Global Trials Focus

October 2022

The ISN-ACT (Advancing Clinical Trials) team presents this monthly round up of randomized trials in nephrology. Trials are selected not just for impact, but also to showcase the diversity of research produced by the global nephrology community. Each trial is reviewed in context and has a risk of bias assessment. We hope to drive improvement in trial quality and promote greater engagement in trial activity.

GTF translations:

ISN Academy: Glomerular Diseases

When weaning is not winning: discontinuation of immunosuppressive treatment in patients with proliferative lupus nephritis was associated with more frequent renal relapse

Trial of the month

Weaning of maintenance immunosuppressive therapy in lupus nephritis (WIN-Lupus): results of a multicentre randomised controlled trial
Jourde-Chiche et al. Ann Rheum Dis (2022).

Reviewed by Anastasiia Zykova

Summary: This multicenter study randomised 96 patients with biopsy-proven proliferative (class III/IV±V) lupus nephritis in complete or partial remission into two parallel arms, where patients continued or ceased their immunosuppressive treatment (IST), to assess the non-inferiority of IST discontinuation regarding renal relapse. All patients were in complete or partial renal remission for at least 12 months and had been receiving standard IST (steroids ≤10md/day with azathioprine (≥50mg/day) or mycophenolate mofetil (≥1000mg/day) or mycophenolate sodium (≥720 mg/day)) for 2-3 years. The follow-up period was 24 months with assessment every 3 months. The frequency of renal relapse was higher in the IST discontinuation group compared with prolonged treatment (27.3% vs 12.5%). The between-group difference was 14.8%, but with wide confidence intervals (95% CI −1.9 to 31.5%). The median time to the first renal relapse after randomization did not significantly differ, but in the discontinuation group severe flares occurred more often (31.8% vs 12.5%, p=0.035) and the period before severe relapse was significantly shorter. The relative changes in eGFR were not reported. Infectious and haematological side effects occurred in comparable proportions. Extrarenal SLE activity, evaluated by the SLEDAI score, was similar between the two groups. IST discontinuation was cost-saving despite higher hospitalization expenses in this group (-40% overall cost, p=0.001).

Comment: The optimal duration of IST in patients with lupus nephritis is still a matter of debate. This is the first RCT comparing the discontinuation or prolongation of IST in proliferative lupus nephritis, and it provides interesting insights. While the majority of patients in both groups remained in remission throughout the study, and no patients developed end-stage kidney disease, the rate of renal relapse was markedly higher with IST discontinuation. Unfortunately, the trial was under-powered, with fewer than half the intended participants, which makes it difficult to quantify the degree of benefit gained by ongoing immunosuppression. While there was no demonstrated difference in rates of infection or haematological abnormalities, prolonged IST would be expected to result in more frequent side effects. Clinicians and patients will likely need to continue to make individually tailored risk-benefit assessments, and this complex decision-making process may need to be incorporated into future research in this area.

ISN Academy: Cardiorenal

Acetazolamide results in more successful fluid decongestion among those hospitalised with acute decompensated heart failure

Acetazolamide in acute decompensated heart failure with volume overload
Mullens et al. N Engl J Med (2022).

Reviewed by Mohamed Elrggal

Summary: The ADVOR Trial (Acetazolamide in Decompensated Heart Failure with Volume Overload) was a multicenter, double-blind placebo-controlled trial, testing the effect of adding 500 mg IV acetazolamide to a standardized loop diuretic regimen to achieve decongestion in acute decompensated heart failure (ADHF). Patients included were presenting to hospital with ADHF defined by clinical signs (edema, pleural effusion or ascites) and either elevated N-terminal Pro B type natriuretic peptide level (>1000pg/ml) or elevated B-type natriuretic peptide level (>250 pg/ml). The trial excluded patients with recent acetazolamide or SGLT2i treatment, eGFR of <20 ml/min/1.73m2, and those receiving more than 80 mg of IV furosemide per day during their hospital stay. Escalation therapies (more diuretics or renal replacement therapy) were mandated when urine output was <3.5L/30-48 hours together with ongoing volume overload. The primary endpoint was successful decongestion (i.e., absence of signs of volume overload) within 3 days of randomization and without the need to escalate the IV loop diuretics. Across 519 patients, successful decongestion occurred in 42.2% of the acetazolamide group and in 30.5% of the placebo group (risk ratio 1.46; 95% CI 1.17-1.82; p<0.001). Key secondary outcomes of death from any cause, or re-hospitalization for heart failure were the same in both groups. The geometric mean length of hospital stay was 8.8 days with acetazolamide compared to 9.9 days with placebo (mean difference 0.89 days, 95%CI 0.81-0.98 days). The rates of adverse effects (worsening kidney function, hypokalemia, hypotension) were similar in each group.

Comment: This well-conducted study showed that the addition of acetazolamide in ADHF resulted in a higher incidence of successful decongestion within 3 days of randomization, faster decongestion, more natriuresis, and shorter hospital stays. The major limitation of this study is that it excluded patients on SGLT2i, in an era where SGLT2i are becoming key therapies for people with heart failure. SGLT2i act on the proximal tubules, and it is not known whether acetazolamide would have similar effects in patients who are already on SGLT2i therapy. Nevertheless, the study provides a strong argument for the addition of acetazolamide for patients with ADHF to enhance decongestion and shorten their hospital stay.

ISN Academy: Glomerular Diseases

When more is not better: intravenous methylprednisolone provides no additional benefit for patients with sarcoidosis tubulointerstitial nephritis

Efficacy and safety of methylprednisolone pulse followed by oral prednisone vs. oral prednisone alone in sarcoidosis tubulointerstitial nephritis: a randomized, open-label, controlled clinical trial
Mahevas et al. Nephrol Dial Transplant (2022).

Reviewed by Nikolay Bulanov

Summary: In this multicenter open-label trial, 40 adult patients with biopsy-proven sarcoidosis tubulointerstitial nephritis, and with acute kidney failure as defined by eGFR <60mL/min/1.73m2 or a 25% increase of serum creatinine level above baseline, were randomized to receive either intravenous methylprednisolone 15mg/kg/day for three consecutive days followed by oral prednisolone 1 mg/kg/day (MP group) or oral prednisolone alone (PRD group). The primary end-point of doubling of eGFR compared to baseline or eGFR returning to ≥60mL/min/1.73m2 at 3 months was achieved less frequently in the MP group (50%) than in the PRD group (80%, p = 0.0467). The median eGFR at months 1, 3, 6 and 12, was, however, similar in both groups, and there was no significant increase in eGFR after the first month of treatment. The rates of adverse events were similar in both arms, the most common being incident and decompensated diabetes.

Comment: Kidney involvement is a rare but potentially severe manifestation of sarcoidosis. High-dose glucocorticoids have remained the standard of care in recent decades, however, the optimal treatment regimen has not been defined. This is the first randomized trial to investigate the role of IV methylprednisolone in the management of sarcoidosis tubulointerstitial nephritis, and found that MP pulses provided no additional benefit to oral prednisolone. The results should be interpreted with some caution owing to the small sample size, which was half of that originally planned, but as a well-conducted trial of a rare condition, it provides helpful evidence to guide the use of glucocorticoids in this group of patients. The finding that the maximum treatment effect was achieved at month 1 highlights the importance of managing this acute period and warrants exploration of other steroid-sparing regimens in patients with kidney sarcoidosis to achieve better results and lower the risks of glucocorticoid therapy.

ISN Academy: Acute Kidney Injury

Multifaceted intervention with clinical decision support and feedback tools could improve risk of acute kidney injury following coronary angiography

Effect of clinical decision support with audit and feedback on prevention of acute kidney injury in patients undergoing coronary angiography: A randomized clinical trial
James et al. J Am Med Assoc (2022).

Reviewed by Lin Lin Myat

Summary: This stepped-wedge, cluster randomized trial recruited 34 interventional cardiologists who conducted coronary angiograms for a total of 7,106 patients with greater than 5% risk of acute kidney injury (AKI). The study was conducted over 2 years and divided into 8 clusters by practice group and center, with a total of 7,820 procedures performed. During the intervention period, cardiologists received a 1-hour education session about AKI and its prevention, clinical decision support including AKI risk prediction and patient-individualized suggestions for safe contrast volume and volume replacement targets guided by left ventricular end-diastolic pressures, as well as audit and feedback on their performance every 3 months. During the pre-intervention or control period, cardiologists provided usual care. The incidence of AKI (defined by serum creatinine–based KDIGO criteria) was lower in the intervention group at 7.2% (310 events after 4,327 procedures) compared to 8.6% (299 events after 3,493 procedures) during the control period (between-group difference, – 2.3% [95%CI, -0.6% to -4.1%]; odds ratio [OR] 0.72 [95%CI, 0.56 to 0.93]; P=0.01). There was no difference in the secondary outcomes of major cardiovascular and kidney events within 30 days.

Comment: AKI is associated with adverse kidney and cardiovascular outcomes. Between 4% and 10% of patients undergoing percutaneous coronary intervention experience AKI, with variation between clinicians and in different studies. Tailored strategies might guide clinicians towards identifying high-risk patients and incorporating tactics to prevent AKI. This study concluded that a multifaceted intervention reduced the incidence of AKI, and the interventions of limiting contrast volume use and increasing intravenous fluid administration did not increase short-term cardiovascular risks. However, this trial was not powered to detect cardiovascular and renal outcomes beyond AKI. The use of only 3 cardiac catheterization laboratories may reduce the study’s generalizability and introduce the risk of physician behavior change prior to the intervention period, as acknowledged by the authors. Further research is needed to explore long-term clinical outcomes of standardized protocols for AKI prevention for patients undergoing coronary angiography, taking into account local practices and resources.

ISN Academy: Cardiorenal

Tolvaptan may safely increase diuresis in advanced CKD and heart failure with preserved ejection fraction

Efficacy of tolvaptan on advanced chronic kidney disease with heart failure: a randomized controlled trial
Komiya et al. J Clin Exp Nephro (2022).

Reviewed by Megan Borkum

Summary: This single-center open-label trial randomized 33 hospitalized patients with stage 3-5 CKD and heart failure with at least one clinical sign of fluid overload to receive either tolvaptan 15mg/d and their usual dose of furosemide, or an augmented dose of furosemide (100mg/day added to their previous dose), for 7 days. All patients were using 20-100mg furosemide daily at recruitment and had a 3-day observation period before the intervention period. Exclusion criteria included anuria, dialysis, hypernatremia, history of tolvaptan use, hypersensitivity to tolvaptan, and difficulty drinking freely. The majority of patients in both groups had heart failure with preserved ejection fraction. The mean baseline furosemide dose was lower in the tolvaptan group at 50.0mg/day compared to 68.6mg/day in the augmented furosemide group. The primary outcome of the change in mean urine volume compared to baseline per day over 7 days (or up to the day of early termination) was significantly greater in the tolvaptan group at 637ml versus 119ml in the furosemide group (p= 0.0029). There was a higher percentage of 7-day weight change with tolvaptan, which did not reach statistical significance (-6.37% vs -4.17%, p=0.052). Tolvaptan was more efficacious in the subgroup of patients with higher urine osmolality and with lower serum sodium before the start of treatment. The incidence of worsening renal function (defined as an increase in serum creatinine of 0.3mg/dl or 26.5μmol/L) was 58.8% in the furosemide group versus 18.8% in the tolvaptan group (p=0.019). Serum sodium decreased significantly in the furosemide group, but not in the tolvaptan group, compared to baseline. No serious adverse effects occurred in either group. Although there was a difference in the baseline dose of furosemide between the two groups, the addition of tolvaptan was an independent factor predictive of increased urine volume after adjustment in a multivariate analysis.

Comment: This trial adds to previous work by the study authors exploring the efficacy of tolvaptan in patients with heart failure who have high urinary osmolality at the start of treatment. Typically, patients with heart failure have elevated ADH which increases water reabsorption (via aquaporin-2 mediated mechanisms) by binding to the V2 receptor in the collecting duct of the kidney tubules with ensuing raised urine osmolality. Tolvaptan is a V2 receptor antagonist which explains why it is scientifically plausible to be beneficial in achieving diuresis among those with heart failure and higher urine osmolality. Although this study encouragingly suggests an alternative, safe pharmacologic treatment option for patients with CKD and heart failure, further studies are needed in larger cohorts, with longer follow-up, including patients with both reduced ejection fraction and advanced CKD.