain (AL) Amyloidosis

Graded Renal Response Criteria for Light Chain (AL) Amyloidosis

OAB-036: Graded renal response criteria and revised renal progression criteria for light chain (AL) amyloidosis

<h3>Background</h3> Renal light chain (AL) amyloidosis manifests as proteinuria with or without renal failure and is associated with a risk of progression to renal replacement therapy (RRT). A significant reduction in circulating amyloidogenic light chain is needed to achieve a renal response. Current renal response criteria are binary defining a renal response as >30% reduction in 24-h proteinuria without worsening estimated glomerular filtration rate (eGFR). Several studies suggest that greater reduction in proteinuria following successful therapy improves renal and overall survival. <h3>Methods</h3> AL amyloidosis patients diagnosed between 2010 to 2015, achieving at least hematological partial response to therapy and with renal involvement were included. Four renal response categories were formulated based on reduction level in pretreatment 24-h proteinuria in the absence of renal progression: renal complete response (renCR, 24-h proteinuria ≤200 mg/24-h); renal very good partial response (renVGPR, >60% reduction in 24-h proteinuria); renal partial response (renPR, 31-60% reduction in 24-proteinuria); and renal no response (renNR, 30% or less reduction). Renal response was assessed at landmark (6-, 12-, and 24 months from treatment initiation) and as best renal response. Graded renal responses were assessed as predictors for time from diagnosis to RRT and overall survival. <h3>Results</h3> Seven hundred and thirty-seven patients were included. The median age was 63. Renal stage I, II and III were assigned to 34%, 52% and 14% of patients, respectively. Reduction in 24-h proteinuria from baseline improved over time with a median reduction of 34%, 50% and 71%, at 6-month, 12-month and 24-months, respectively. At best response, renCR, renVGPR, renPR and renNR were achieved in 27%, 34%, 15% and 24% of patients, respectively. A renal response as early as 6 months after therapy initiation was able to predict time to RRT with an increase in RRT risk with lower level of renal response at that time point (5-year RRT 0%, 3%, 9% and 16% for renCR, renVGPR, renPR and renNR, respectively, P<0.001). Prediction of risk for RRT based on renal response depth improved at 12- and 24-months and at best renal response. Overall survival discrimination based on renal response depth was noted as early as 12 months from therapy initiation and improved with time. eGFR progression (≥25% decrease in eGFR) and proteinuria progression (at least 50% increase to ≥3g/day) were predictive for time to RRT. <h3>Conclusions</h3> We validated new graded renal response criteria based on reduction in 24-h proteinuria. These 4-level renal response criteria highlight the importance of achieving a deep renal response to improve renal and overall survival. These findings will allow clinicians to make decision on therapy changes or augmentation based on response depth as early as 6-month before irreversible renal failure has developed.

Comparative efficacy of different renin angiotensin system blockade therapies in patients with IgA nephropathy: a Bayesian network meta-analysis of 17 RCTs.

BackgroundIgA nephropathy (IgAN) is still one of the most prevalent forms of primary glomerulonephritis globally. However, no guidelines have clearly indicated which kinds of renin angiotensin system blockade therapies (ACEIs or ARBs or their combination) in patients with IgAN result in a greater reduction in proteinuria and a better preservation of kidney function. Thus, we conducted a Bayesian network analysis to evaluate the relative effects of these three therapy regimens in patients with IgAN.MethodsThe protocol was registered in PROSPERO with ID CRD42017073726. We comprehensively searched the PubMed, the Cochrane Library, Embase, China Biology Medicine disc, WanFang and CNKI databases for studies published since 1993 as well as some grey literature according to PICOS strategies. Pairwise meta-analysis and Bayesian network analysis were conducted to evaluate the effect of different regimens.ResultsSeventeen randomized controlled trials (RCTs) involving 1,006 patients were analyzed. Co-administration of ACEIs and ARBs had the highest probability (92%) of being the most effective therapy for reducing proteinuria and blood pressure, but ACEIs would be the most appropriate choice for protecting kidney function in IgAN.ConclusionThe combination of ACEIs and ARBs seems to have a significantly better antiproteinuric effect and a greater reduction of blood pressure than ACEI or ARB monotherapy in IgAN. ACEIs appear to be a more renoprotective therapy regimen among three therapies.

Therapeutic transformation for diabetic kidney disease

Risks of kidney failure and heart failure are markedly reduced by inhibition of the sodium glucose cotransporter 2 (SGLT2) in patients with diabetic kidney disease. In a post hoc analysis of the Study of Diabetic Nephropathy with Atrasentan (SONAR) trial, drop-in SGLT2 inhibitor usage during the atrasentan enrichment period led to greater reduction in albuminuria compared with atrasentan alone. These data support the hypothesis of greater longer-term kidney protection by combination SGLT2 inhibition and endothelin A receptor antagonism that could be tested in future clinical trials.

Endothelin receptor antagonists for the treatment of diabetic nephropathy: A meta-analysis and systematic review.

BACKGROUNDDiabetic nephropathy (DN) is the main cause of chronic kidney disease and end-stage renal disease worldwide. Although available clinical trials have shown that endothelin receptor (ER) antagonists may be a novel and beneficial drug for DN, no consistent conclusions regarding their sufficient effectiveness and safety for patients with DN have been presented.AIMTo assess the effectiveness and safety of ER antagonists among patients with DN.METHODSThe EMBASE, PubMed, MEDLINE, Cochrane, and ClinicalTrials.gov databases were searched without any language restrictions. Relative risks with 95% confidence intervals (CIs) for dichotomous data and mean differences or standardized mean difference with 95%CIs for continuous data were calculated using Review Manager 5.3 software. Publication bias was assessed using Egger’s test with Stata/SE software.RESULTSWe enrolled seven studies with six data sets and 5271 participants. The ER antagonists group showed a significantly greater reduction in albuminuria and more patients with 40% reduction in urinary albumin-to-creatinine ratio than the control group (P < 0.0001 and P = 0.02, respectively). Subgroup analysis for reductions in estimated glomerular filtration rate (eGFR) showed that for the middle-dosage subgroup, the ER antagonists group exhibited lower eGFR reduction than the control group (P < 0.00001; mean difference, 0.70 95%CI: 0.66, 0.74). Moreover, significant reductions in systolic and diastolic blood pressure were observed in the invention group.CONCLUSIONER blockades combined with angiotensin converting enzyme inhibitor /angiotensin II type 1 receptor blockers may be an effective treatment to lower blood pressure and reduce proteinuria in DN with declined eGFR. However, attention should be given to adverse events, including cardiac failure, anemia, and hypoglycemia, as well as serious adverse events.

LB001EFFICACY AND SAFETY OF BELIMUMAB IN PATIENTS WITH ACTIVE LUPUS NEPHRITIS: A PHASE 3, RANDOMISED, PLACEBO-CONTROLLED TRIAL

Abstract Background and Aims Belimumab (BEL), an anti-B-cell-activating factor (BAFF) monoclonal antibody, is approved in patients (pts) ≥5 years of age with active systemic lupus erythematosus (SLE). Post hoc analyses of pooled renal outcomes data from two Phase 3 SLE studies showed favourable trends of greater reduction in proteinuria, haematuria, pyuria and lower renal flare rates in BEL-treated pts vs placebo (PBO).1 This is the largest study in acute lupus nephritis (LN) to date that evaluated efficacy and safety of intravenous (IV) BEL plus standard therapy (ST) in pts with active LN. Method BLISS-LN is a Phase 3, randomised, double-blind, placebo-controlled, 104-week study (GSK study BEL114054, NCT01639339); eligible pts (≥18 years) with autoantibody-positive SLE and active, biopsy-proven LN (classes III, IV and/or V) were randomised (1:1) to monthly BEL 10 mg/kg IV or PBO, plus ST. Randomisation was stratified by induction regimen: high dose corticosteroids [HDCS] plus either cyclophosphamide (CyC), followed by azathioprine + low dose corticosteroids (LDCS), or mycophenolate mofetil (MMF), followed by MMF + LDCS. Primary endpoint: primary efficacy renal response (PERR; defined as urine protein creatinine ratio [uPCR] ≤0.7; estimated glomerular filtration rate [eGFR] no more than 20% below pre-flare value or ≥60 ml/min/1.73m2; no rescue therapy) at Week (Wk) 104. Key secondary endpoints: complete renal response (CRR; defined as uPCR &amp;lt;0.5; eGFR no more than 10% below pre-flare value or ≥90 ml/min/1.73m2; no rescue therapy) at Wk 104; PERR at Wk 52; risk of renal-related event (defined as end-stage renal disease/doubling of serum creatinine/renal worsening/renal disease-related treatment failure) or death at any time up to Wk 104. Other endpoints: PERR and CRR at Wk 104 by induction regimen; proportions of pts with baseline uPCR ≥0.5 with uPCR shift to &amp;lt;0.5 while on study. Results Overall, 448 pts were randomised (efficacy: 223/treatment group; safety: 224/treatment group); 118 pts received CyC induction and 328 MMF induction; 278 (62.3%) completed the treatment. At Wk 104, 43.0% BEL and 32.3% PBO pts achieved PERR (OR [95% CI] vs PBO 1.55 [1.04, 2.32], p=0.0311); 30.0% BEL and 19.7% PBO pts achieved CRR (OR [95% CI] vs PBO 1.74 [1.11, 2.74], p=0.0167). Over 104 weeks, more BEL than PBO pts achieved CRR at each visit (Figure 1A). PERR at Wk 52 was achieved by 46.6% BEL and 35.4% PBO pts (OR [95% CI] vs PBO 1.59 [1.06, 2.38], p=0.0245). The risk of a renal-related event or death was 49% lower with BEL than PBO (HR [95%CI] 0.51 [0.34, 0.77]; p=0.0014) at any time point during the study. Overall, 15.7% of BEL and 28.3% of PBO pts experienced a renal-related event or death. When analysed by induction regimen, PERR at Wk 104 was achieved by 33.9% BEL and 27.1% PBO CyC-induced pts (OR [95% CI] vs PBO 1.52 [0.66, 3.49], p=0.3272), and by 46.3% BEL and 34.1% PBO MMF-induced pts (OR [95% CI] vs PBO 1.58 [1.00, 2.51], p=0.0501). CRR at Wk 104 was achieved by 18.6% BEL and 18.6% PBO CyC-induced pts (OR [95% CI] vs PBO 1.07 [0.41, 2.78], p=0.8843), and by 34.1% BEL and 20.1% PBO MMF-induced pts (OR [95% CI] vs PBO 2.01 [1.19, 3.38], p=0.0085). Proportions of pts with uPCR shift from ≥0.5 at baseline to &amp;lt;0.5 while on study (calculated post hoc) are presented in the Figure 1B. Overall, 95.5% BEL and 94.2% PBO pts had ≥1 adverse event (AE); 25.9% BEL and 29.9% PBO pts had ≥1 serious AE; 13.8% BEL and 17.0% PBO pts had serious infections; 12.9% pts in each group had ≥1 AE resulting in study treatment discontinuation; on-treatment fatal AEs were reported in 1.8% BEL and 1.3% PBO pts. Conclusion BEL demonstrated improved renal responses vs PBO in pts with active LN, with a safety profile consistent with previous BEL trials.

SUN-037 NO IMPACT OF NEWLY INITIATED IMMUNOSUPPRESSIVE THERAPY OBSERVED ON LONG-TERM ANTIPROTEINURIC EFFECT OF SPARSENTAN IN FOCAL SEGMENTAL GLOMERULOSCLEROSIS: INTERIM 84-WEEK ANALYSIS OF THE DUET TRIAL

Sparsentan, a first-in-class, orally active, dual-acting, selective antagonist of the angiotensin II type 1 receptor and the endothelin type A receptor, is in development for the treatment of focal segmental glomerulosclerosis (FSGS). In the ongoing DUET trial in patients with FSGS, sparsentan 200, 400, and 800 mg/d resulted in greater reduction in proteinuria versus irbesartan 300 mg/d over an 8-week double-blind period. Sparsentan continues to be evaluated in an open-label extension (OLE) of the DUET trial. Treatment with sparsentan alone in the OLE resulted in further decline in proteinuria over a total of 84 weeks. The current interim 84-week analysis examined whether newly initiated immunosuppressive therapy (IST) in some patients during the OLE contributed to the observed long-term benefits of sparsentan. DUET patients were aged 8-75 years in the US or 18-75 years in the EU and had biopsy-proven FSGS, baseline (BL) urinary protein-to-creatinine ratio (UP/C) ≥1 g/g, and estimated glomerular filtration rate (eGFR) >30 mL/min. In the OLE, patients randomized to double-blind treatment with sparsentan continued sparsentan (SPAR:SPAR) and those randomized to irbesartan were switched to sparsentan (IRB:SPAR). UP/C, FSGS partial remission endpoint (FPRE; UP/C ≤1.5 g/g and >40% UP/C decrease from BL), eGFR, and blood pressure (BP) were measured every 12 weeks to Week 84 and were compared with BL (Week 0 for SPAR:SPAR; Week 8 for IRB:SPAR). Treatment-emergent adverse events (TEAEs) were examined from first dose of sparsentan through Week 84. Data from all patients and from the remaining population after exclusion of data obtained from patients after initiation of new IST in the OLE were analyzed separately. At Week 84, a total of 22% (22/102) of patients in the OLE safety population had initiated a new IST, including cyclosporine, fluorouracil, prednisone, dexamethasone, hydrocortisone, methylprednisolone, mycophenolate mofetil, rituximab, tacrolimus, and triamcinolone. In the SPAR:SPAR group (n=67), sparsentan resulted in rapid, sustained reduction in UP/C from BL (Table). Sixteen (24%) SPAR:SPAR patients received newly initiated IST during the OLE, which had no effect on UP/C decline. In the IRB:SPAR group (n=35), switching to sparsentan resulted in significant reduction in UP/C (Week 16), which was sustained in the OLE, suggesting additional effect of sparsentan following irbesartan cessation (Table). Similar to the SPAR:SPAR group, the IRB:SPAR group showed no effect of newly initiated IST (n=6; 17%) on UP/C decline. The proportion of patients reaching FPRE was similar over the 84 weeks, regardless of use of newly initiated IST, in both the SPAR:SPAR and IRB:SPAR groups. Newly initiated IST had no effect on the course of eGFR or BP in the SPAR:SPAR or IRB:SPAR groups. Sparsentan was well tolerated through Week 84 with similar or slightly lower frequency of TEAEs in SPAR:SPAR and IRB:SPAR patients not initiating new IST versus total patients. Sparsentan in FSGS resulted in sustained and progressive antiproteinuric effects, early BP reduction, and stable eGFR over 84 weeks. Newly initiated IST had no meaningful impact on the effects of sparsentan over 84 weeks of sparsentan treatment in patients with FSGS.

ASK1 contributes to fibrosis and dysfunction in models of kidney disease.

Oxidative stress is an underlying component of acute and chronic kidney disease. Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redox-sensitive serine threonine kinase that activates p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase kinases, and induces apoptotic, inflammatory, and fibrotic signaling in settings of oxidative stress. We describe the discovery and characterization of a potent and selective small-molecule inhibitor of ASK1, GS-444217, and demonstrate the therapeutic potential of ASK1 inhibition to reduce kidney injury and fibrosis. Activation of the ASK1 pathway in glomerular and tubular compartments was confirmed in renal biopsies from patients with diabetic kidney disease (DKD) and was decreased by GS-444217 in several rodent models of kidney injury and fibrosis that collectively represented the hallmarks of DKD pathology. Treatment with GS-444217 reduced progressive inflammation and fibrosis in the kidney and halted glomerular filtration rate decline. Combination of GS-444217 with enalapril, an angiotensin-converting enzyme inhibitor, led to a greater reduction in proteinuria and regression of glomerulosclerosis. These results identify ASK1 as an important target for renal disease and support the clinical development of an ASK1 inhibitor for the treatment of DKD.

Dual Renin-Angiotensin-Aldosterone System Inhibition for the Treatment of Diabetic Kidney Disease: Adverse Effects and Unfulfilled Promise.

Diabetic nephropathy (DN) is a major complication of diabetes mellitus (DM) affecting individuals with type 1 or type 2 DM and is the leading cause of chronic kidney disease and end-stage kidney disease (ESKD) in the USA. Estimates of disease burden are projected to increase, with prevalence of nearly one in five adults by 2050. The role of renin-angiotensin-aldosterone system (RAAS) inhibition in delaying the progression of DN utilizing angiotensin-converting enzyme inhibitors or angiotensin receptor blockers has been well established in multiple controlled trials. Given greater reduction of proteinuria with dual RAAS blockade compared to monotherapy alone, the potential benefit of dual therapy on progression of DN has been tested in three large randomized clinical trials. Unfortunately, results from these studies demonstrated lack of benefit of dual blockade on renal or cardiovascular outcomes in patients with diabetes. The overall objectives of this review are to provide both the rationale for dual blockade as potential therapy as well as review the literature of its use in patients with DN.

Impact of combined losartan/hydrochlorothiazide on proteinuria in patients with chronic kidney disease and hypertension.

It is unknown whether the use of diuretics is optimal over other antihypertensive agents in patients with chronic kidney disease (CKD) whose blood pressure remains uncontrolled despite treatment with renin-angiotensin system (RAS) inhibitors. In this study, we assessed the additive effects of hydrochlorothiazide (HCTZ) on reducing proteinuria in CKD patients under treatment with losartan (LS). We conducted a multicenter, open-labeled, randomized trial. One hundred and two CKD patients with hypertension and overt proteinuria were recruited from nine centers and randomly assigned to receive either LS (50 mg, n=51) or a combination of LS (50 mg per day) and HCTZ (12.5 mg per day) (LS/HCTZ, n=51). The primary outcome was a decrease in the urinary protein-to-creatinine ratio (UPCR). The target blood pressure was <130/80 mm Hg, and antihypertensive agents (other than RAS inhibitors and diuretics) were added if the target was not attained. Baseline characteristics of the two groups were similar. After 12 months of treatment, decreases in the UPCR were significantly greater in the LS/HCTZ group than in the LS group. There were no significant differences in blood pressure or the estimated glomerular filtration rate between the two groups. LS/HCTZ led to a greater reduction in proteinuria than treatment with LS, even though blood pressure in the LS group was similar to that in the LS/HCTZ group following the administration of additive antihypertensive agents throughout the observation period. This finding suggests that LS/HCTZ exerts renoprotective effects through a mechanism independent of blood pressure reduction.

Reduced tubular proteinuria in hypertensive rats treated with losartan is associated with higher renal cortical megalin expression.

Several clinical studies have demonstrated that angiotensin II antagonists exert renoprotective effects beyond blood pressure control in hypertensive patients. The present work aimed to test the hypothesis that the antiproteinuric effects of losartan are associated with upregulation of the multi-ligand endocytic receptors megalin and cubilin in the proximal tubule of spontaneously hypertensive rats (SHR). Fourteen-week-old SHRs were orally treated for 7 weeks with losartan (50 mg/kg, SHR-L), hydralazine (30 mg/kg, SHR-H), or vehicle (SHR-V). Blood pressure and renal function were determined prior to and following drug treatment. Expression of renal cortical proteins was determined by immunoblotting. Losartan and hydralazine reduced systolic blood pressure from pretreatment levels in SHRs to a similar extent. However, SHR-L displayed a much greater reduction in proteinuria than SHR-H (44±3% vs. 15±1%, p<0.01) relative to pretreatment urinary protein excretion levels. In SHRs treated with vehicle, proteinuria increased from 87±5 to 153±15 mg/(day kg BW). Reduced tubular proteinuria in SHRs treated with losartan was accompanied by a higher expression of megalin (125±28%) relative to either SHR-V or SHR-H. Neither losartan nor hydralazine significantly altered the renal cortical expression of cubilin in SHRs. Collectively, our data demonstrate that the additional renoprotective effects of angiotensin II blockade by losartan are associated with upregulation of megalin in the renal proximal tubule of SHRs. Moreover, it strengthens the view that tubular dysfunction may represent an important contributing mechanism underlying proteinuria in hypertension.

T/L-type calcium channel blocker reduces the composite ranking of relative risk according to new KDIGO guidelines in patients with chronic kidney disease.

BackgroundRecently, the Kidney Disease: Improving Global Outcomes (KDIGO) group recommended that patients with chronic kidney disease (CKD) be assigned according to stage and composite relative risk on the basis of glomerular filtration rate (GFR) and albuminuria criteria. The aim of this post-hoc analysis was to investigate the effects of add-on therapy with calcium channel blockers (CCBs) on changes in the composite ranking of relative risk according to KDIGO guidelines. Benidipine, an L- and T-type CCB, and amlodipine, an L-type CCB to angiotensin II receptor blocker (ARB), were examined.MethodsPatients with blood pressure (BP) > 130/80 mmHg, an estimated GFR (eGFR) of 30–90 mL/min/1.73 m2, and albuminuria > 30 mg/gCr, despite treatment with the maximum recommended dose of ARB, were randomly assigned to two groups. Each group received one of two treatments: 2 mg benidipine daily, increased to 8 mg daily (n = 52), or 2.5 mg amlodipine daily, increased to 10 mg daily (n = 52).ResultsAfter 6 months of treatment, a significant and comparable reduction in systolic and diastolic BP was observed in both groups. The eGFR was significantly decreased in the amlodipine group, but there was no significant change in the benidipine group. The decrease in albuminuria in the benidipine group was significantly lower than in the amlodipine group. The composite ranking of relative risk according to the new KDIGO guidelines was significantly improved in the benidipine group; however, no significant change was noted in the amlodipine group. Moreover, significantly fewer cases in the benidipine group than the amlodipine group showed a reduced risk category score.ConclusionThe present post-hoc analysis showed that compared to amlodipine benidipine results in a greater reduction in albuminuria accompanied by an improved composite ranking of relative risk according to the KDIGO CKD severity classification.Trial registrationTrial registration Number: UMIN000002644

Aliskiren reduces home blood pressure and albuminuria in patients with hypertensive nephrosclerosis

The aim of this study was to investigate the antialbuminuric and antihypertensive effects of aliskiren by monitoring home blood pressure (BP) in comparison with the effects of the angiotensin receptor blocker (ARB) valsartan in patients with hypertensive nephrosclerosis and albuminuria. We conducted an open-label, randomized trial to compare the effects of aliskiren with those of valsartan. Patients with BP <150/90mmHg, an estimated glomerular filtration rate of 90-30mL/min/1.73m(2), and albuminuria >30mg/g, despite treatment with a 160mg daily dose of valsartan, were randomly assigned to the following two groups: the aliskiren group, who switched from 160mg/day valsartan to 150mg/day aliskiren, which was later increased to 300mg/day (n=20); and the valsartan group, who continued with 160mg/day valsartan (n=20). After 12weeks of treatment, although there was no significant difference in clinic BP between groups, a significant reduction in morning and evening systolic BP was observed in the aliskiren group. The decrease in albuminuria in the aliskiren group was significantly better than that in the valsartan group, and a significant correlation was noted between the change in morning systolic BP and the change in albuminuria in the aliskiren group (r=0.564, P=0.0084). We showed that aliskiren treatment leads to a greater reduction in albuminuria and home systolic BP values than valsartan in patients with nephrosclerosis. We propose that aliskiren therapy should be considered as a therapeutic modality to complement ARBs in hypertensive patients with nephrosclerosis.

Interaction of eNOS polymorphism with MTHFR variants increases the risk of diabetic nephropathy and its progression in type 2 diabetes mellitus patients

Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients.In hypertensive type 2 diabetic patients, treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with a lower incidence of cardiovascular events than those treated with calcium channel-blocking agents. However, the long-term renal effects of ACE inhibitors in these patients remain inconclusive. In 1989, we commenced a placebo-controlled, double-blind, randomized study to examine the anti-albuminuric effects of enalapril versus nifedipine (slow release) in 102 hypertensive, type 2 diabetic patients. These patients have been followed up for a mean trial duration of 5.5 ± 2.2 years. We examined the determinants, including the effect of ACE inhibition on clinical outcomes in these patients.After a six-week placebo-controlled, run-in period, 52 patients were randomized double-blind to receive nifedipine (slow release) and 50 patients to receive enalapril. After the one-year analysis, which confirmed the superior anti-albuminuric effects of enalapril (-54%) over nifedipine (+11%), all patients were continued on their previously assigned treatment with informed consent. They were subdivided into normoalbuminuric (N = 43), microalbuminuric (N = 34), and macroalbuminuric (N = 25) groups based on two of three 24-hour urinary albumin excretion (UAE) measurements during the run-in period. Renal function was shown by the 24-hour UAE, creatinine clearance (CCr), and the regression coefficient of the yearly plasma creatinine reciprocal (β-1/Cr). Clinical endpoints were defined as death, cardiovascular events, and/or renal events (need for renal replacement therapy or doubling of baseline plasma creatinine).In the whole group, patients treated with enalapril were more likely to revert to being normoalbuminuric (23.8 vs. 15.4%), and fewer of them developed macroalbuminuria (19.1 vs. 30.8%) compared with the nifedipine-treated patients (P < 0.05). In the microalbuminuric group, treatment with enalapril (N = 21) was associated with a 13.0% (P < 0.01) reduction in 24-hour UAE compared with a 17.3% increase in the nifedipine group (N = 13). In the macroalbuminuric patients, enalapril treatment (N = 11) was associated with stabilization compared with a decline in renal function in the nifedipine group, as shown by the β-1/Cr (0.65 ± 4.29 vs. -1.93 ± 2.35 1/μmol × 10-3, P < 0.05) after adjustment for baseline values. Compared with the normoalbuminuric and microalbuminuric patients, those with macroalbuminuria had the lowest mean CCr (75.5 ± 24.1 vs. 63.5 ± 21.3 vs. 41.9 ± 18.5 mL/min, P < 0.001) and the highest frequency of clinical events (4.7 vs. 5.9 vs. 52%, P < 0.001). On multivariate analysis, β-1/Cr (R2 = 0.195, P < 0.001) was independently associated with baseline HbA1c (β = -0.285, P = 0.004), whereas clinical outcomes (R2 = 0.176, P < 0.001) were independently related to the mean low-density lipoprotein cholesterol (β = 2.426, P = 0.018), high-density lipoprotein cholesterol (β = -8.797, P = 0.03), baseline UAE (β = 0.002, P = 0.04), and mean CCr during treatment (β = -0.211, P = 0.006).In this prospective cohort analysis involving 102 hypertensive, type 2 diabetic patients with varying degrees of albuminuria followed up for a mean duration of five years, we observed the importance of good metabolic and blood pressure control on the progression of albuminuria and renal function. Treatment with enalapril was associated with a greater reduction in albuminuria than with nifedipine in the entire patient group, and especially in those with microalbuminuria. In the macroalbuminuric patients, the rate of deterioration in renal function was also attenuated by treatment with enalapril.

Synergistic effects of the MTHFR C677T and A1298C polymorphisms on the increase risk of micro- and macro-albuminuria and progression of diabetic nephropathy among Iranians with type 2 diabetes mellitus

Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients.In hypertensive type 2 diabetic patients, treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with a lower incidence of cardiovascular events than those treated with calcium channel-blocking agents. However, the long-term renal effects of ACE inhibitors in these patients remain inconclusive. In 1989, we commenced a placebo-controlled, double-blind, randomized study to examine the anti-albuminuric effects of enalapril versus nifedipine (slow release) in 102 hypertensive, type 2 diabetic patients. These patients have been followed up for a mean trial duration of 5.5 ± 2.2 years. We examined the determinants, including the effect of ACE inhibition on clinical outcomes in these patients.After a six-week placebo-controlled, run-in period, 52 patients were randomized double-blind to receive nifedipine (slow release) and 50 patients to receive enalapril. After the one-year analysis, which confirmed the superior anti-albuminuric effects of enalapril (-54%) over nifedipine (+11%), all patients were continued on their previously assigned treatment with informed consent. They were subdivided into normoalbuminuric (N = 43), microalbuminuric (N = 34), and macroalbuminuric (N = 25) groups based on two of three 24-hour urinary albumin excretion (UAE) measurements during the run-in period. Renal function was shown by the 24-hour UAE, creatinine clearance (CCr), and the regression coefficient of the yearly plasma creatinine reciprocal (β-1/Cr). Clinical endpoints were defined as death, cardiovascular events, and/or renal events (need for renal replacement therapy or doubling of baseline plasma creatinine).In the whole group, patients treated with enalapril were more likely to revert to being normoalbuminuric (23.8 vs. 15.4%), and fewer of them developed macroalbuminuria (19.1 vs. 30.8%) compared with the nifedipine-treated patients (P < 0.05). In the microalbuminuric group, treatment with enalapril (N = 21) was associated with a 13.0% (P < 0.01) reduction in 24-hour UAE compared with a 17.3% increase in the nifedipine group (N = 13). In the macroalbuminuric patients, enalapril treatment (N = 11) was associated with stabilization compared with a decline in renal function in the nifedipine group, as shown by the β-1/Cr (0.65 ± 4.29 vs. -1.93 ± 2.35 1/μmol × 10-3, P < 0.05) after adjustment for baseline values. Compared with the normoalbuminuric and microalbuminuric patients, those with macroalbuminuria had the lowest mean CCr (75.5 ± 24.1 vs. 63.5 ± 21.3 vs. 41.9 ± 18.5 mL/min, P < 0.001) and the highest frequency of clinical events (4.7 vs. 5.9 vs. 52%, P < 0.001). On multivariate analysis, β-1/Cr (R2 = 0.195, P < 0.001) was independently associated with baseline HbA1c (β = -0.285, P = 0.004), whereas clinical outcomes (R2 = 0.176, P < 0.001) were independently related to the mean low-density lipoprotein cholesterol (β = 2.426, P = 0.018), high-density lipoprotein cholesterol (β = -8.797, P = 0.03), baseline UAE (β = 0.002, P = 0.04), and mean CCr during treatment (β = -0.211, P = 0.006).In this prospective cohort analysis involving 102 hypertensive, type 2 diabetic patients with varying degrees of albuminuria followed up for a mean duration of five years, we observed the importance of good metabolic and blood pressure control on the progression of albuminuria and renal function. Treatment with enalapril was associated with a greater reduction in albuminuria than with nifedipine in the entire patient group, and especially in those with microalbuminuria. In the macroalbuminuric patients, the rate of deterioration in renal function was also attenuated by treatment with enalapril.

Antihypertensive and renoprotective effects of trandolapril/verapamil combination: a meta-analysis of randomized controlled trials

Both trandolapril and verapamil are effective and widely used antihypertensive agents. The aim of this study was to estimate the efficacy and tolerability of trandolapril/verapamil (Tr/Ve) combination for blood pressure control and renoprotection. PubMed, EMBASE and Cochrane Library were searched for relevant studies. A meta-analysis of all randomized controlled trials (RCTs) meeting the criteria was performed. Twelve RCTs were ultimately included out of 62 studies. (1) Combination versus trandolapril: a greater diastolic blood pressure (DBP) reduction (weighted mean difference (WMD): 3.71, 95% confidence interval (CI): 1.84-5.57); a greater reduction in albuminuria (WMD: 136.77, 95% CI: 12.44-261.09). There were no differences in reduction in systolic blood pressure (SBP), blood pressure response rate or proteinuria. (2) Combination versus verapamil: a greater SBP reduction (WMD: 6.14, 95% CI: 3.59-8.70); a greater DBP reduction (WMD: 2.49, 95% CI: 0.81-4.17); a greater reduction in proteinuria (standardized mean difference: 0.84, 95% CI: 0.22-1.45); a greater reduction in albuminuria (WMD: 255.00, 95% CI: 119.26-390.74). (3) Incidence of all-cause adverse events (AEs) was comparable between combination and monotherapy. The present meta-analysis indicates that Tr/Ve combination provides a superior blood pressure control and a favourable renoprotective effect without an increase of overall AEs than verapamil monotherapy. The combination also shows a slight advantage over trandolapril monotherapy by reducing DBP and albuminuria to a greater extent.