Global Trials Focus

November 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: Chronic Kidney Disease

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers show reassuring renal safety profile in advanced kidney disease

Trial of the month

Renin–angiotensin system inhibition in advanced chronic kidney disease
Bhandari et al., N Engl J Med (2022)..

Reviewed by Anastasiia Zykova

Summary: : In this open-label trial, 411 patients with CKD 4-5 from 37 medical centers in England were randomized to continue or discontinue renin-angiotensin system (RAS) inhibitors. Patients were required to have had progression of their CKD over the 2 years before enrolment, defined as eGFR deterioration >2ml/min/1.73m2 per year, and to have received a RAS inhibitor for at least 6 months prior to the trial. The median age was 63 years, 68% were men, 85% were white, the median eGFR was 18ml/min/1.73m2 , and the median level of proteinuria was 115mg/mmol. The underlying causes of CKD included diabetic nephropathy (21%), hypertensive or renovascular nephropathy (17%), genetic diseases (including ADPKD, in 20%) and glomerulonephritis without having received immunosuppression (18%). At 3 years, the least-squares mean eGFR was similar between the two groups at 12.6±0.7 ml/min/1.73 m2 in the discontinuation group and 13.3±0.6 ml/min/1.73 m2 in the continuation group (difference, −0.7; 95% CI, −2.5 to 1.0; p=0.42). The frequency of ESKD or renal-replacement therapy was also comparable at 62% in the discontinuation group and 56% in the continuation group (adjusted HR, 1.28; 95% CI, 0.99 to 1.65). The total numbers of hospitalization events for any reason were similar in the discontinuation group and the continuation group (414 vs 413, respectively, including 108 vs 88 cardiovascular cases), as were deaths (20 vs 22, respectively) and serious adverse events (107 vs 101).

Comment: RAS inhibitors have well-established benefits for lowering blood pressure, reducing proteinuria and slowing the progression of CKD in its milder stages, but the risk/benefit ratio in advanced kidney disease is less clear. Observational studies had raised concerns about RAS inhibitors contributing to unstable renal function, but this had not been assessed in a large, randomized trial, and premature discontinuation of RAS could contribute to higher blood pressure and increased cardiovascular risk. This high-quality study found no increase in kidney or cardiovascular risk among those continuing RAS inhibition in advanced kidney disease, although it was not powered to detect a difference in cardiovascular events. While the nephroprotective effects are likely diminished at low levels of kidney function, there was no evidence of lower eGFR or higher ESKD rates with continuation, and cardiovascular events were numerically lower. Further research with more balanced ethnicity, and among those with high-range proteinuria, would be beneficial.

ISN Academy: Dialysis

Over a 6-month period, low-dose atorvastatin can safely and effectively prevent worsening arterial stiffness in non-diabetic hemodialysis patients

Atorvastatin can delay arterial stiffness progression in hemodialysis patients
Elsayed M, et al. Int Urol Nephrol. (2022) 54:2969–2976..

Reviewed by Megan Borkum

Summary: This double-blind, placebo-controlled trial randomized 50 maintenance hemodialysis (HD) patients from two clinical centers to receive either atorvastatin 10mg/d or a placebo for 6 months to prevent arterial stiffness. Exclusion criteria included diabetes mellitus, an irregular heart rhythm, a history of aortic surgery, a history of myocardial infarction in the previous 6 months, and those already receiving lipid-lowering drugs. The Mobil-O-Graph device, which uses brachial oscillometric blood pressure (BP) waves for non-invasive estimation of aortic BP, was used to determine the primary outcome of arterial stiffness indices, pulse wave velocity (PWV) and augmentation index (AIx). These measurements were taken at baseline and at 6 months. There were no significant baseline differences (including duration of HD, age and BP) between the atorvastatin and placebo groups. At 6 months, aortic PWV remained stable in the atorvastatin group (7.88 vs 7.86, p=0.136), as did Aix (26.0 vs 26.04, p=0.714), but these indices showed statistically significant increases in the placebo group (7.63 vs 7.80, p<0.001 for PWV and 25.04 vs 25.88, p< 0.0001 for Aix), with a statistically significant difference in mean change from baseline when the two groups were compared. Peripheral and central BP parameters (systolic BP, diastolic BP, pulse pressure) were not significantly different between atorvastatin and placebo groups either at baseline or after 6 months.

Comment: The benefits of statins in secondary prevention of cardiovascular events are well-established in the general population, but no benefit was seen for dialysis patients in the 4-D or AURORA trials. Adults treated with dialysis experience cardiovascular complications as a result of myocardial hypertrophy and fibrosis as well as vascular calcification and stiffness, disease processes that are less modifiable by statin therapy than occlusive atherosclerosis. This trial is novel as arterial stiffness is assessed as the outcome in non-diabetic HD patients, in contrast to the 4-D study where all participants had diabetes, and the AURORA study where ~25% had diabetes, and it’s conceivable that diabetes could negate the effect of statins, hence warranting further investigation in those without diabetes. Although the study’s findings might suggest a potential role for atorvastatin to delay arterial stiffness progression in such patients, larger RCTs with longer follow-up periods are needed to confirm these findings. Further, a change in pulse wave velocity and augmentation index is a surrogate outcome for cardiovascular disease, how much of this would actually translate into a change in clinical outcomes is uncertain.

ISN Academy: Acute Kidney Injury

Regularly dosed acetaminophen can improve renal function in patients with severe Plasmodium knowlesi malaria and hemolysis

The effect of regularly dosed acetaminophen vs no acetaminophen on renal function in Plasmodium knowlesi malaria (PACKNOW): a randomized, controlled trial
Cooper et al. Clin Infect Dis (2022)..

Reviewed by Maria Chiara Pelle

Summary: In this open-label trial, 365 Malaysian patients with malaria caused by Plasmodium knowlesi were randomized to receive acetaminophen (paracetamol; 500 mg or 1000 mg every 6 hours for 72 hours) or usual care, which included giving acetaminophen if fevers remained higher than 39.5ºC for >30 min despite other treatment. Median age was 36 years, 85% were male, the diagnosis in all cases was confirmed by PCR, and all patients received antimalarial drugs. There was no difference in the change in log-transformed creatinine level during the first three days (a reduction of 14.9% and 14.6% in the acetaminophen and control groups, respectively). Subgroup analysis revealed that in patients with severe malaria and haemolysis, the creatinine decreased by 35.8 % (SD, 26.7) over 72 hours in the acetaminophen arm, compared with 19.0% (SD, 16.6) in the control arm (p = 0.07). Similar results were seen in patients with AKI and haemolysis, when creatinine decreased by a mean 34.5% (SD, 20.7) over 72 hours in the acetaminophen arm compared with 25.8% (SD, 15.8) in control group (P =0.041). Treatment was well-tolerated, with no cases of hepatoxicity or fatal outcomes.

Comment: Malaria caused by Plasmodium knowlesi is very common in Malaysia and some regions of western Indonesia and is characterized by prominent hemolysis and risk of acute kidney injury. Previous trials in other hemolysis contexts demonstrated that acetaminophen can improve renal function by reducing ferryl heme formed from the cell-free haemoglobin through inhibition of prostaglandin H2-synthase, which could otherwise initiate oxidative stress. This benefit was demonstrated with acetaminophen usage for kidney outcomes in patients with severe falciparum malaria with hemolysis (Plewes et al, Clin Infect Dis 2018). As a result, it was hoped that acetaminophen could show nephroprotective effects in patients with P. knowlesi, particularly since this form of disease is characterized by higher concentration of cell-free haemoglobin. While this hypothesis was not confirmed in the full study population, subgroup analysis suggest that such an approach may be beneficial for patients with hemolysis and a severe course of disease, which should be investigated by future trials.

ISN Academy: Chronic Kidney Disease

Chlorthalidone amplifies the efficacy of bumetanide for the treatment of volume overload and hypertension in CKD stage 4-5 without kidney replacement therapy

Effect of the combination of bumetanide plus chlorthalidone on hypertension and volume overload in patients with chronic kidney disease stage 4–5 KDIGO without renal replacement therapy: a double‑blind randomized HEBE‑CKD trial
Solis-Jimenez et al. BMC Nephrology (2022)..

Reviewed by Nikolay Bulanov

Summary: In this single center, double-blind study, 34 adult patients with CKD stage 4-5 (without kidney replacement therapy), uncontrolled hypertension (systolic BP>140 mmHg and/or diastolic BP>90 mmHg), volume overload and loop diuretic use for ≥3 months, were given bumetanide 3 mg daily and were randomized to either combination therapy with chlorthalidone 50 mg or to placebo. Volume overload was diagnosed by bioelectrical impedance analysis and defined as fluid volume above the 90th percentile of a presumed healthy reference population. The median total body fluid was similar at 32.7L for the experimental group compared to 33.1 for the control group. Between baseline and day 7, the combination therapy resulted in a significantly greater reduction in total body water (-2.5L vs -0.59 L in the control group, p=0.003) and in extracellular water (-1.58 vs -0.43L, p=0.028). By day 30, extracellular water was markedly lower with the combination treatment (-3.05 vs -0.15L, p<0.001), and there was also a significantly more prominent decrease in systolic BP (-26.1 vs -10 mmHg p=0.028) and diastolic BP (-13.5 vs. 3.4 mmHg, p =0.018). The most common adverse event was the rise in serum creatinine >0.3 mg/dL that occurred in 11 patients in the chlorthalidone group and in 4 patients in the placebo group (p=0.013). However, a doubling of serum creatinine levels was not observed in any of these cases.

Comment: Volume overload and poorly controlled hypertension are among the most common problems in people with advanced CKD stages. A combination of loop and thiazide diuretics has been successfully used for decades in patients with heart failure and nephrotic syndrome, however, the efficacy of this regimen in CKD stages 4-5 has not been thoroughly investigated. HEBE-CKD trial showed that the addition of chlorthalidone dramatically increases short-term efficacy of the loop diuretic in the treatment of fluid overload, assessing by bioimpedance analysis, and hypertension in this category of patients. However, the long-term efficacy and safety of thiazide diuretics in this setting should be tested in further trials.

ISN Academy: Chronic Kidney Disease

The expanding EMPire of SGLT2-inhibitors: empagliflozin decreases CKD progression including in patients with advance stages not requiring kidney replacement therapy

Empagliflozin in patients with chronic kidney disease
The EMPA-KIDNEY Collaborative Group N Engl J Med (2022)..

Reviewed by Chiara Abenavoli

Summary: The EMPA-KIDNEY study was a multicenter double-blinded placebo control trial, designed to evaluate the effects of empagliflozin 10 mg/d in patients with CKD with eGFR 20-25mL/min/1.73m2 regardless of proteinuria, or eGFR 45-90mL/min/1.73m2 with an albumin-creatinine ratio of ≥200mg/g. The study randomized 6604 patients; the mean age was 83.8 years, 33.2% were women, 54% were diabetic, mean eGFR was 37.3 ml/min/1.72m2 , 34.5% of patients had eGFR less than 30 ml/min/1.72m2 , median urinary albumin-to-creatinine ratio was 329mg/g, and all patients received appropriate dosage of RAS blockers. The composite primary outcome included progression of kidney disease (progression to end-stage kidney disease, kidney replacement therapy, sustained decrease in eGFR to <10 mL/min/1.73 m2 or  ≥ 40% decline from baseline, and death from renal causes) or death from cardiovascular diseases. The total follow-up period was 2 years. The primary outcome occurred in 13.1% of patients treated with empagliflozin compared with 16.9% of patients in the placebo group (HR 0.72; 95%CI 0.64 to 0.82, p<0.001). The rate of hospitalization from any cause was lower in the treatment arm, but no significant difference regarding hospitalization for cardiovascular diseases was seen (4% in the treatment arm and 4.6% in the control arm, HR 0.84; 95% CI 0.67 1.07, p=0.15). In subgroup analysis, the beneficial effects of treatment were seen regardless of diabetic status and eGFR, but the risk reduction was higher in patients with more prominent albuminuria (albumin-tocreatinine ratio >300mg/g). Ketoacidosis was seen in 0.2% patients of empagliflozin group and in <0.1% (1 patient) of the control group, while severe hypoglycemia was seen in 2.3% of patients in both groups. There were no statistically significant differences in other adverse effects including mortality, serious acute kidney injury, severe genital infection or serious urinary tract infection.

Comment: The use of SGLT2-inhibitors, as already demonstrated in the large, high-quality trials such as CREDENCE (canagliflozin; see Global Trials Focus review), and DAPA-CKD (dapagliflozin), reduces the progression of renal damage and cardiovascular events. EMPA-KIDNEY has broader eligibility criteria, including advanced CKD with a minimum eGFR of 20 mL/min/1.73 m2 and varying degrees of albuminuria in a larger cohort. As expected, EMPA-Kidney demonstrated a benefit for the primary composite outcome of CKD progression or death from cardiovascular diseases and for the secondary outcome of hospitalization rate for any cause. These results were included in the recently published large-scale meta-analysis SMART-C, which found SGLT2 inhibitors decrease the risk of CKD progression by 37% (RR 0·63, 95% CI 0·58–0·69) and of the composite outcome of CV death or hospitalization for heart failure by 23% (RR 0·77, 95% CI 0·74–0·81) irrespective of diabetes status. There is at least one ongoing trial (NCT05374291) which will examine the role of the SGLT2 inhibitor, dapagliflozin, in the management people receiving kidney replacement therapy or with a functioning kidney transplant.

ISN Academy: Dialysis

Anakinra’s ACTION in hemodialysis patients seems to be safe, but is it effective?

A randomized controlled pilot trial of anakinra for hemodialysis inflammation
Dember et al., Kidney Int. (2022).

Reviewed by Anastasiia Zykova

Summary: ACTION was a pilot double-blind multicenter trial, in which 80 hemodialysis patients were randomized to receive anakinra (IL-1 receptor antagonist) or placebo three times a week during dialysis sessions for 24 weeks, and were then followed for the next 24 weeks to assess safety. The eligibility criteria included high-sensitivity C-reactive protein (hsCRP) level ≥2.0 mg/l at two consecutive screening visits within 10 days before randomization. Patients with a haemodialysis central venous catheter were excluded. At baseline, study groups were well-balanced, except for the age of patients in experimental group, which was slightly higher (59.6 vs 54.1 years). The median duration of HD was 4.4 years, and 41.2% of patients were white. While the median decrease in log-transformed hsCRP concentration over 24 weeks was 41% with anakinra compared with 6% with placebo, the difference between groups was not statistically different. There was, however, a significant reduction in the level of IL-6 of 0.7 pg/ml in the anakinra group compared to this level remaining stable in the placebo group (p = 0.02 for between-group difference). The number of adverse events was numerically lower in the anakinra group (96 vs 129), and the rate of adverse events of interest (predominantly infection) was lower in the anakinra group (0.48 per patient-year vs 1.40 per patient-year; p = 0.01). Eight patients were withdrawn from experimental and control group (21.1% vs 19.0%, respectively); the most common reasons for this were death (not deemed as related to study drug) and kidney transplantation (six cases in each clinical scenario). The permanent discontinuation of the study drug for a medical reason (infection, cytopenia, kidney transplantation) occurred in 4 participants in the anakinra group and 5 participants in the placebo group.

Comment: Inflammation is a well-known factor accelerating atherosclerosis, while increasing levels of inflammatory biomarkers are associated with high cardiovascular risks. Unfortunately, it is still unclear whether medications to reduce inflammation can improve long-term cardiovascular outcomes in patients with kidney disease. According to the results of this pilot trial, anakinra was at least non-inferior with placebo regarding safety and tolerability, while the impact of such costly approach on the levels of pro-inflammatory biomarkers remains unclear. Further trials with a larger cohort and more definitive clinical outcomes during prolonged follow-up are needed.

Edited by Daniel O’Hara, Michele Provenzano, and Anastasiia Zykova