Management of Acute Kidney Injury in Critically Ill Children

Acute kidney injury (AKI) is common in critically ill patients, afecting almost one in four critically ill children and one in three neonates. Higher stages of AKI portend worse outcomes. Identifying AKI timely and instituting appropriate measures to prevent and manage severe AKI is important, since it is independently associated with mortality. Methods to predict severe AKI should be applied to all critically ill patients. Assessment of volume status to prevent the development of fuid overload is useful to prevent adverse outcomes. Patients with metabolic or clinical complications of AKI need prompt kidney replacement therapy (KRT). Various modes of KRT are available, and the choice of modality depends most on the technical competence of the center, patient size, and hemodynamic stability. Given the signifcant risk of chronic kidney disease, patients with AKI require long-term follow-up. It is important to focus on improving awareness about AKI, incorporate AKI prevention as a quality initiative, and improve detection, prevention, and management of AKI with the aim of reducing acute and long-term morbidity and mortality

Lupus Nephritis in Indian Children: Flares and Refractory Illness

Objective: To evaluate the incidence of flares and treatment resistance in children with lupusnephritis and their association with renal outcomes. Methods: We retrospectively reviewedthe case records of 34 children treated for lupus nephritis (Class II-IV) at a single center.Patients were followed for a minimum of five years to evaluate treatment response, onset offlares, and renal survival. Regression analyses were performed to identify the factorsassociated with treatment refractoriness, incidence of flares and renal survival. Results: Theincidence of flares was 0.16 episodes/person/year. Eight patients (23.5%) were refractory totreatment. The five-year renal survival was 79%. Multiple episodes of flares (P=0.028) andtherapy refractoriness (P=0.003) were associated with poor renal survival. Conclusions:Prevention and aggressive management of renal flares is expected to prevent progression toend stage renal disease in lupus nephritis.

Therapies for Glomerular Diseases in Children

Nephrotic syndrome is an important chronic disease of childhood, with a steroid sensitive course in most patients. Research on pathogenesis has emphasized the importance of T-lymphocyte dysregulation and vascular permeability factors that alter podocyte function and glomerular permselectivity. Mutations in genes that encode important podocyte proteins and therapeutic targets within podocytes have been identified. Ahypothesis unifying available evidence on pathogenesis is yet to be proposed. An important proportion of patients have difficult disease course, characterized by frequent relapses, steroid dependence or steroid resistance, requiring therapy with alternative immunosuppressive agents. Clinical studies support the use of levamisole, cyclophosphamide, mycophenolate mofetil, calcineurin inhibitors (CNIs) and rituximab in patients with frequent relapses or steroid dependence. The management of steroid-resistant nephrotic syndrome is difficult and patients failing to achieve remission show progressive renal damage. Prospective studies in patients with steroid sensitive and steroid resistant nephrotic syndrome are the basis of current guidelines while ongoing studies will help identify and formulate effective and safe therapies.

Phenotype of Dent Disease in a Cohort of Indian Children.

Objective: To describe the clinical and genotypic features of Dent disease in children diagnosed at our center over a period of 10 years. Design: Case series. Setting: Pediatric Nephrology Clinic at a referral center in Northern India. Methods: The medical records of patients with Dent disease diagnosed and followed up at this hospital from June 2005 to April 2015 were reviewed. The diagnosis of Dent disease was based on presence of all three of the following: (i) low molecular weight proteinuria, (ii) hypercalciuria and (iii) one of the following: nephrolithiasis, hematuria, hypophosphatemia or renal insufficiency, with or without mutation in CLCN5 or OCRL1 genes. Results: The phenotype in 18 patients diagnosed with Dent disease during this period was characterized by early age at onset (median 1.8 y), and polyuria, polydipsia, salt craving, hypophosphatemic rickets and night blindness. Rickets was associated with severe deformities, fractures or loss of ambulation in six patients. Nephrocalcinosis was present in three patients, while none had nephrolithiasis. Generalized aminoaciduria was seen in 13 patients, two had glucosuria alone, and one had features of Fanconi syndrome. Over a median follow up of 2.7 years, one patient developed renal failure. Genetic testing (n=15) revealed 5 missense mutations and 3 nonsense mutations in CLCN5 in 13 patients. Five of these variations (p.Met504Lys, p.Trp58Cys, p.Leu729X, p.Glu527Gln and p.Gly57Arg) have not been reported outside the Indian subcontinent. Conclusion: Our findings suggest a severe phenotype in a cohort of Indian patients with Dent disease.

Discussion: The Heart of the Paper.

The discussion section explains the meaning of results to the readers, and addresses the implications of the findings emanating from the particular study. Authors should compare their results with previous reports, and attempt to explain similarities and differences. It is useful to outline the limitations and strengths of the study, and suggest a future line of work. A concise, convincing and meticulous discussion with scholarly referencing is the key to a lasting impression.

Oscillometric Blood Pressure in Indian School Children: Simplified Percentile Tables and Charts.

Background: Data on blood pressure recorded by oscillometric method is limited. Objective: To develop simplified tables and charts of blood pressure recorded by oscillometric method in children. Design: Cross-sectional. Setting:Ballabhgarh, Haryana. Participants: Healthy school-children. Main outcome measures: Blood pressure measured by oscillometric method. Results: The study group included 7,761 children (58.4% males) with mean (SD) age of 10.5 (2.8) years. Age and gender were used to create simplified percentile tables and charts, as height was seen to explain very little variability of either systolic or diastolic blood pressure. Formulae for SBP and DBP thresholds for hypertension were derived as [110 + 1.6 x age] and [79 + 0.7 x age], respectively, with 1 mm Hg to be added for females. 95th percentile values suggest simple levels indicating hypertension to be 120/80, 125/85 and 135/90 at ages of 5, 10 and 15 years, respectively. Conclusions: Simplified reference tables and charts, formulae for SBP and DBP, and simple convenient thresholds may be useful for rapid screening of hypertension using oscillometric method.

Plasma Exchanges and Immunosuppression for Anti-complement Factor H Associated Hemolytic Uremic Syndrome.

Background: Atypical hemolytic uremic syndrome associated with autoantibodies to complement factor H is an important cause of acute kidney injury; most patients require dialysis and are at risk of progressive renal failure. Case Characteristics: 7 patients with gastrointestinal symptoms, acute kidney injury, thrombotic microangiopathy and elevated levels of anti-complement factor H antibodies. Intervention: Prompt initiation of plasma exchanges and immunosuppression. Outcome: Remission of hematological and kidney functions. Message: Prompt and specific management of antibody associated hemolytic uremic syndrome is associated with favorable outcome.

Cystatin C-based Glomerular Filtration Rate Estimating Equations in Early Chronic Kidney Disease.

Objective: To Compare performance of combined creatinine and cystatin C-based equation with equations based on either cystatin C or creatinine alone, in early chronic kidney disease. Design: Diagnostic accuracy study. Setting: Tertiary-care hospital. Patients: One hundred children with chronic kidney disease who underwent 99mTc diethylenetriamine pentaacetic acid (DTPA) glomerular filtration rate measurement. Methods: Estimating equations for glomerular filtration rate (GFR) based on serum cystatin C alone and in combination with serum creatinine were generated using regression analyses. These equations and the creatinine-based equation [0.42 x height/creatinine] were validated in 42 children with glomerular filteration rate between 60 and 90 mL/min/1.73 m2. Bias, precision and accuracy of estimating equations using DTPA glomerular filteration rate as gold standard. Results: Cystatin C-based equation (GFR=96.9 - 30.4 x cystatin) overestimated while the combined cystatin C-and creatininebased equation [GFR=11.45 x (height/creatinine) 0.356 x (1/ cystatin) 0.188] underestimated the measured GFR. Cystatin Cbased equation had less bias (1.9 vs. 12.4 ml/min/1.73 m2), and higher precision (13.1 vs. 25.6 mL/min/1.73 m2) and accuracy (92.1% vs. 75.7%) than creatinine-based equation. The combined cystatin C and creatinine equation had bias (-1.4 mL/ min/1.73 m2) precision (15.2 mL/min/1.73 m2) and accuracy (91.2%) similar to cystatin C-based equation. Conclusions: Cystatin C-based equation has a better performance in estimating glomerular filtration rate than creatinine-based equation in children with early chronic kidney disease. Addition of creatinine equation does not improve the performance of the cystatin C-based equation.

Effect of Enalapril on Glomerular Filtration Rate and Proteinuria in Children with Chronic Kidney Disease: A Randomized Controlled Trial.

Objective: To evaluate the efficacy of enalapril treatment on decline in glomerular filtration rate and reduction in proteinuria in children with chronic kidney disease (CKD). Design: Open-label, randomized controlled trial. Setting: Pediatric nephrology clinic at a tertiary-care referral hospital. Intervention: Children with GFR between 15-60 mL/min/1.73 m2 were randomized to receive either enalapril at 0.4 mg/kg /day or no enalapril for 1 year. Outcome measures: Change in GFR using 99mTc-DTPA and urine protein to creatinine ratio. Secondary outcomes included occurrence of composite outcome (30% decline in GFR or end stage renal disease) and systolic and diastolic blood pressure SDS during the study period. Results: 41 children were randomized into two groups; 20 received enalapril while 21 did not receive enalapril. During 1 year, GFR decline was not different in the two groups (regression coefficient (r) 0.40, 95% CI -4.29 to 5.09, P=0.86). The mean proteinuria reduction was 65% in the enalapril group, significantly higher than control group. The difference was significant even after adjustment for blood pressure was 198.5 (CI 97.5, 299.3; P<0.001). 3 (17.6%) patients in enalapril and 7 (36.8%) in nonenalapril group attained the composite outcome. Conclusions: Enalapril is effective in reducing proteinuria in children with CKD and might be renoprotective in proteinuric CKD.

Etiology and Outcome of Crescentic Glomerulonephritis.

Objective: To determine the etiology, course and predictors of outcome in children with crescentic glomerulonephritis (GN). Study design: Retrospective, descriptive study. Setting: Pediatric Nephrology Clinic at a referral center in Northern India. Methods: Clinic records of patients aged <18 year with crescentic GN diagnosed from 2001-2010 and followed at least 12-months were reviewed. Crescentic GN, defined as crescents in ≥50% glomeruli, was classified based on immunofluorescence findings and serology. Risk factors for renal loss (chronic kidney disease stage 4-5) were determined. Results: Of 36 patients, (median age 10 yr) 17 had immune complex GN and 19 had pauci-immune crescentic GN. The etiologies of the former were lupus nephritis (n=4), postinfectious GN (3), and IgA nephropathy, Henoch Schonlein purpura and membranoproliferative GN type II (2 each). Three patients with pauci-immune GN showed antineutrophil cytoplasmic antibodies (ANCA). Rapidly progressive GN was present in 33 patients, and required dialysis in 12. At median 34 (19-72) months, 2 patients with immune complex GN and 8 with pauci-immune GN showed renal loss. Renal survival was 94.1% at 3 yr, and 75.3% at 8 yr in immune complex GN; in pauci-immune GN survival was 63.2% and 54.1%, respectively (P=0.054). Risk factors for renal loss were oliguria at presentation (hazards ratio, HR 10.50; P=0.037) and need for dialysis (HR 6.33; P=0.024); there was inverse association with proportion of normal glomeruli (HR 0.91; P=0.042). Conclusions: Pauci-immune GN constitutes one-half of patients with crescentic GN at this center. Patients with pauci-immune GN, chiefly ANCA negative, show higher risk of disease progression. Renal loss is related to severity of initial presentation and extent of glomerular involvement.

Revised Guidelines on Management of Antenatal Hydronephrosis.

Widespread antenatal screening has resulted in increased detection of anomalies of the kidneys and urinary tract. The present guidelines update the recommendations published in 2000. Antenatal hydronephrosis (ANH) is transient and resolves by the third trimester in almost one-half cases. The presence of oligohydramnios and additional renal or extrarenal anomalies suggests significant pathology. All patients with ANH should undergo postnatal ultrasonography; the intensity of subsequent evaluation depends on anteroposterior diameter (APD) of the renal pelvis and/or Society for Fetal Urology (SFU) grading. Patients with postnatal APD exceeding 10 mm and/or SFU grade 3-4 should be screened for upper or lower urinary tract obstruction and vesicoureteric reflux. Infants with vesicoureteric reflux should receive antibiotic prophylaxis through the first year of life, and their parents counseled regarding the risk of urinary tract infections. The management of patients with pelviureteric junction or vesicoureteric junction obstruction depends on clinical features and results of sequential ultrasonography and radionuclide renography. Surgery is considered in patients with increasing renal pelvic APD and/or an obstructed renogram with differential renal function <35-40% or its subsequent decline. Further studies are necessary to clarify the role of prenatal intervention, frequency of follow up investigations and indications for surgery in these patients.

Disease Course in Steroid Sensitive Nephrotic Syndrome.

Objective: To review the disease course in patients with steroid sensitive nephrotic syndrome (SSNS) and the factors that determine outcome Design: Retrospective, analytical Setting: Pediatric Nephrology Clinic at referral center in North India Participants/patients: All patients with SSNS evaluated between 1990 and 2005 Intervention: None Main outcome measures: Disease course, in patients with at least 1-yr follow up, was categorized as none or infrequent relapses (IFR), frequent relapses or steroid dependence (FR), and late resistance. Details on complications and therapy with alternative agents were recorded. Results: Records of 2603 patients (74.8% boys) were reviewed. The mean age at onset of illness and at evaluation was 49.7±34.6 R E S E A R C H P A P E R INDIAN PEDIATRICS 881 VOLUME 49__NOVEMBER 16, 2012 and 67.5±37.9 months respectively. The disease course at 1-yr (n=1071) was categorized as IFR in 37.4%, FR in 56.8% and late resistance in 5.9%. During follow up, 224 patients had 249 episodes of serious infections. Alternative medications for frequent relapses (n=501; 46.8%) were chiefly cyclophosphamide and levamisole. Compared to IFR, patients with FR were younger (54.9±36.0 vs. 43.3±31.4 months), fewer had received adequate (≥8 weeks) initial treatment (86.8% vs. 81.7%) and had shorter initial remission (7.5±8.6 vs. 3.1±4.8 months) (all P<0.001). At follow up of 56.0±42.6 months, 77.3% patients were in remission or had IFR, and 17.3% had FR. Conclusions: A high proportion of patients with SSNS show frequent relapses, risk factors for which were an early age at onset, inadequate initial therapy and an early relapse.

Incidence of Acute Kidney Injury in Hospitalized Children.

Objective: To determine the incidence and outcome of acute kidney injury (AKI) in hospitalized patients. Design: Prospective, observational. Setting: Tertiary care center in North India. Participants/patients: Inpatients, 1 month to 18-yr-old. Intervention: None. Main Outcome Measures: Incidence of AKI based on the serum creatinine criteria proposed by the AKI Network. Results: During February to September 2008, thirty nine of 108 (36.1%) critically ill patients and 34 of 378 (9.0%) patients who were not critically ill developed AKI (P <0.001); the respective incidence densities were 45.1 and 11.7 cases/1000 patient days, respectively. The maximal stage of AKI was stage 1 in 48 (65.8%) patients, stage 2 in 13 (17.8%) and stage 3 in 12 (16.4%) patients; 11 (15.1%) required dialysis. Patients with AKI had a significantly longer duration of hospital stay (9 days vs 7 days, P<0.02) and higher mortality (37% vs 8.7%; hazard ratio, HR 2.73; 95% CI 1.64, 4.54). Independent risk factors for AKI were young age (HR 0.89; 95% CI 0.83, 0.95), shock (HR 2.65; 95% CI 1.32, 5.31), sepsis (HR 3.64; 95% CI 2.20, 6.01), and need for mechanical ventilation (2.18; 95% CI 1.12, 4.26). Compared to patients without AKI, the mortality was higher for AKI stage 2 (HR 5.18; 95% CI 2.59, 10.38) and stage 3 (HR 4.34; 95% CI 2.06, 9.16). Shock was an independent risk factor for mortality (HR 10.7; 95% CI 4.96, 22.98). Conclusions: AKI is common in critically ill children, especially younger patients with septicemia and shock, and results in increased hospital stay and high mortality.

Crescentic glomerulonephritis: A clinical and histomorphological analysis of 46 cases.

Background: Crescentic glomerulonephritis (CrGN), defined as crescents involving more than 50% of the glomeruli, includes pauci-immune, immune complex-mediated and anti-glomerular basement membrane disease. Objectives: The present study was aimed at evaluating the various clinical, biochemical and histological parameters in CrGN with respect to these categories and clinical outcome. Materials and Methods: Renal biopsies diagnosed as CrGN between Jan 2008 and Feb 2010 were included. Clinical and laboratory parameters were retrieved along with the therapeutic approach and clinical outcome, wherever available. Renal biopsy slides were evaluated for various glomerular, tubulo-interstitial and arteriolar features. Appropriate statistical tests were applied for significance. Results: A total of 46 cases of CrGN were included; majority (71.7%) of cases were pauci-immune (PI) while 28.3% were immune complex-mediated (IC). Among clinical features, gender ratio was significantly different between PI and IC groups (P = 0.006). The various histological parameters, including proportion of cellular crescents, tuft necrosis and Bowman's capsule rupture, were similar in both the groups. Four unusual associations, including idiopathic membranoproliferative glomerulonephritis (MPGN), multibacillary leprosy, acute lymphoblastic leukemia and C1q nephropathy were detected. Adequate follow-up information was available in 21 (46%) of the patients. Of these, 11 (52.4%) were dialysis-dependent at the last follow-up. Adult patients required renal replacement therapy more frequently than pediatric cases (P = 0.05). Presence of arteriolar fibrinoid necrosis also showed association with poor clinical outcome (P = 0.05). Conclusions: Crescentic glomerulonephritis remains one of the main causes of acute renal failure with histological diagnosis. Immunohistologic examination is essential for accurate classification into one of the three categories. This condition should be considered in rare causal associations like leprosy or MPGN with renal failure, to allow for timely performed renal biopsy and appropriate aggressive therapy.

Genetic studies in a family with distal renal tubular acidosis and sensorineural deafness.

Distal renal tubular acidosis (RTA) with sensorineural deafness is a rare entity, inherited in an autosomal recessive manner. It is caused by mutations in the ATP6V1B1 gene, leading to defective function of H+-ATPase pump in the distal nephron, cochlea and endolymphatic sac. We report two siblings with distal RTA and sensorineural deafness having mutation C>T in the first coding exon of the gene, resulting in a non functional protein. The parents were found to be carriers for the mutation.

Primary hyperoxaluria type 1 with a novel mutation.

Primary hyperoxaluria type 1 [PH1] is an autosomal recessive disorder caused by a deficiency of alanine-glyoxylate aminotransferase AGT, which is encoded by the AGXT gene. We report an Indian family with two affected siblings having a novel mutation in the AGXT gene inherited from the parents. The index case progressed to end stage renal disease at 5 months of age. His 4 month old sibling is presently under follow up with preserved renal function.

Management of steroid resistant nephrotic syndrome.

JUSTIFICATION: There is a lack of evidence based guidelines for management of children with steroid resistant nephrotic syndrome (SRNS). PROCESS: Experts of the Indian Society of Pediatric Nephrology were involved in a two-stage process, the Delphi method followed by a structured face to face meeting, to formulate guidelines, based on current practices and available evidence, on management of these children. Agreement of at least 80% participants formed an opinion. OBJECTIVES: To develop specific, realistic, evidence based criteria for management of children with idiopathic SRNS. RECOMMENDATIONS: The Expert Group emphasized that while all patients with SRNS should initially be referred to a pediatric nephrologist for evaluation, the subsequent care might be collaborative involving the primary pediatrician and the nephrologist. Following the diagnosis of SRNS (lack of remission despite treatment with prednisolone at 2 mg/kg/day for 4 weeks), all patients (with initial or late resistance) should undergo a renal biopsy, before instituting specific treatment. Patients with idiopathic SRNS secondary to minimal change disease or focal segmental glomerulosclerosis should receive similar therapy. Effective regimens include treatment with calcineurin inhibitors (tacrolimus, cyclosporine), intra-venous cyclophosphamide or a combination of pulse corticosteroids with oral cyclophosphamide, and tapering doses of alternate day corticosteroids. Supportive management comprises of, when indicated, therapy with angiotensin converting enzyme inhibitors and statins. It is expected that these guidelines shall enable standardization of care for patients with SRNS in the country.

Pulse steroid therapy.

Intravenous supra-pharmacological doses of corticosteroids are used in various inflammatory and autoimmune conditions because they are cumulatively less toxic than sustained steroid treatment at lower quantitative dosage. Their action is supposed to be mediated through non-genomic actions within the cell. Common indications for use in children include steroid resistant and steroid dependent nephrotic syndrome, rapidly progressive glomerulonephritis, systemic vasculitis, systemic lupus erythematosus, acute renal allograft rejection, juvenile rheumatoid arthritis, juvenile dermatomyositis, pemphigus, optic neuritis, multiple sclerosis and acute disseminated encephalomyelitis. Methylprednisolone and dexamethasone show similar efficacy in most conditions. Therapy is associated with significant side effects including worsening of hypertension, infections, dyselectrolytemia and behavioral effects. Adequate monitoring is essential during usage.