|Year : 2020 | Volume
| Issue : 2 | Page : 89-91
Department of Pediatrics, Division of Nephrology, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||31-Dec-2020|
Department of Pediatrics, Division of Nephrology, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Yadav M. Journal scan. Asian J Pediatr Nephrol 2020;3:89-91
| BLISS for the Kidneys|| |
Lupus nephritis, which occurs in ~60% of patients with systemic lupus erythematosus (SLE), is a life-threatening feature of the disease. Despite advances in therapeutics, the disease outcome has almost reached a plateau in the past few years. Belimumab, a recombinant human IgG-1 λ monoclonal antibody that inhibits B-cell-activating factor, is approved for patients (≥5 years old) with active autoantibody-positive SLE. Trials demonstrated its efficacy in reducing disease flare but excluded patients with lupus nephritis. In this phase 3, multinational, randomized, double-blind placebo-controlled trial, Furie et al. randomized 448 adults with biopsy-proven active lupus nephritis to receive intravenous (IV) belimumab (10 mg/kg body weight) or matching placebo, in a 1:1 ratio, in addition to standard therapy. The primary efficacy of renal response was urinary protein-to-creatinine ratio of ≥0.7, estimated glomerular filtration rate (eGFR) that was no worse than 20% below the value before the renal flare or ≥60 ml/min/1.73 m2 body surface area, and no use of rescue therapy.
Over a follow-up of 104 weeks, the primary endpoint of patients meeting the primary renal response was higher in the belimumab group (43 vs. 32%; odds ratio 1.6). Complete renal response and time to a renal-related event or death also favored the intervention group. However, the subgroup that received induction with cyclophosphamide did not show significant differences in patients receiving belimumab or placebo.
The trial extends the efficacy of belimumab to patients with SLE and lupus nephritis. The generalizability of these data to severe/relapsing illness is unexplored. While the trial included a large number of adults, the study does have certain biases. The sponsor had a role in the study from designing to collection and analysis of data; pharmacists plus data analyzers were not blinded. Furthermore, the primary outcome changed almost 5 years into the trial. Nevertheless, the study extends the armamentarium of drugs available with the nephrologists – probably as an add-on to standard therapy for now. The role of belimumab in patients receiving alternate immunosuppression (e.g., calcineurin inhibitors and rituximab) and those with relapsing or refractory lupus needs to be explored.
Furie R, Rovin BH, Houssiau F, Malvar A, Teng YKO, Contreras G et al. Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis. N Engl J Med. 2020;383:1117-28.
| Early PRO-TECT Trial: A Randomized Controlled Trial in a Rare Pediatric Disease|| |
Alport syndrome, caused by mutations in genes encoding collagen type IV in the glomerular basement membrane, is an important monogenic cause of end-stage kidney disease. Since the first evidence of increased longevity in mice models with angiotensin-converting enzyme (ACE) inhibition (2003), and data showing benefit in patients with chronic kidney disease stage 3–4 due to Alport syndrome (2012), this is the first randomized controlled trial (RCT) in oligosymptomatic children with the disease.
Gross et al. report the results of this randomized and placebo-controlled study to investigate the safety and nephroprotective properties of RAAS blockade in children. The authors planned to randomize eighty children, 2–18 years of age with stage 0 or 1 Alport syndrome (upto 300 mg albumin/g creatinine), to receive ramipril or placebo in a 1:1 ratio. It was changed to 2:1 later to make randomization more attractive to parents. The treatment period was 3 years and later extended to 6 years. Evidence synthesis using observational data was planned. It included patients whose parents refused randomization or if children were already on ACE inhibition. This arm received ramipril as open label (n = 42) and was compared against prospectively untreated patients (n = 28).
Progression was defined using albuminuria as a surrogate marker. Outcomes such as end-stage kidney disease or doubling of serum creatinine would have further extended the study duration, making it less feasible to continue. Although progression was reduced by 50% (adjusted hazard ratio [HR]: 0.51), the difference was not statistically significant (95% confidence interval [CI]: 0.12–2.0). Only 27.3% (3 of 11) in the ramipril group but 55.6% (5 of 9) in the placebo group progressed during follow-up. Using a Bayesian approach, the investigators showed a reduction in the risk of disease progression by 50%, although the results were not significant (HR: 0.52; 95% CI: 0.19–1.39). Such alternate approaches are used to mitigate the challenge of slow enrollment of children with a rare disease into clinical trials.
At enrollment, all children had normal blood pressure and normal eGFR. Parents were instructed to stop therapy during intercurrent illness. Twenty percent of patients were on dual blockade. One child had hyperkalemia with acute kidney injury (AKI), highlighting the need for monitoring electrolytes in practice. Nevertheless, over 200 patient-years on ramipril and numerous adverse events for analysis allowed the conclusion on safety of this therapy. Even with the failure to achieve significant results, the number needed to treat was ~5.4 to avoid the progression of the disease with demonstrated safety as a co-primary outcome. The effect on extrarenal manifestations is awaiting publication as exploratory outcomes of this trial.
This trial is one of the few RCTs in children and emphasizes the slow recruitment and hesitancy of enrollment in intervention trials. While awaiting newer drugs and directed therapies such as antisense oligonucleotide(s), this trial provides us with a possible delay of progression to such a point when these therapies may be available in clinical practice. The demonstrated safety strengthens confidence in treating patients when they do not manifest overt disease.
Gross O, Tönshoff B, Weber LT, Pape L, Latta K, Fehrenbach H, et al. A multicenter, randomized, placebo-controlled, double-blind phase 3 trial with open-arm comparison indicates safety and efficacy of nephroprotective therapy with ramipril in children with Alport's syndrome. Kidney Int 2020;97:1275-86.
| Fluid Restriction in Syndrome of Inappropriate Antidiuresis|| |
Hyponatremia is the most common electrolyte abnormality encountered in clinical practice. The syndrome of inappropriate antidiuresis (SIAD) remains the most frequent cause of hyponatremia. While guidelines argue against, observational data show that effective treatment of hyponatremia can improve cognitive function and reduce mortality. Despite lack of prospective data to support its efficacy, fluid restriction is recommended as the first-line therapy for SIAD. Garrahy et al. report the results of an open-label, single-center RCT of fluid restriction versus no treatment in patients with chronic SIAD, recruited from medical, surgical, and oncology wards and endocrinology outpatient clinic. Forty-six patients with chronic asymptomatic SIAD were then randomized to either fluid restriction (1000 ml/day) or no specific hyponatremia treatment for 1 month. The primary endpoints were a change in plasma sodium concentration at days 4 and 30.
The study attempted to enrich the cohort with patients with chronic SIAD who are unlikely to revert, unlike acute SIAD secondary to transient medication use. The authors excluded patients with symptoms of cerebral irritation and those who required IV fluids or diuretic therapy or had already been on fluid restriction. Patients were withdrawn from the study if plasma sodium fell by ≥5 mEq/L from baseline or to <120 mEq/L.
Investigators found that plasma sodium rose by 3 mEq/L (interquartile range [IQR]: 2–4) after three days of fluid restriction, compared with 1 mEq/L (IQR: 0–3) on no specific therapy (P = 0.005). There was a minimal additional rise by day 30; no significant difference was evident in the number of patients who achieved plasma sodium ≥130 mEq/L in either arm. In short, fluid restriction (intake up to 1000 ml/day) induces a modest early rise in plasma sodium in patients with chronic SIAD, with minimal additional rise thereafter, and is well tolerated. More than one-third of patients fail to reach a plasma sodium ≥130 mEq/L after 3 days of fluid restriction, emphasizing the clinical need for additional therapies for SIAD, in some patients. The level of supervision did not significantly affect treatment response as the effect was similar in inpatient as well as outpatient enrollees. Baseline urine osmolality or Furst ratio (urine Na+ + K+/serum Na+) did not predict treatment response to fluid restriction, although the study was not powered to investigate this. Larger cohort studies would be needed to test the predictive power of these variables. The incidence of AKI was significantly low compared to the EFFUSE-FLUID trial, due to less stringent fluid restriction in this study.
To summarize, the study shows that fluid restriction has a modest effect on the correction of hyponatremia in chronic SIAD. This effect appears to wane with the time, but a falloff in compliance may also be responsible. The authors note a dip in urine osmolality on day 18, and self-reporting of fluid intake may limit the reliability of the data. Despite these limitations and lack of sufficient information on predictors of response, the study adds evidence to some benefit of an otherwise safe intervention in a prospective, randomized design. The clinical relevance of this modest benefit needs to be carefully examined.
Garrahy A, Galloway I, Hannon AM, Dineen R, O'Kelly P, Tormey WP et al. Fluid Restriction Therapy for Chronic SIAD; Results of a Prospective Randomized Controlled Trial. J Clin Endocrinol Metab. 2020;105:dgaa619
| Time to STAR(R)T Kidney Replacement Therapy?|| |
AKI is common in critically ill patients. Severe AKI requires prompt initiation of kidney replacement therapy, the timing of which remains uncertain! The STARRT AKI investigators report the results of a large RCT on timing of initiating kidney replacement therapy in severe AKI.
When complicated by major metabolic and fluid disturbances, there is consensus on the urgent need for kidney replacement therapy in AKI. However, when severe AKI is unaccompanied by any of these complications, the benefits of kidney replacement therapy are unclear. To answer this equipoise in intensive care practice, a 15-nation randomized, controlled trial enrolled critically ill patients with severe AKI from 168 hospitals. The attending physicians confirmed patient eligibility by affirming a clinical equipoise, noting the absence of any circumstances that would mandate either immediate initiation of kidney replacement therapy or deferral of such therapy because of clinical judgment regarding the likelihood of imminent recovery of kidney function. After determination of full eligibility, a 12-h window was allotted for consent, randomization, and initiation of renal replacement therapy for patients in the accelerated-therapy group. Patients were randomly assigned (1:1) to receive an accelerated strategy of kidney replacement therapy (therapy initiated within 12 h after the patient had met eligibility criteria) or a standard strategy (therapy discouraged unless conventional indications developed or AKI persisted for >72 h). The primary outcome was death from any cause at 90 days.
Over 4 years of recruitment and 11,852 provisional eligible patients, 3019 were randomly assigned to receive either an accelerated strategy for initiation of kidney replacement therapy (1512 patients) or the standard strategy (1507 patients). Finally, 1465 and 1462 patients were included in the accelerated-strategy and standard-strategy groups, respectively, as the modified intention-to-treat analysis due to crossover or withdrawal of consent. Of these patients, kidney replacement therapy was performed in 1418 (96.8%) in the accelerated-strategy group and 903 (61.8%) in the standard-strategy group. At 90 days, death had occurred in 43.9% and 43.7% in the accelerated-strategy and standard-strategy groups, respectively (relative risk: 1.00; 95% CI: 0.93, 1.09; P= 0.92). Among survivors at 90 days, continued dependence on kidney replacement therapy was confirmed in 10.4% of patients in the accelerated-strategy group and 6.0% in the standard-strategy group. Adverse events occurred in 23.0% in the accelerated-strategy group and 16.5% in the standard-strategy group (P<0.001). The difference remained insignificant in various subgroups. The standard-therapy arm had a longer stay in the intensive care unit but lower rehospitalization rates.
The trial confirmed the equipoise of accelerated and standard initiation of kidney replacement therapy with potential higher adverse events in the former, in a situation where equipoise existed to begin.
STARRT-AKI Investigators; Canadian Critical Care Trials Group; Australian and New Zealand Intensive Care Society Clinical Trials Group; United Kingdom Critical Care Research Group; Canadian Nephrology Trials Network; Irish Critical Care Trials Group, Bagshaw SM, Wald R, Adhikari NKJ, Bellomo R, da Costa BR, Dreyfuss D et al. Timing of initiation of renal-replacement therapy in acute kidney Injury. N Engl J Med. 2020;383:240-51
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