|Year : 2018 | Volume
| Issue : 2 | Page : 103-106
Department of Pediatrics, Division of Pediatric Nephrology, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||27-Dec-2018|
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Yadav M. Journal Scan. Asian J Pediatr Nephrol 2018;1:103-6
| Predicting progression in childhood chronic kidney disease|| |
The staging system for chronic kidney disease (CKD) proposed by the Kidney Disease: Improving Global Outcomes (KDIGO) uses three domains, namely, estimated glomerular filtration rate (eGFR) category, albuminuria category, and etiology of CKD, to identify patients at highest risk of morbidity and mortality, and to rank their risk of disease progression. However, this prediction is validated only in adult, not pediatric patients. Anticipating the rate of progression to advanced CKD stages in children with CKD would enable clinicians to preempt complications and plan interventions in a timely manner. In a recent publication, longitudinal data collected in two prospective multicenter international cohorts of children with CKD, namely, the North American chronic kidney disease in children (CKiD) study and the European effect of strict blood pressure control and angiotensin-converting enzyme inhibition on the progression of CRF in pediatric patients (ESCAPE) trial, was used to modify the KDIGO classification to categorize children with CKD into six risk groups differing in their rates of progression to advanced CKD.
Of 1269 children in the two cohorts, patients lacking follow-up, missing baseline eGFR or urine protein to creatinine ratio (UPCR) data, and/or with baseline eGFR <15 ml/min/1.73 m2 were excluded to restrict analysis of risk of progression to 1169 children, 1–18 years old with eGFR of 15–90 ml/min/1.73 m2, followed over 4968 person-years. The primary outcome, progression of CKD, was a composite of the earliest of three events, 50% reduction in baseline eGFR, occurrence of eGFR <15 ml/min/1.73 m2, or initiation of renal replacement therapy. Baseline factors used as predictors included eGFR, estimated by the modified Schwartz equation and categorized as 15–29, 30–44, 45–59, 60–89, and ≥90 ml/min/1.73 m2, and proteinuria, assessed by early morning spot UPCR, and categorized as <0.5, 0.5–2.0, and >2.0 mg/mg, to develop 15 baseline disease categories. Two categories, with baseline eGFR ≥90 ml/min/1.73 m2 and UPCR ≥0.5 mg/mg, were excluded from principal analysis as they included very few (total 16) patients. The time to event was modeled for accelerated failure time in a conventional generalized gamma distribution while adjusting for types of cohort (CkiD or ESCAPE) and etiology of CKD (glomerular vs. nonglomerular). Using a recursive amalgamation algorithm, in which eGFR and UPCR levels with similar progression risks were combined iteratively until no further amalgamation was possible, the authors derived six risk stages (A and F, indicating best and worst risk, respectively). The robustness of the risk order and discriminating ability of the risk stages were cross-validated in the two cohorts and etiology categories separately, using area under receiver operating characteristic curves. Further, the authors generated parametric and nonparametric survival curves for each risk stage specific for glomerular and nonglomerular disease diagnosis. Thus, they estimated the time to the outcome for the 10th, 25th, and 50th percentiles of the study population in each diagnosis-specific risk stage. As expected, glomerular diseases showed faster progression across eGFR and UPCR categories.
The report represents a major progress in validating eGFR, level of proteinuria, and type of CKD etiology, as predictors of disease progression in pediatric CKD. Survival estimates, color-coded for risk groups, provide a valuable and easy to interpret adjunct to aid decision making in case management. The strengths of the study are the inclusion of a large number of pediatric patients with longitudinal follow-up on the medium term and cross-validation of results across individual study cohorts and diagnosis categories. The use of UPCR, compared to albuminuria, is expected to have increased the relevance of results by including information from tubular and structural disease-that constitute the majority of pediatric CKD and lack albuminuria. Possible limitations of the results are inclusion of studies differing in their study design (CKiD was observational and ESCAPE was interventional) and lack of adequate information in the lowest proteinuric categories. Future studies should attempt to validate these risk categories in other prospective cohorts across the world and/or using other estimates of GFR and albuminuria.
Furth SL, Pierce C, Hui WF, White CA, Wong CS, Schaefer F, et al. Estimating time to ESRD in children with CKD. Am J Kidney Dis 2018;71:783-92.
| ABO-incompatible kidney transplantation: Is it safe to go across?|| |
The advent of ABO-incompatible kidney transplantation (ABOi-KT) has led to significant expansion of the donor pool and decline in time on the waiting list for patients with end-stage renal disease (ESRD). With large prospective studies demonstrating short-term outcomes comparable to conventional ABO-compatible KT (ABOc-KT), ABOi-KT is accepted as a valid alternative therapy for patients with ESRD. However, multicentric controlled studies of long-term outcomes and complications are lacking.
In their systematic review and meta-analysis, de Weerd et al. compared allograft and patient survival between 1346 patients who underwent ABOi-KT and 4943 center-matched patients receiving ABOc-KT, reported in 26 single-centered cohort studies published as manuscripts (not conference abstracts) up to July 2017. Studies were excluded if splenectomy was used for desensitization or patients had combined human leukocyte antigen and ABO-incompatibility. The studies included had low risks of bias and negligible statistical heterogeneity. Subclinical and borderline rejections were usually excluded from the definition of biopsy-proven acute rejection, and outcomes were mostly reported at 1-year follow-up. Complications recorded included severe nonviral infections, except urinary tract infections, and postoperative bleeding or need for transfusions. Baseline clinical features, including immunological risk profiles, were similar for patients in the two categories.
The meta-analysis found small but statistically significant differences in allograft survival between patients receiving ABOi-KT and ABOc-KT at 1 year (96% vs. 98%; P = 0.002; relative risk [RR], 0.97; 95% confidence interval [CI] 0.96–0.98; P = 0.001) and 3 years (92% vs. 94%; P = 0.04). The results were similar for subgroups of studies between centers performing plasmapheresis and relying chiefly on immune adsorption for desensitization (I2 = 0%; P = 0.66 for subgroup difference), suggesting homogeneity. Similarly, patient survival was slightly but significantly lower for patients receiving ABO-iT compared to ABO-cT (98% vs. 99%; P = 0.03). Infections were more often a cause of death in patients receiving ABO-iT than ABO-cT (49% vs. 13%; P = 0.02). Biopsy-proven acute rejection was more common in ABO-iT than ABO-cT (RR 1.4; 95% CI 1.2–1.6; P < 0.001), especially antibody-mediated rejection (RR 3.9; 95% CI 2.1–7.3; P < 0.001).
The results of these meta-analysis echo findings of various registries, including Collaborative Transplant Study and United Network for Organ Sharing, that indicate similar small differences in allograft survival and infection-related mortality between ABO-iT and ABO-cT patients. Importantly, none of the included 26 studies had found significant differences in outcomes, likely due to small numbers. The lack of statistical heterogeneity and similarity between groups at baseline add strength to the meta-analysis. In the absence of randomized controlled trials, this meta-analysis of unicentric cohort studies possibly provides the highest quality of evidence possible on the topic. However, the meta-analysis is limited by publication bias, which may have overestimated success of ABO-iT, and lack of information on severity and risk factors of infections. In conclusion, while ABO-iT offers considerable survival advantages over dialysis, the meta-analysis cautions about small but significant differences in key outcomes between ABO-iT and ABO-cT, including worse allograft and patient survival and increased risk of infection-related deaths and allograft rejection with the former strategy.
de Weerd AE, Betjes MG. ABO-incompatible kidney transplant outcomes: A meta-analysis. Clin J Am Soc Nephrol 2018;13:1234-43.
| Atypical hemolytic uremic syndrome: lessons from a global snapshot|| |
Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease with diverse clinical findings and varying severity of illness. A high proportion of patients progresses to ESRD or dies within a year of presentation, and disease relapses are common, including recurrence after transplantation. Despite recent advances in understanding of role of complement dysregulation and genetic basis of thrombotic microangiopathy (TMA) in aHUS, precise genotype-phenotype correlations and the impact of therapeutic strategies on long-term outcomes remain to be established. Given the rarity of the diagnosis, international collaborative efforts are essential to address these questions.
The global aHUS registry (www. ClinicalTrials.gov Identifier NCT 01522183), managed by Alexion Pharmaceuticals Inc.(New Haven, CT), was established to assess the natural history of aHUS. Patients diagnosed clinically as aHUS are enrolled, prospectively or retrospectively, regardless of age, genetic testing, or diagnosis and management strategy, while excluding known Shiga toxin-associated HUS and ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif) related disorders. The presentation, outcomes, and rates of TMA in 851 patients (including 45% of children) with aHUS diagnosed up to November 2015, and not (or up till) treated with eculizumab, were described in a recent publication in Kidney International. Despite its intent to be global, patients were predominantly Caucasian (86%). The median age at presentation was 21 years; interestingly, boys with aHUS were younger than girls (10 vs. 26 years). At enrolment, over half of the patients were receiving plasma (exchanges or infusions) and a similar proportion had been dialyzed; 27% had reached ESRD and 19% had received an allograft. Family history of aHUS was reported in 16% cases.
Of those tested, 47% had defect (s) in complement dysregulation, most commonly mutations in complement factor H (CFH)or anti-FH antibodies (21% each). The latter was the most frequently identified etiology in children (24%; 45% in those 6–17 years of age), followed by mutations in CFH (21%) and membrane cofactor protein (MCP) (14%); DGKE mutations were found exclusively in young children (median age: 0.6 years). Patients presenting in adulthood were most likely to carry mutations in CFH (21%) or CFI (10%) or anti-FH antibodies (19%). CFI and MCP mutations were most likely to present in adulthood and childhood, respectively. Children, compared to adults, had significantly lower risk of ESRD at 1 year (79% vs. 69%) and 5 years (73% vs. 51%) (adjusted hazard ratio: 0.55; 95% CI: 0.41–0.73), contrasting with previous reports of relatively worse outcomes in pediatric patients. Interestingly, there were no differences in outcomes between patients with or without an identified genetic cause, between sexes or among races. Compared to patients testing negative, patients with CFH mutations or anti-FH antibodies had inferior, whereas those with MCP mutations had superior, outcomes.
The manuscript provides interesting insights into phenotypic differences in aHUS based on age at presentation, sex, and underlying genetic abnormalities. The chief drawbacks are possible selective reporting, heterogeneity caused by inclusion of secondary forms of HUS (malignancy, drugs, and pregnancy), incomplete assessment of genetic basis of disease (31.4% cases), and nonstandard definition of “mutations” (any rare variants; hetero- or homozygous). However, it is the single largest database on aHUS with wide representation from several regions. Future work from such international collaboration is expected to further our understanding of disease subtypes, potential triggers, and impact of therapeutic strategies.
Schaefer F, Ardissino G, Ariceta G, Fakhouri F, Scully M, Isbel N, et al. Clinical and genetic predictors of atypical hemolytic uremic syndrome phenotype and outcome. Kidney Int 2018;94:408-18.
| Antibiotics: A “role in” stone?|| |
Nephrolithiasis in childhood is usually secondary to an inherited metabolic and/or genetic defect and may injure renal parenchyma. The incidence of stones appears to be increasing, particularly in childhood, and the reasons for this rise remain unclear. The increase is not explained by genetic and metabolic risk factors and changes in dietary patterns, and a role for altered urinary and intestinal tract microbiota has been suggested. In a recent publication, Taisan et al. explored whether the use of antibiotics, which alter intestinal and urinary microbiome, is associated with the risk of nephrolithiasis.
Using clinical data entered into the health improvement network during outpatient visits to general practitioners, authors conducted a population-based case–control study nested within 641 general practices (GPs) in the United Kingdom. For each patient, <90 years of age, followed in the GP for at least 6 months, and with a new diagnosis of nephrolithiasis, ten controls were matched for age, sex, and GP practice at index date by incidence density sampling. The exposure of interest was prescription of an outpatient oral antibiotic 3–12 months before the index date (diagnosis of nephrolithiasis). Multivariable conditional logistic regression models were fit to estimate the association between antibiotic exposure and nephrolithiasis while including relevant covariates (e.g., comorbidity such as inflammatory bowel disease, cystic fibrosis, gout or diabetes, immobility, neurogenic bladder, congenital and acquired urinary tract obstruction, neoplasm, urinary tract infection, use of proton-pump inhibitors, statins, and thiazide or and loop diuretics) and rate of health-care encounter. Sensitivity analyses were performed by excluding patients with a history of urinary tract infections, brief (<5 days) or continuous (prophylaxis) antibiotic exposure, obesity, and doubtful or prior diagnosis of nephrolithiasis. Using data from 25,981 cases and 259,797 controls observed for a median of 5.4 years, the authors report that exposure to oral cephalosporins, fluoroquinolones, sulfas, nitrofurantoin, and broad-spectrum penicillin are associated with increased adjusted odds of nephrolithiasis, both in children and adults. The greatest risk was estimated for prescriptions at younger ages and for more recent exposures; exposure even 3–5 years ago was associated with increased risk of nephrolithiasis. The results remained stable and significant on robust sensitivity analysis.
It is estimated that 30% of patients visiting GP receive an oral antibiotic prescription annually. Hence, the study raises an important concern that calls for rational prescription of antibiotics. The strengths of the study are its large sample size, transnational coverage, uniform method for selection of cases and controls, and demonstration of robustness of results through multiple sensitivity analyses. The exclusion of recent antibiotic exposure should have minimized false risk attribution. However, there are certain limitations. Included covariates did not account for the prevalence of metabolic abnormalities conventionally linked to nephrolithiasis. It is unclear whether the risk implied is for a certain stone composition or all types of stones. Adherence to prescription and antibiotic administration by oral or intravenous route on visits to emergency room were not covered. The possibility that nephrolithiasis was missed on visits before index date when antibiotics were prescribed for symptoms attributable to stones, is not ruled out. The study does not provide any evidence to directly support the hypothesis of antibiotics altering gut or urinary tract microbiota; an alternative hypothesis may be that antibiotics form the nidus for crystallization.
In summary, the study suggests that exposure to some antibiotics might represent a novel risk factor for nephrolithiasis, contributing to the rising incidence of kidney stones, particularly among children. Further studies are required to substantiate this association across ethnicities while accounting for underlying metabolic risk, age at exposure and stone type, and examining for changes in gut and urinary microbiota.
Tasian GE, Jemielita T, Goldfarb DS, Copelovitch L, Gerber JS, Wu Q, et al. Oral antibiotic exposure and kidney stone disease. J Am Soc Nephrol 2018;29:1731-40.
| A plasma biomarker to simplify differential diagnosis of polyuria|| |
The diagnosis of diabetes insipidus in patients presenting with polyuria and polydipsia requires administering the water deprivation test to distinguish primary polydipsia from diabetes insipidus, followed by vasopressin administration to differentiate central from nephrogenic form of diabetes insipidus. The water deprivation test, meant to test maximal urine concentration after prolonged fasting, is based on sound physiological principles. However, it is indirect, and cumbersome to administer, requiring repeated sampling of blood and urine during a period of fasting. To avoid erroneous classification due to overreliance on urinary osmolality, the test is performed more than once, and healthy controls are simultaneously subjected to the same test. Further, washout of medullary interstitial concentration gradient with prolonged diuresis often impairs the response of urinary osmolality to water deprivation. Direct measurement of plasma arginine vasopressin following osmotic stimulation is desirable but not feasible. Hence, measurement of plasma copeptin, a precursor segment of arginine vasopressin which is more stable and reliable, is proposed as a surrogate.
In a multicenter prospective study, the water deprivation test was compared to plasma copeptin levels stimulated by infusion of hypertonic saline and water deprivation, in 144 polyuric patients older than 16 years and with hypotonic (urine osmolality <800 mOsm/kg) polyuria (>50 ml/kg/day) or confirmed central diabetes insipidus. Plasma copeptin levels were measured at baseline and at the end of test in both the 17-h water deprivation and 3-h hypertonic saline stimulation tests. The first objective was to examine for diagnostic utility of plasma copeptin levels during either test as compared to the water deprivation test, and if found to be superior, to test whether plasma copeptin measurement during hypersaline infusion was noninferior to that during water deprivation. The presumed diagnosis, revisited upon reevaluation by independent experts 3 months following testing with consideration to other laboratory tests and response to therapy, was primary polydipsia in 58% of patients, and central diabetes insipidus in the remainder. Stimulated copeptin, referring to change in copeptin between baseline and 8 h of water deprivation or hypertonic saline infusion to achieve plasma sodium ≥150 mEq/L, had higher diagnostic accuracy in distinguishing between primary polydipsia and central DI than the water deprivation (96.5% [95% CI: 92.1%–98.6%] vs. 76.6% [68.9%–83.2%]; P < 0.001). Further, plasma copeptin level following hypertonic saline infusion had significantly higher diagnostic accuracy than water deprivation, with or without copeptin measurement, in distinguishing between primary polydipsia and either complete or partial central diabetes insipidus. The authors also found, post hoc, that the most accurate copeptin threshold was 6.5 pmol/L rather than the previously specified value of 4.9 pmol/L. Patients rated the water deprivation test as more burdensome and less as well tolerated than was the hypertonic saline infusion; however, the latter was associated with objective adverse effects more frequently. The authors also reported that measuring basal plasma sodium and ratio of urine to plasma osmolality has limited utility in discriminating one from another etiology.
Overall, the study was limited by the lack of gold standard(s) in diagnosing primary polydipsia and central diabetes insipidus and possible selection bias. To summarize, while the high discriminatory accuracy of copeptin-based assays tempts readers to move away from the indirect water deprivation test, the assay requires validation in prospective studies including detailed evaluation for safety.
Fenske W, Refardt J, Chifu I, Schnyder I, Winzeler B, Drummond J, et al. A copeptin-based approach in the diagnosis of diabetes insipidus. N Engl J Med 2018;379:428-39.
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