Ambrisentan as adjunctive therapy for IgA nephropathy: a retrospective single-center analysis.

Prevalence of Anemia in African-Americans with Diabetes Mellitus: Role of Angiotensin Converting Enzyme Inhibitors

IgA Nephropathy: A Disease in Search of a Large-Scale Clinical Trial to Reliably Inform Practice

IgA Nephropathy

Key Points Patients with IgA nephropathy and significant proteinuria are at high risk of progressive kidney function loss and kidney failure.We report the results of a clinical trial assessing the selective endothelin receptor antagonist SC0062 for the treatment of IgA nephropathy.SC0062 led to clinically meaningful improvements in proteinuria and did not increase risk of peripheral edema at higher doses. Background Endothelin receptor type A activation contributes to kidney injury in patients with IgA nephropathy. SC0062 is a novel selective endothelin receptor type A antagonist. We report the results of a phase 2 dose-finding trial to characterize the efficacy and safety of SC0062 in patients with IgA nephropathy. Methods We conducted a randomized, placebo-controlled, double-blind, clinical trial in adults with biopsy-proven IgA nephropathy and eGFR ≥30 ml/min per 1.73 m2 with urine protein-creatinine ratio (UPCR) ≥0.75 g/g or proteinuria ≥1 g/24 hour despite using maximum tolerated doses of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Patients were randomized 1:1:1:1 to 24-week treatment with SC0062 5, 10, and 20 mg or matching placebo once daily. The primary efficacy outcome was percent change from baseline in UPCR in 24-hour urine samples after 12 weeks of treatment. Secondary end points included changes in eGFR. Safety outcomes including treatment-emergent adverse events and serious adverse events were recorded. Results Overall, 131 patients (mean age 42 years [SD 11]; mean eGFR 72 ml/min per 1.73 m2 [SD 24] and median 24-hour UPCR 1.2 g/g [25th–75th percentile, 0.9–1.5 g/g]) were randomized to placebo (n=34) or SC0062 5 mg (n=33), 10 mg (n=32), or 20 mg (n=32). All SC0062 doses reduced UPCR versus placebo throughout treatment. At week 12, placebo-corrected geometric mean changes (95% confidence interval) from baseline in UPCR with SC0062 5, 10, and 20 mg were−27.6% (−43.0 to −8.2), −20.5% (−37.4 to 1.0), and −38.1% (−51.4 to −21.0), respectively, and at week 24 they were−22.4% (−42.2 to 4.3), −30.9% (−48.6 to −7.0), and −51.6% (−64.2 to −34.6), respectively. No differences in eGFR were observed among treatment groups. The proportion of participants with treatment-emergent adverse events or serious adverse events was balanced among treatment groups. Peripheral edema was reported by two (6%), one (3%), one (3%) participants in the 5, 10, and 20 mg SC0062-treated groups, respectively, compared with five (15%) in the placebo group. Conclusions In patients with IgA nephropathy, SC0062 reduced proteinuria and did not increase risk of peripheral edema. Clinical Trial registry name and registration number: A Study to Evaluate the Efficacy and Safety of SC0062 in the Treatment of CKD, NCT05687890. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_10_26_KTS_October2024.mp3

Clinical Challenges in Diagnosis and Management of Diabetic Kidney Disease

Background. Patients with chronic heart failure (chronic HF) are at high risk of cardiovascular death and recurrent hospital admissions. The authors aimed to find out whether the use of an angiotensin receptor blocker could reduce mortality and morbidity. Methods. In parallel, randomized, double-blind, controlled clinical trials, candesartan was compared with placebo in three distinct populations. The authors studied patients with left-ventricular ejection fraction (LVEF) ≤40% who were not receiving angiotensin-converting enzyme (ACE) inhibitors because of previous intolerance or who were currently receiving ACE inhibitors, and patients with LVEF >40%. Overall, 7601 patients (7599 with data) were randomly assigned candesartan (n=3803, titrated to 32 mg q.d.) or matching placebo (n=3796) and followed-up for at least 2 years. The primary outcome of the overall program was all-cause mortality, and the primary outcome for all the component trials was cardiovascular death or hospital admission for chronic HF. Analysis was by intention to treat. Findings. Median follow-up was 37.7 months. Eight hundred eighty-six (23%) patients in the candesartan group and 945 (25%) in the placebo group died (unadjusted hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.83–1.00; p=0.055; covariate adjusted HR, 0.90; 95% CI, 0.82–0.99; p=0.032), with fewer cardiovascular deaths (691 [18%] vs. 769 [20%], unadjusted HR, 0.88; 95% CI, 0.79– 0.97; p=0.012; covariate adjusted HR, 0.87; 95% CI, 0.78–0.96; p=0.006) and hospital admissions for chronic HF (757 [20%] vs. 918 [24%]; p<0.0001) in the candesartan group. There was no significant heterogeneity for candesartan results across the component trials. More patients discontinued candesartan than placebo because of concerns about renal function, hypotension, and hyperkalemia. Interpretation. Candesartan was generally well tolerated and significantly reduced cardiovascular deaths and hospital admissions for HF. Ejection fraction or treatment at baseline did not alter these effects.—Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;362:759–766. Comment. The Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARMOverall) program is the largest trial program ever undertaken in chronic HF patients. The 7601-patient trial evaluated candesartan in addition to optimal treatment for HF and was made up of three smaller studies in separate populations: patients with left ventricular (LV) dysfunction intolerant to ACE inhibitors (the CHARM-Alternative trial),1 patients with LV dysfunction already taking ACE inhibitors (the CHARM-Added trial),2 and patients with preserved LV function (the CHARM-Preserved trial).3 These three different populations of patients with HF were studied individually and concurrently as a group. For this study design to be successful, each trial had to be similar in terms of inclusion and exclusion criteria, drug therapy utilized, and dose of drug used. This was necessary for data to be combined into the CHARM-Overall program to determine total mortality. In addition, each individual trial had adequate statistical power for analysis in each separate chronic HF population. For the CHARM-Alternative trial, investigators enrolled 2028 patients with symptomatic HF and LVEF ≤40% who were not receiving ACE inhibitors because of previous intolerance. Patients were randomly assigned candesartan (target dose 32 mg q.d.) or matching placebo. The primary outcome of the study was the composite of cardiovascular death or hospital admission for HF. Analysis was by intention to treat. The most common manifestation of ACE-inhibitor intolerance was cough (72%), followed by symptomatic hypotension (13%) and renal dysfunction (12%). During a median follow-up of 33.7 months, 334 (33%) of 1013 patients in the candesartan group and 406 (40%) of 1015 in the placebo group had cardiovascular death or hospital admission for chronic HF (unadjusted HR, 0.77; 95% CI, 0.67–0.89; p=0.0004; covariate adjusted HR, 0.70; 95% CI,0.60–0.81; p<0.0001). Each component of the primary outcome was reduced, as was the total number of hospital admissions for chronic HF. No statistical difference in overall drug discontinuations (21% candesartan vs. 19% placebo) was found, but there were significant increases in discontinuations due to hypotension (3.7% vs. 0.9%), increased creatinine levels (6.1% vs. 2.7%), and increased potassium levels (1.9% vs. 0.3%) in the candesartan group. Despite intolerance to ACE inhibitors, patients can tolerate candesartan and show a reduction in morbidity/mortality, but we still need to monitor hypotension, creatinine, and potassium. Candesartan was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic chronic HF and intolerance to ACE inhibitors. Over the duration of the trial, 33% of candesartan compared with 40% of placebo patients had cardiovascular death or first admission to hospital for chronic HF. This absolute reduction of seven major events per 100 patients treated corresponds to the need to treat 14 patients with candesartan to prevent one patient from having cardiovascular death or hospital admission for HF. In addition, multiple chronic HF hospital admissions were reduced. Adequate attempts should be made to place patients with chronic HF and reduced LVEF on ACE inhibitors and β blockers; however, irrespective of the tolerance of an ACE inhibitor, the addition of candesartan improves outcome. In conclusion, candesartan was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic chronic HF who were not receiving ACE inhibitors because of intolerance. For the CHARM-Added trial, the investigators enrolled 2548 patients with New York Heart Association functional class II-IV, chronic HF, LVEF ≤40%, and who were being treated with ACE inhibitors. They randomly assigned patients to candesartan (n=1276, target dose 32 mg q.d.) or placebo (n=1272). At baseline, 55% of patients were also treated with β blockers and 17% were treated with spironolactone. The primary outcome of the study was the composite of cardiovascular death or hospital admission for chronic HF. Analysis was done by intention to treat. The median follow-up was 41 months. Four hundred eighty-three (38%) patients in the candesartan group and 538 (42%) in the placebo group experienced the primary outcome (unadjusted HR, 0.85; 95% CI, 0.75–0.96; p=0.011; covariate adjusted p=0.010. Candesartan reduced each of the components of the primary outcome significantly, as well as the total number of hospital admissions for chronic HF. The benefits of candesartan were similar in all predefined subgroups, including patients receiving baseline β-blocker treatment. Overall, the addition of candesartan to ACE inhibitor and other treatment leads to a further clinically important reduction in relevant cardiovascular events in patients with chronic HF and reduced LVEF. The results of the CHARM-Added trial differ in some ways from those of the Valsartan Heart Failure Trial (Val-HeFT). Like the CHARM-Added trial, Val-HeFT studied the effect of an angiotensin receptor blocker in HF patients, 93% of whom also received treatment with an ACE inhibitor. While Val-HeFT did show a reduction in the combined end point of morbidity and mortality in valsartan patients compared with placebo, it did not show a significant decrease in total or cardiovascular mortality. Also, it demonstrated an increase in mortality in a subgroup of patients who were receiving a β blocker in addition to an ACE inhibitor and valsartan. It was postulated that extensive blockade of multiple neurohormonal systems in patients with chronic HF may be detrimental. In contrast, patients in the CHARM-Added trial who received the triple therapy combination of ACE inhibitor, β blocker, and angiotensin receptor blocker, the benefit was explained by the different angiotensin receptor blockers utilized or the dose of these agents employed. Another possible explanation is that subgroup analyses (like the one used in Val-HeFT) are often underpowered, and the results may have occurred due to chance. Candesartan had a similar rate of mortality compared with patients not treated with a β blocker. The CHARM-Preserved trial investigators randomly assigned 3023 patients to candesartan (n=1514, target dose 32 mg q.d.) or matching placebo (n=1509). Patients had New York Heart Association functional class II-IV, chronic HF, and LVEF >40%. The primary outcome was cardiovascular death or admission to a hospital for chronic HF. Analysis was done by intention to treat. Median follow-up was 36.6 months. Three hundred thirty-three (22%) patients in the candesartan and 366 (24%) in the placebo group experienced the primary outcome (unadjusted HR, 0.89; 95% CI, 0.77–1.03; p=0.118; covariate adjusted HR, 0.86; 95% CI, 0.74–1.0; p=0.051). Cardiovascular death did not differ between groups (170 vs. 170), but fewer patients in the candesartan group than in the placebo group were admitted to a hospital for chronic HF once (230 vs. 279; p=0.017) or multiple times. Composite outcomes that included nonfatal myocardial infarction and nonfatal stroke showed results similar to the primary composite (388 vs. 429; unadjusted HR, 0.88; 95% CI, 0.77–1.01; p=0.078; covariate adjusted HR, 0.86; 95% CI, 0.75–0.99; p=0.037). Candesartan has a moderate impact in preventing admissions for chronic HF among patients who have HF and LVEF >40%. The management of patients with preserved LVEF and HF is based on sparse data. This trial provides direct information on this large group of patients with HF. Among patients with preserved LVEF who have no contraindications, candesartan reduces the number of hospital admissions for chronic HF. It is not absolutely conclusive, but it is highly persuasive. We need more data on this group. This should be the beginning of many studies in this population, and the results of the Irbesartan in chronic HF Patients With Preserved LV Function (I-PRESERVE) trial are anxiously awaited. All patients were considered in the CHARM-Overall trial, with a primary end point of all-cause mortality. This was reduced by 9%, which was borderline significant in the unadjusted analysis (p=0.055); the p value dropped to 0.032 after adjustment for baseline variables. Cardiovascular death was also significantly reduced by 12%, and cardiovascular death and HF hospitalization, the primary end point of the component trials, was reduced by a highly statistically significant 16%, wagain mostly driven by a reduction in hospitalization. There was no effect of candesartan on myocardial infarction, stroke, or revascularization procedures, but a significant reduction in the development of new diabetes was seen with the angiotensin II blocker (7.6% placebo vs. 6.0% candesartan; HR, 0.78; p=0.02). In terms of side effects in the CHARMOverall program, as in the individual trials, candesartan was associated with significant increases in hypotension (3.5% vs. 1.7%), serum creatinine levels (6.2% vs. 3.0%), and hyperkalemia (2.2% vs. 0.6%). CHARM-Overall suggests that 23 patients need to be treated with candesartan for 3 years to prevent one cardiovascular death or chronic HF hospitalization. In an editorial in The Lancet, Dr. Harvey White of Green Lane Hospital, Auckland, New Zealand, calculates that over 3 years the treatment effect seen in CHARM equates to one death prevented per 63 patients treated, one first hospitalization with HF prevented per 23 patients treated, and one new case of diabetes prevented per 71 patients treated.

<scp>ACE Inhibitor</scp>s and <scp>ARB</scp>s: Do They Reduce the Risk of Cancer?

Oral Calcitriol for the Treatment of Persistent Proteinuria in Immunoglobulin A Nephropathy: An Uncontrolled Trial

POS-380 A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF ATRASENTAN IN PATIENTS WITH IGA NEPHROPATHY (THE ALIGN STUDY)

The authors conclude that, in patients with renal insufficiency (serum creatinine>1.4 mg/dL) treated with ACE inhibitors, there is a strong association between early (within the first 2 months) and moderate (not exceeding 30% over baseline) rise in serum creatinine and slowing of the renal disease progression in the long run. The authors recommend that ACE inhibitor therapy should not be discontinued unless serum creatinine level rise above 30% over baseline during the first 2 months after initiation of therapy or hyperkalemia (serum potassium level >or=5.6 mmol/L) develops.

Background/Aimsβ2-microglobulin (β2-MG) is freely filtered at the glomerulus and subsequently reabsorbed and catabolized by proximal renal tubular cells. Urinary β2-MG is an early and sensitive biomarker of acute kidney injury; however, its utility as a biomarker of immunoglobulin A nephropathy (IgAN) is unclear.MethodsWe included urinary β2-MG levels in the routine laboratory examination of all inpatients with biopsy-proven IgAN at our hospital from 2006 to 2010. We retrospectively analyzed the correlation between β2-MG levels and clinical parameters as a prognostic biomarker of IgAN.ResultsA total of 51 patients (30 males, 21 females; mean age, 33.01 ± 12.73 years) with IgAN were included in this study. Initial demographic, clinical, and laboratory data for all patients are listed. The mean initial estimated glomerular filtration rate and 24-hour urine protein levels were 94.69 ± 34.78 mL/min/1.73 m2 and 1.28 ± 1.75 g/day, respectively. The mean level of urinary β2-MG was 1.92 ± 7.38 µg/mg creatinine. There was a significant correlation between initial serum creatinine (iSCr), urine protein creatinine ratio (UPCR), and the level of β2-MG (r = 0.744, r = 0.667, p < 0.01). There was also a significant correlation between renal function tests and the level of urinary β2-MG (p < 0.01). Cox regression analysis showed that albumin, β2-MG, iSCr, and UPCR were significant predictors of disease progression in IgAN.ConclusionsUrinary β2-MG levels showed a significant correlation with renal function and proteinuria in IgAN. Thus, we propose that urinary β2-MG may be an additional prognostic factor in patients with IgAN.

Study Design and Baseline Characteristics of ALIGN, a Randomized Controlled Study of Atrasentan in Patients With IgA Nephropathy

Section 7: Heart Failure in Patients With Left Ventricular Systolic Dysfunction

Резюме. Актуальність. Інфікування SARS-CoV-2 пацієнтів з хронічною хворобою нирок (ХХН) та артеріальною гіпертензією 1-2-го ступеня погіршує стан серцево-судинної системи та може сприяти реалізації негативних серцево-судинних подій та ниркових ризиків. Наявність хронічної хвороби нирок у поєднанні з артеріальною гіпертензією 1-2-го ступеня та її медикаментозною корекцією інгібіторами ренін-ангіотензин-альдостеронової системи (РААС) значно впливає на стан здоров'я пацієнтів, які інфіковані SARS-CoV-2. SARS-CoV-2 як інструмент для проникнення в клітину використовує РААС, а саме рецептор ангіотензинперетворюючого ферменту 2 (АПФ-2). Для вибору подальшої тактики лікування це поєднання трьох патологічних станів потребує ретельного аналізу і дослідження. Мета дослідження: вивчення функціонального стану нирок у пацієнтів з ХХН та артеріальною гіпертензією,

Background and Aims Immunoglobulin A nephropathy (IgAN) is the leading cause of primary glomerulonephritis with limited treatment options. Zigakibart is an investigational, humanised monoclonal antibody that blocks A PRoliferation-Inducing Ligand (APRIL), a cytokine which promotes pathogenic galactose-deficient IgA1 (Gd-IgA1) production, leading to inflammation and kidney injury. Herein, we report changes in proteinuria and kidney function according to patient subgroups defined using categories of baseline Gd-IgA1 in the ongoing Phase 1/2 trial of zigakibart. Method ADU-CL-19 is an ongoing Phase 1/2 trial (NCT03945318) of zigakibart. Part 3 of the study enrolled patients aged ≥18 years with biopsy-proven IgAN, total urine protein of ≥0.5 g/24 h or 24 h urine protein-to-creatinine ratio (UPCR) of ≥0.5 g/g, estimated glomerular filtration rate (eGFR) of ≥30 mL/min per 1.73 m2, and on a stable/optimised dose of renin–angiotensin system inhibitor (RASi) for ≥3 months before screening (or RASi intolerant). Patients received zigakibart 450 mg once every 2 weeks (Q2W) intravenously, transitioning to 600 mg Q2W subcutaneously (SC) at ≥24 weeks (Cohort 1, n = 10) or 600 mg Q2W SC (Cohort 2, n = 30) for up to 124 weeks. In this exploratory analysis, patients were categorised into four subgroups according to quartiles of baseline Gd-IgA1 level. The subgroups were defined as (1) ≤Q1, (2) &amp;gt;Q1 and ≤median, (3) &amp;gt;median and ≤Q3, and (4) &amp;gt;Q3. UPCR and eGFR percent changes from baseline to Week 76 were calculated for each Gd-IgA1 quartile subgroup and reported descriptively. Results Clinical outcomes from baseline to Week 76 were comparable in all subgroups defined by Gd-IgA1 at baseline. Mean Gd-IgA1 percent change from baseline was −74.4% for the overall population. Mean UPCR percent changes from baseline were −49.8%, −60.9%, −70.2%, and −60.9% for Gd-IgA1 subgroups 1, 2, 3, and 4, respectively (Fig. 1). Mean eGFR percent changes from baseline were −6.93%, 6.25%, 2.63%, and 7.59% for Gd-IgA1 subgroups 1, 2, 3, and 4, respectively (Fig. 2). Conclusion Following 76 weeks of zigakibart treatment patients achieved 74.4% mean percent reduction of Gd-IgA1. Zigakibart provides clinically meaningful treatment benefits in terms of proteinuria reduction and eGFR stabilisation in patients with IgAN, independent of their baseline Gd-IgA1 levels.