Global Trials Focus

January - February 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: General Nephrology

Combination diuretics had a similar effect on kidney function and dyspnoea improvement as stepped doses of furosemide in patients with type 1 cardiorenal syndrome

Trial of the month

The effect in renal function and vascular decongestion in Type 1 cardiorenal syndrome treated with two strategies of diuretics, a pilot randomized trial
Chávez-Iñiguez et al. BMC Nephrol 2022. DOI: 10.1186/s12882-021-02637-y

Reviewed by A Zykova

Summary: In this double-blind trial, 80 patients admitted to hospital with acute decompensation of heart failure and a concomitant acute kidney injury, and meeting criteria for cardiorenal type 1 syndrome, were randomly assigned to stepped furosemide (SF) or combined diuretics (CD) groups for 4 days. Patients in the SF group received a continuous infusion of furosemide with a stepwise dose increase from 100mg on day 1 to 400mg by day 4. Patients in the CD group received a furosemide infusion at 100mg/24 hours with the addition of oral chlorthalidone 50mg and spironolactone 50mg. All patients also received a daily 80mg furosemide bolus, and were on a <1 litre fluid restriction, and a <2.4g sodium restriction. There was no statistically significant difference in the incidence of kidney function recovery after 4 days of treatment (relative risk 1.5, 95% confidence interval 0.4–5.2; p =0.49), although this endpoint only occurred in 8 patients in the SF group and 5 patients in the CD group. After 4 days, the daily urine output had increased by 125mL with stepped furosemide (with a large interquartile range [IQR] of 1662) compared with 200mL with combined diuretics (IQR 988; p for comparison =0.30). There were no significant differences in serum creatinine worsening at 96h, improvement in dyspnoea, in-hospital mortality, mortality at follow-up, or requirement for kidney replacement therapy. The rates of hyponatraemia, hypokalaemia and metabolic acidosis were similar between groups. There were more hypotension events with stepped furosemide (10%) compared with combined diuretics (2.5%).

Comment: Despite the high frequency of cardiorenal syndrome type 1, a lack of large-scale trials has resulted in ongoing uncertainty about the best evidence-based use of diuretics. Diuretic resistance in acute heart failure is associated with kidney impairment, increased risk of rehospitalisation, and mortality. A combined diuretic regimen can potentially overcome this phenomenon and decrease the dosage of loop diuretics to reduce additional RAAS stimulation and further kidney impairment. In this trial the sequential blockade of the renal tubule with a combination of diuretics in patients with cardiorenal syndrome was similar to stepped furosemide alone. Further trials with larger sample size may be needed to answer the question of optimal diuretic therapy in type 1 cardiorenal syndrome more definitively.

ISN Academy: Glomerular Diseases

Searching for effective steroid-sparing regimens in IgA

Leflunomide plus low-dose prednisone in patients with progressive IgA nephropathy: a multicenter, prospective, randomized, open-labeled, and controlled trial
Ni et al. Ren Fail. 2021. DOI: 10.1080/0886022X.2021.1963775

Reviewed by A Gallagher

Summary: One hundred and eight participants with IgA nephropathy (IgAN) on optimal RAS inhibition deemed high risk of progression (proteinuria >1g/day, eGFR <60mL/min/1.73m2 , or histological features suggestive of high risk) were randomised to either leflunomide and low dose steroids (0.5-0.8mg/kg/day with a maximum of 40mg for 12 weeks then 10mg maintenance) or conventional dose steroids alone (1mg/kg/day for 12 weeks with a maximum of 60mg/day then 10mg maintenance). After 12 months of therapy, both groups had significantly lower 24-hour protein excretion, with a median of 0.6g/day in the leflunomide group (range 0.3 to 1.4) from 1.8g/day at baseline (1.3 to 3.5; p<0.01) compared to 0.6g/d (0.3 to 1.0) at 12 months with the conventional prednisone group from a baseline of 1.9 (1.2 to 2.9; p<0.01). Both arms also achieved significantly higher serum albumin concentrations compared to baseline, and serum creatinine and eGFRs remained stable in both groups. These effects were sustained over a total 24 month follow up period. The total amount of prednisone used was significantly lower in the leflunomide arm (21.5mg/day ±13.41 vs. 28.83mg/day ±19.95, p=0.031). There was no difference in the number of adverse advents, which were mostly infectious in nature.

Comment: IgAN is a common cause of kidney disease with a significant proportion of those affected at risk of progression to end-stage kidney disease. Evidence for the role of immunosuppressive agents, including the risk-benefit profile of steroid therapy, remains unclear. This small, single ethnicity study suggests that the combination of leflunomide with lower dose steroids has comparable efficacy and safety in the management of proteinuria in high risk IgAN. Further studies with placebo, leflunomide only, and variable steroid dosing arms would be helpful to differentiate treatment effects from disease evolution, and delineate which treatment offers the best outcome.

ISN Academy: Chronic Kidney Disease

Intervention shows persistent physical activity improvements at 3 years for people with CKD

Effect of a 3-year lifestyle intervention in patients with chronic kidney disease: a randomized clinical trial
Beetham et al. J Am Soc Nephrol 2021. DOI: 10.1681/ASN.2021050668

Reviewed by DV O’Hara

Summary: In the LANDMARK III trial, 160 patients with stage 3–4 CKD were randomised to usual care or a 3-year lifestyle intervention. The intervention included quarterly review with a nurse practitioner-led multi-disciplinary team, a 4-week behaviour and lifestyle modification group program with a clinical psychologist and a dietitian, third-monthly dietitian review, 8 weeks of supervised exercise, and encouragement of ongoing home exercise through regular phone calls. At baseline, 29% of the intervention group met physical activity guidelines, which increased to 63% at 3 years. In contrast, 40% of the usual care group met guidelines at baseline, and this declined to 32% at 3 years (p=0.001). Cardiopulmonary exercise tests at 12 months showed an improvement in peak oxygen uptake (VO2peak) by 9.7% with the intervention, before declining below baseline levels at 3 years, whereas the standard care group gradually declined by 14.7% from baseline to 3 years, with a final result 10.7% lower than the intervention group.

Comment: Clinical experience, and the results of many clinical trials with unsuccessful interventions, attest to the difficulty of effecting behavioural change for patients’ physical activity, and in particular to maintaining improvements in the long term. The LANDMARK III intervention resulted in impressive benefits to physical activity levels and exercise capacity over 3 years, in a population at high risk of adverse cardiovascular outcomes. The program does appear resource intensive and may therefore be difficult to replicate in other settings. Cost-effectiveness analysis of the intervention, including the ability to reduce adverse patient outcomes, would support a case to expand the program to other areas.

ISN Academy: Transplant

High dose or boosted influenza vaccination superior to standard dose regimen among people with kidney transplants with low pre-vaccination antibody titres

An open-label randomized controlled parallel-group pilot study comparing the immunogenicity of a standard-, double-, and booster-dose regimens of the 2014 seasonal trivalent inactivated influenza vaccine in kidney transplant recipients
Odongo et al. Transplantation 2022. DOI: 10.1097/TP.0000000000003702

Reviewed by DV O’Hara

Summary: This open-label study conducted in 2014 randomised 176 patients who had previously undergone kidney transplantation to receive either a standard dose of influenza trivalent vaccine containing 15 microg of each influenza antigen (A/H1N1, A/H3N2, and B), or a high dose of 30 microg of each antigen, or a booster dose regimen involving two standard dose vaccines given 21 days apart. 91.9% of participants had received influenza vaccination the year prior. Among those with high pre-vaccination antibody titres, all three regimens achieved seroprotection rates of 96.4-100% (interquartile range) of their participants. Among those with low pre-vaccination antibody titres, however, only the high dose and booster dose regimens achieved the goal of seroprotection of more than 70% of participants, but only for one antigen each, with inadequate seroprotection rates of 50-65% for the remaining 2 antigens. In this sub-group of low pre-vaccination titres, the single dose regimen achieved lower seroprotection rates for 2 antigens (25% for A/H1N1 and 29.2% for A/H3N2), while all 3 regimens had similarly low rates for the remaining antigen (B antigen; 50-64.3% seroprotection). There were no significant differences in adverse events.

Comment: Kidney transplant recipients are at markedly higher risk of hospitalisation with influenza, and vaccination is a key strategy to prevent this. Known risk factors for poorer vaccination response include mycophenolate use (dose-dependent), older age, a regimen of triple immunosuppression, and lower graft function. The present study adds to the growing body of evidence that high dose or booster regimens offer superior seroprotection than standard dosing, in particular among those with low antibody titres at baseline. This is the first study to compare all three vaccination regimens simultaneously among kidney transplant recipients. The trial does not clearly answer the question of whether the high dose or the booster regimen is the optimum treatment strategy, particularly in light of the wide confidence intervals of the results. Due to the convenience of use, a high dose strategy may be preferable at present, with larger studies required to compare to booster therapy.

ISN Academy: Hypertension

Vitamin D supplementation: not so STURDY after all?

Effects of vitamin D supplementation on orthostatic hypotension: results from the STURDY trial
Juraschek et al. Am J Hypertens 2022. DOI: 10.1093/ajh/hpab147

Reviewed by D Kim

Summary: The Study to Understand Fall Reduction and Vitamin D in You (STURDY) is a double-blind trial conducted between July 2015 to March 2019. This secondary analysis explores the relationship between vitamin D3 supplementation and orthostatic hypotension (OH) in high falls-risk patients aged 70 years and older. 688 participants were randomized to 200 IU/day (n = 339) or 1000+ IU/day (n = 349) of vitamin D3. Sitting and standing blood pressures were measured at baseline, 3-, 12-, and 24- months. OH was defined by a systolic blood pressure drop >20mmHg or diastolic drop >10mmHg. Postural symptoms experienced in the preceding 30 days upon standing were also reported at each follow-up. Baseline sitting and standing blood pressures in the low vs. high-dose groups were 128.8/67.2mmHg and 131.7/69.8mmHg vs. 130.7/67.6mmHg and 133.2/69.8mmHg respectively. At baseline, 2.4% of patients on 200 IU/day and 3.2% on 1000+ IU/day had OH (odds ratio [OR] 1.36, 95% CI 0.54-3.42, p=0.52). There was no significant change in OH rates over time within each individual arm, and no difference between the two groups over the course of the study (OR 0.63, 95% CI 0.25-1.59, p=0.33). The only positive effect of high dose vitamin D3 supplementation on symptoms was the reduction of “bracing yourself after standing” (OR 0.59, 95% CI 0.38-0.92, p = 0.020), although there was no discussion of adjustment for multiplicity of the many symptom outcomes.

Comment: Falls in the elderly are associated with significant morbidity and mortality and place a heavy burden on already strained health care systems. Cost-effective, accessible, and widely implemented interventions for falls prevention are therefore paramount in the perpetually aging society of the developed world. STURDY attempts to address this concern, however the primary results showed no reduction in falls rates with higher vitamin D3 supplementation, and this secondary analysis similarly does not support its use in reducing OH, a known risk factor for falls. Whilst these negative findings may potentially reduce unnecessary pill burden in the elderly, several limitations must first be noted. At baseline, there was a low prevalence of OH, reducing the power of the study, and early OH may have been missed due to the absence of supine blood pressure recordings. The cohort had reasonably well-controlled hypertension and a low rate of diabetes at baseline, thus capturing a population group with reduced risk of OH.

ISN Academy: Glomerulonephritis

Promising results of B-cell depletion with obinutuzumab for the treatment of lupus nephritis

B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebocontrolled trial
Furie et al. Ann Rheum Dis 2022. DOI: 10.1136/annrheumdis-2021-220920

Reviewed by N Bulanov

Summary: In this double-blind, placebo-controlled trial 160 patients with type 2 diabetes and urinary albumin-tocreatinine ratio (uACR) 30 to 300 mg/g were randomized to either colchicine 0.5 mg/day or placebo. All patients received ACE inhibitors or angiotensin receptor blockers for at least 3 months before enrolment. Over 36 months of follow up, the primary end-point of transition to overt nephropathy (uACR >300 mg/g) was registered in 51.4% patients in the colchicine group and in 54.1% patients in the placebo group (HR 1.07, 95% CI 0.68 to 1.67, p = 0.78). None of the patients developed doubling of serum creatinine, the need for renal replacement therapy or died of renal disease, and there were no significant differences in eGFR or uACR. However, the levels of markers of neutrophil-related chronic inflammation (NRCI), including C-reactive protein levels, neutrophil counts and neutrophil-to-lymphocyte ratio, were significantly lower in the colchicine group (all p < 0.05). The rates of adverse events were similar in both groups.

Comment: Type 2 diabetes mellitus is one of the most common causes of CKD worldwide. Previous clinical and experimental studies demonstrated strong associations between NRCI and diabetic kidney disease (DKD) occurrence and progression. However, this RCT showed that continuous NRCI suppression with colchicine does not prevent the progression of early DKD to overt nephropathy. The limitations of the study include relatively small sample-size and short follow-up, that could prevent the detection of long-term outcomes in both groups. In conclusion, the results of the trial do not support the use of colchicine in the treatment of early DKD.

ISN Academy: Pediatric Nephrology

No benefit seen for dexamethasone in the prevention of kidney scarring among children with acute pyelonephritis

Dexamethasone to prevent kidney scarring in acute pyelonephritis: a randomized clinical trial
Rius-Gordillo et al. Pediatr Nephrol 2022. DOI: 10.1007/s00467-021-05398-w

Reviewed by L Myat

Summary: Ninety-one children with acute pyelonephritis aged between 1 month and 14 years were randomised to either a 3- day course of an intravenous dexamethasone 0.30mg/kg/day twice daily or a placebo saline solution. A technetium-99m dimercaptosuccinic acid (DMSA) scan was performed within the first 3 days to confirm the diagnosis of acute pyelonephritis through multifocal or diffuse photopenia and was repeated after at least 6 months to evaluate the persistence of kidney scarring. There was no significant difference in scarring with dexamethasone compared to placebo (22% vs 21%, p = 0.907). The incidence of kidney scarring was also similar between the two groups in subgroup analysis of high-risk features (i.e., age older 2 years, prolonged fever, vesicoureteral reflux, elevated acute phase reactants, or magnitude of kidney damage on DMSA). No safety concerns were reported with dexamethasone: a reduction in the number of fever days with steroids compared to placebo suggests that immunosuppression did not impede recovery from infection.

Comment: Acute pyelonephritis can result in kidney scarring and permanent kidney damage leading to hypertension, proteinuria and chronic kidney disease. The pathogenesis is likely due to activation of inflammatory mediators in infected kidney tissue, providing rationale for a benefit of steroid therapy. Animal studies have supported this concept, and a small RCT of 18 children with acute pyelonephritis at high risk of scarring found a 50% reduction in the likelihood of kidney scars with prednisolone. The current study did not show a benefit of dexamethasone for the risk of kidney scarring. As discussed by the authors, the study was underpowered to detect a difference, as the goal of 80 participants per group was not reached, with many of the screened patients having a normal acute phase DMSA despite a clinical diagnosis of acute pyelonephritis. Further investigation with a larger sample size may be warranted, perhaps restricted to those with greatest risk factors for kidney scarring.

ISN Academy: Peritoneal Dialysis

Which glucose “solution” for automated peritoneal dialysis is optimal: data from OptiStAR pilot trial

Optimised versus standard automated peritoneal dialysis regimens pilot study (OptiStAR): A randomised controlled crossover trial
Bergling et al. Perit Dial In 2022. DOI: 10.1177/08968608211069232

Reviewed by A Zykova

Summary: In order to reduce the burden of glucose absorption during peritoneal dialysis (PD), a new “optimized” glucose regimen has been proposed (Öberg et al, Kidney Int Rep 2017) involving alternation between “clearance cycles” with low or no PD fluid glucose content, and “ultrafiltration cycles” with a higher glucose concentration. In this open-label crossover trial, 21 patients on PD were initially randomized to a session of a standard or optimized regimen of automated PD (APD), then a session of the alternative regimen within 4 weeks. The standard APD regimen consisted of 6×2 litre 1.36% glucose bags delivered over 540 minutes. The optimized APD involved a 280-minute ultrafiltration session with 7×2 litre 2.27% glucose bags followed immediately by a 200-minute clearance session using 5 x 2 litre 0.1% glucose bags. There was no significant difference in the primary outcome of glucose absorption between treatment arms at 44g with the optimized regimen (interquartile range [IQR] 40-55) vs 43g with the standard regimen (IQR 41-54g; p=1). The median ultrafiltration for the optimized regimen was higher than the standard regimen (153mL vs -3mL, p<0.01), as was the weekly clearance (Kt/V for creatinine and urea). The difference in sodium removal was not statistically significant. There were no reported serious adverse events, but one patient had an episode of drainage pain during an optimized regime but continued without further discomfort after a short pause.

Comment: The use of glucose-based dialysis fluids is limited by gradually deteriorating peritoneal membrane structure, and confers a risk of worsening glycemic control. In the present study, a reduction in glucose absorption with “optimized” PD fluid glucose concentration was unfortunately not seen, perhaps owing to the small sample size. The improved ultrafiltration and clearance may relate to the rapidity of PD cycles in the optimized regimen, with twice as many fluid exchanges over a similar amount of time to the standard regimen. Larger-scale and longer-term studies may be required to demonstrate a benefit to glucose absorption and membrane preservation.