|Year : 2018 | Volume
| Issue : 1 | Page : 45-48
Department of Pediatrics, Division of Nephrology, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||28-Jun-2018|
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Khandelwal P. Journal Scan. Asian J Pediatr Nephrol 2018;1:45-8
| Multiethnic Trial of Levamisole for Relapsing Nephrotic Syndrome: Lessons Learned|| |
The management of patients with frequently relapsing nephrotic syndrome is challenging and requires monitoring for complications of disease and therapy-related adverse events. While patients with frequent relapses are initially managed on long-term alternate-day prednisolone, a significant proportion of children continue to relapse frequently, necessitating use of alternative agents. Although levamisole, cyclophosphamide, mycophenolate mofetil, calcineurin inhibitors and rituximab enable steroid sparing, evidence for the use of these agents is limited to cohort studies and few randomized controlled trials. Levamisole, an anthelmintic agent, is suggested to have an immunomodulatory effect in steroid-sensitive nephrotic syndrome, with upregulation of interleukin (IL)-8 and IL-24 and cytokines secreted by Th1-lymphocytes. Modulation of glucocorticoid receptor expression and signaling on podocytes may contribute to the response. While withdrawn from most international markets in 2004 levamisole continues to be used off-label in patients with frequent relapses in Asia and a few European countries, particularly given its advantages of low cost and relatively few adverse effects. Based on moderate quality evidence, the current Kidney Disease Improving Global Outcomes clinical practice guidelines recommend its use as steroid-sparing agent in patients who continue to relapse despite standard alternate-day therapy. A meta-analysis of randomized trials demonstrates about 50% reduction in relapses over 1–2 years of therapy; however, included studies had several methodological flaws.
The Levamisole Study Group conducted an international, multicenter, double-blind, placebo-controlled, randomized clinical trial to evaluate the safety and efficacy of therapy with levamisole over 1 year in 99 children with frequent relapses or steroid dependence. The results, recently published in Kidney International, show that levamisole increased the time to relapse compared to placebo (hazard ratio 0.22; 95% confidence interval [CI] 0.11, 0.43; P = 0.001) and this effect was visible after termination of prednisolone treatment (100 days postrandomization). Moreover, 26% of patients receiving levamisole were in sustained remission at 12 months compared to 6% in the placebo group. However, 8% patients developed moderate neutropenia (500–1000 cells/ml) that recovered spontaneously. Prolonged therapy was rarely associated with elevated transaminases and antineutrophil cytoplasmic antibody-positive arthritis. Hence, careful vigilance of blood counts and liver function appears necessary in patients treated with levamisole.
This adequately powered, methodologically sound, multicenter study conducted in five European countries and India demonstrates efficacy of levamisole in children with frequently relapsing nephrotic syndrome. However, efficacy of therapy in steroid-dependent patients was not clearly demonstrated, the prevalence of steroid dependence had marked regional differences, and the subgroup analysis was inadequately powered to detect meaningful differences by region and disease course. Further, the optimal dose, dosing interval, duration, and timing of introduction of levamisole remain unanswered. While a dose of 2.5 mg/kg on alternate days has conventionally been recommended and used in the present trial, there is a suggestion of increased remission rates with daily administration of levamisole. In the current study, the duration of follow-up after discontinuation of levamisole was insufficient to evaluate its long-term effects and gauge the optimal duration of therapy. Furthermore, the use of cytotoxic therapy before therapy with levamisole might have been a potential source of bias, because it has been suggested that levamisole may be more effective in patients previously treated with cyclophosphamide. Nevertheless, use of levamisole is an attractive option in children showing frequent relapses with the potential of inducing long-lasting sustained remission. Satisfactory safety and efficacy, demonstrated across a multiethnic cohort in this study, prompted the authors to suggest its use as the first second-line agent in children with frequent relapses, preferably early in the course of the disease, before the use of more toxic therapies.
Gruppen MP, Bouts AH, Jansen-van der Weide MC, Merkus MP, Zurowska A, Maternik M, et al. Arandomized clinical trial indicates that levamisole increases the time to relapse in children with steroid-sensitive idiopathic nephrotic syndrome. Kidney Int 2018;93:510-8.
| First Targeted Therapy for X-Linked Hypophosphatemic Rickets Approved for Children|| |
X-linked hypophosphatemia, caused by inactivating mutations in the gene encoding phosphate-regulating endopeptidase homolog X-linked (PHEX), is the most prevalent inherited form of hypophosphatemic rickets. While the precise regulatory role of PHEX on fibroblast growth factor 23 (FGF-23) expression remains to be determined, loss of function of PHEX induces enhanced expression of FGF-23 in bone and increased circulating levels. FGF-23 is central to phosphate homeostasis; excess levels cause hypophosphatemia by suppressing proximal tubular phosphate reabsorption and reducing 1,25-dihydroxy vitamin D synthesis. The resulting chronic hypophosphatemia results in refractory rickets, lower limb deformity and stunted growth.
Conventional replacement therapy by oral phosphate and activated vitamin D only transiently increases serum phosphate levels, resulting in incomplete healing of rickets, residual skeletal deformity, persistent short stature, gastrointestinal side effects and risk of hypercalciuria, nephrocalcinosis and hyperparathyroidism. Therefore, inhibition of FGF-23 activity by anti-FGF-23 antibodies was explored as a novel therapeutic maneuver. Burosumab (KRN23; Crysvita), a recombinant fully human IgG1 monoclonal antibody against FGF-23, showed safety and efficacy in improving biochemical abnormalities and quality of life in dose-escalation studies in adults with X-linked hypophosphatemia; until recently, it had not been evaluated in children.
In a recent issue of the New England Journal of Medicine, Carpenter et al. published the results of an open-label phase II randomized trial to evaluate the efficacy and safety of burosumab in children with X-linked hypophosphatemic rickets. Fifty-two patients, aged 5–12 years, with active rickets despite oral phosphate and vitamin D supplements, were randomized to receive subcutaneous burosumab either bi-weekly or monthly, and outcomes were assessed at 40 and 64 weeks. Therapy with burosumab corrected hypophosphatemia and improved renal tubular phosphate reabsorption. Serum phosphorus levels increased after the first dose; more than half the patients had serum phosphorus levels within normal range by 6 weeks and near-normal levels were sustained throughout follow-up with bi-weekly dose of 1 mg/kg. This was associated with remarkable amelioration of rickets; by week 40, rickets had healed in more than one-half of the patients, including nearly all patients with severe rickets at presentation and changes were sustained at 64 weeks. There were concurrent improvements in linear growth, walking ability, patient-reported pain, and functional disability. Nearly, all adverse events were mild-to-moderate in severity; blood levels of calcium, parathyroid hormone and urinary calcium were not significantly altered. These results indicate that burosumab administered subcutaneously at a dose of 1 mg/kg every 2 weeks improves clinical outcomes in children with X-linked hypophosphatemia.
Based on its potential for substantial improvement over other available therapies, the US Food and Drug Administration (FDA) had granted a Breakthrough Therapy Designation to burosumab in 2016. In February 2018, the European Medicines Agency granted conditional marketing authorization, and in April 2018, the US FDA approved burosumab for treatment of children 1 year of age or older with X-linked hypophosphatemia. While holding promise for children with this debilitating disease, the long-term safety of burosumab requires careful evaluation, for which several phase II and III clinical trials are ongoing. Two multicenter phase III trial (ClinicalTrials.gov number, NCT02915705 and NCT03233126) will examine the relative safety and efficacy of burosumab compared to conventional therapy in children. phase II trials are underway in younger children between 1 and 4 years of age (NCT02750618) and in adults with tumor-induced osteomalacia and epidermal nevus syndrome. Given the association between high FGF-23 levels and cardiovascular mortality, disease progression and left ventricular hypertrophy in chronic kidney disease (CKD), studies are necessary to establish the benefit of anti-FGF-23 antibody in these patients. Other than burosumab, inhibitors of binding of FGF-23 to Klotho–FGF receptor complex, inhibitors of FGF receptor and its downstream effectors such as mitogen-activated protein kinase have been tested in preclinical trials but are yet to find support in clinical studies.
Carpenter TO, Whyte MP, Imel EA, Boot AM, Högler W, Linglart A, et al. Burosumab therapy in children with X-linked hypophosphatemia. N Engl J Med 2018;378:1987-98.
| Resolved Childhood Renal Disease Might Have a Lasting Ominous Consequence|| |
A significant proportion of adult renal diseases are initiated during childhood. Progressive impairment of glomerular filtration rate (GFR), hypertension and proteinuria are established sequelae of childhood-onset renal diseases. However, precise estimates of their risks during longitudinal follow-up and factors associated with decline in GFR remain unclear. An understanding of these risk factors might enable preemptive intervention in susceptible patients. Calderon-Margalit et al., in their article published in the New England Journal of Medicine, demonstrated that a history of mild or resolved childhood renal disease portends more than fourfold risk of end-stage renal disease (ESRD) in adulthood, despite having normal renal function and absence of hypertension or proteinuria during adolescence (adjusted hazard ratio 4.19; 95% CI 3.52, 4.99). This large nationwide study retrospectively included long-term data of 1.5 million healthy adolescents from the Israeli Defense Forces Database, who were screened for a prior history of clinically evident renal diseases including congenital anomalies of the kidney and urinary tract, pyelonephritis and glomerular disease and underwent routine medical examination between 16 and 25 years of age. Linking these data to the Israeli ESRD registry showed that 2490 participants developed ESRD over three decades of follow-up.
The epidemiological association of early-onset ESRD and hypertension in adulthood with low birth weight and prematurity suggests a perinatal origin of CKD. Developmental programming is hypothesized to cause low nephron endowment and hyperfiltration in the residual nephrons, conferring subsequent risk of impaired renal function. Similarly, authors of the present study attribute the increased susceptibility to CKD to an antecedent insult possibly causing nephron loss and low nephron numbers. They hypothesize that ongoing subclinical damage because of a seemingly resolved renal disease might reduce renal reserve and cause progressive decline in renal function.
The increased risk of ESRD in this report was irrespective of the type of childhood kidney disease. However, the retrospective nature of data collection limited a detailed evaluation of the primary disease; information on age of presentation, severity, histopathological subtype, urological intervention, medications and imaging after resolution of renal disease is lacking. Despite these limitations, this study is significant in indicating that any degree of renal injury or structural renal abnormality in childhood confers a lifetime risk of ESRD and all such patients require appropriate counseling and prolonged follow-up. The results of this study may influence selection of potential kidney donors who would require thoughtful consideration of any past renal disease. The authors rightly conclude that a legacy of childhood renal disease may be associated with a considerable unrecognized risk of early stages of CKD in adults and identification of these at-risk individuals may enable timely intervention to retard disease progression.
Calderon-Margalit R, Golan E, Twig G, Leiba A, Tzur D, Afek A, et al. History of childhood kidney disease and risk of adult end-stage renal disease. N Engl J Med 2018;378:428-38.
| Remarkable Diagnostic Yield of Sequencing 37 Genes in Inherited Tubulopathies|| |
High-throughput sequencing technology has enabled simultaneous sequencing of multiple genes in large cohorts of patients. The overall reported diagnostic yield from genetic screening of cohorts with inherited renal disorders such as ciliopathies, steroid-resistant nephrotic syndrome, atypical hemolytic uremic syndrome or congenital anomalies of the kidney and urinary tract, has ranged between 5% and 50%. Prior genetic sequencing in modestly large cohorts of patients with tubular disorders was either limited to specific disorders (distal renal tubular acidosis, Bartter type 3) or had low diagnostic yield (nephrocalcinosis/nephrolithiasis).
To facilitate screening of a large group of children with inherited tubulopathies, the working group for tubulopathies in the European Consortium for High-Throughput Research in Rare Kidney Diseases designed a kit for targeted amplification of 37 known genes. In a recent study published in Kidney International, Ashton et al. screened a multinational cohort of 410 patients from European Tubulopathy Networks by targeted next-generation sequencing using the above panel. They found a genetic explanation of the clinical phenotype in almost two-third of the cohort which clearly surpasses diagnostic yield from next-generation sequencing of other inherited renal disorders. This also indicates that a considerable proportion of causative genes for inherited tubulopathies have already been identified. Common clinical diagnoses included Bartter/Gitelman syndrome and distal renal tubular acidosis, in whom diagnostic yield was about 60–75% and enabled further subcategorization to better understand genotype–phenotype correlations. Novel mutations comprised a large fraction (100 of 267) of variants; 25 of 36 variants of unknown significance corroborated with the clinical diagnosis and would provide a genetic explanation if pathogenicity was proven. Therefore, it appears that the actual diagnostic yield is likely to be even greater.
Although tubulopathies can have varied manifestations, recognition of a constellation of clinical and biochemical findings enables classification into general diagnoses that facilitate therapy. The results of this study similarly suggest that an accurate clinical diagnosis can be established in majority and genetic results chiefly corresponded to the broad clinical categorization. However, a small fraction of cases had discrepant clinical and genetic diagnosis; most patients with variations in the SCLA43 gene causing hypophosphatemic rickets with hypercalciuria were clinically misclassified. Interestingly, patients with Gitelman syndrome accounted for about 20% of the cohort and were similar in number to Bartter syndrome, suggesting the importance and under-recognition of this condition in pediatric cohorts.
A molecular etiology is required for the establishment of a precise diagnosis in inherited tubulopathies, especially for complex or overlapping phenotypes, to facilitate genetic counseling and early diagnosis of asymptomatic relatives. The decreasing cost and wider accessibility to next-generation sequencing have made single-gene approaches obsolete, especially when large number of genes gives rise to a similar phenotypic spectrum. Compared to whole-exome or whole-genome approaches, targeted sequencing enables high coverage of areas of interest and is cost efficient, especially in patients with inherited tubulopathies, where diagnostic yield with a relatively small panel of genes is expected to be high.
Ashton EJ, Legrand A, Benoit V, Roncelin I, Venisse A, Zennaro MC, et al. Simultaneous sequencing of 37 genes identified causative mutations in the majority of children with renal tubulopathies. Kidney Int 2018;93:961-7.
| Sodium Bicarbonate or Acetyl Cysteine Do not “preserve” Renal Function|| |
Pharmacological strategies to prevent contrast-induced acute kidney injury (AKI) include parenteral volume expansion, minimizing contrast-media volume, use of low-osmolar, iso-osmolar or noniodinated contrast media. The mechanism of contrast-induced AKI is multifactorial; oxidant damage is a final common pathway. Agents with anti-oxidant properties, acetyl cysteine and sodium bicarbonate, have been compared with normal saline in over 40 prospective randomized trials. Despite >4000 patients studied with each therapy, majority have been underpowered studies with heterogeneous inclusion criteria and trial end points and uncertainty about long-term effect of these interventions; meta-analyses have shown a moderate degree of heterogeneity. Equipoise has lingered far too long regarding the efficacy of either of these agents in reducing the incidence of postcontrast AKI.
The authors of the Prevention of Serious Adverse Events Following Angiography (PRESERVE) Trial report robust evidence in the New England Journal of Medicine concerning potential benefit of both interventions. This large multicenter, prospective trial randomized almost 5000 adults with mild CKD (median estimated GFR 50 mL/min/1.73 m 2; interquartile range, 41–59 mL/min/1.73 m 2), scheduled for elective angiography, to intravenous normal saline or 1.26% sodium bicarbonate solution and 5 days of oral acetyl cysteine or placebo in a 2 × 2 factorial design. The trial end points comprised death, dialysis requirement or sustained 50% increase in serum creatinine at 90 days. These primary outcome measures were clinically more meaningful than transient rise in serum creatinine immediately following contrast exposure. The trial was stopped after a prespecified interim analysis indicated a low likelihood of seeing a meaningful difference in the primary end point. Outcomes, including rates of AKI, were similar between the normal saline and sodium bicarbonate solution groups (4.7% vs. 4.4%, respectively) and between those who received acetyl cysteine and those who did not (4.6% vs. 4.5%, respectively). Subgroups by renal function, albuminuria and contrast volume showed similar results.
While the incidence of contrast-induced AKI, chiefly assessed in adults following cardiac catheterization, ranges from 3% to 25% depending on risk factors, limited information is available in pediatric population. The high incidence of contrast-induced AKI, reported to affect 5–10% patients in two small retrospective series in a heterogenous population of children, is concerning and requires validation. The risk of AKI following contrast administration in the pediatric population would be expected to be lower due the lack of typical risk factors usually prevalent in adults (advanced age, diabetes, hypertension and congestive heart failure). Nevertheless, time-tested practices of judicious use of contrast, attention to type, volume and route of administration of contrast, intravenous volume expansion, and discontinuation of nephrotoxic medication are the principles of prevention of contrast-induced AKI in both adults and children. The PRESERVE Trial appears to put an end to the use of oral acetyl cysteine or sodium bicarbonate solution for this purpose in patients with impaired renal function.
Weisbord SD, Gallagher M, Jneid H, Garcia S, Cass A, Thwin SS, et al. Outcomes after angiography with sodium bicarbonate and acetylcysteine. N Engl J Med 2018;378:603-14.
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