Delbert R. Wigfall

Management of Childhood Onset Nephrotic Syndrome

The therapeutic approach to childhood nephrotic syndrome is based on a series of studies that began with an international collaborative effort sponsored by the International Study of Kidney Disease in Children in 1967. The characteristics of children presenting with nephrotic syndrome have changed over recent decades with greater frequency of the challenging condition focal segmental glomerulosclerosis and a greater prevalence of obesity and diabetes mellitus, which may be resistant to glucocorticoids in the former and exacerbated by long-term glucocorticoid therapy in the latter 2 conditions. The Childrens Nephrotic Syndrome Consensus Conference was formed to systematically review the published literature and generate a childrens primary nephrotic syndrome guideline for use in educational, therapeutic, and research venues.

Prevelance and clinical correlates of glomerulopathy in children with sickle cell disease

Objectives: Glomerular disease and renal failure cause substantial morbidity for patients with sickle cell disease (SCD). Proteinuria is an early manifestation of sickle nephropathy, but the prevalence of proteinuria and its clinical correlations in children with SCD are unknown. Study design: Data were collected prospectively on children with SCD for 10 years including physical measurements, laboratory test results, and clinical complications. Persistent proteinuria was defined as ≥1 + protein on urinalysis for at least 6 months. The glomerular filtration rate was estimated with serum creatinine concentration and height. Proteinuria was correlated with other variables by χ 2 analysis. Results: Proteinuria occurred in 20 of 442 pediatric patients including 15 (6.2%) with sickle cell anemia. Proteinuria increased with age, affecting 12% of older teenagers with sickle cell anemia. Proteinuria was significantly associated with lower hemoglobin concentration, higher mean corpuscular volume, and higher leukocyte count. For children of some ages, proteinuria was associated with complications including stroke, acute chest syndrome, cholelithiasis, and hospitalizations. Glomerular filtration rate hyperfiltration occurred early in life, followed by normalization. Conclusions: Sickle nephropathy, manifested as persistent proteinuria, begins early in life, occurs in all forms of SCD, and is associated with severity of disease. Early detection of proteinuria may allow therapy to prevent progressive renal insufficiency.

GENITOURINARY COMPLICATIONS OF SICKLE CELL DISEASE

PURPOSE In the last half century the molecular biology, pathophysiology and natural history of sickle cell disease have been well defined. Sickle cell disease causes microvascular occlusion, which is manifested in most organ systems. The genitourinary tract is most commonly affected by hematuria, urinary tract infection and priapism but other more serious sequelae have been identified. MATERIALS AND METHODS We performed a computerized MEDLINE search from 1965 to the present and a bibliographic review of cross references. These references were analyzed for meaningful findings and case reports. RESULTS The diagnosis and management of sickle cell disease have advanced rapidly with a significant increase in the life expectancy of affected patients and recognition of a greater number of genitourinary complications. Renal function may be mildly altered or lost completely. Patients with sickle cell disease are at increased risk for urinary tract infection. Priapism is a painful complication of sickle cell disease that is poorly understood and challenging to treat and prevent. Testicular infarction has also been noted. Furthermore, renal medullary carcinoma, a highly lethal tumor, develops almost exclusively in young patients with sickle cell trait. CONCLUSIONS Heightened awareness of the genitourinary complications of sickle cell disease may prevent end stage disease, including renal failure and impotence. New forms of therapy for sickle cell disease, such as hydroxyurea, may prevent these complications in the future.

Enalapril and hydroxyurea therapy for children with sickle nephropathy

Proteinuria in children with sickle cell anemia (SCA) is an early sign of sickle nephropathy, and portends the development of nephrotic syndrome and chronic renal failure. Enalapril has been shown to reduce proteinuria in adult patients with SCA, but the potential benefits of hydroxyurea in this clinical setting have not been reported. A single institution retrospective analysis was performed. Children with sickle nephropathy were identified, and the laboratory effects of enalapril and hydroxyurea therapy were evaluated in children with substantial proteinuria. Three children developed proteinuria at 8 ± 1 years of age. Pre‐treatment laboratory studies included a low serum albumin (2.8 ± 0.8 g/dl) and a highly elevated urine protein/creatinine ratio (6.9 ± 3.7, normal <0.2). Enalapril treatment for 3.0 ± 1.3 years normalized serum albumin (3.9 ± 0.3 g/dl) without significant changes in serum potassium, serum creatinine, or systolic blood pressure. However, urine protein/creatinine remained elevated in the nephrotic range (1.6 ± 0.7). The addition of hydroxyurea therapy for 3.5 ± 1.2 years increased fetal hemoglobin levels (7.0 ± 3.6% to 21.0 ± 3.2%) and was associated with a near‐normal urine protein/creatinine ratio (0.5 ± 0.1). Enalapril therapy for children with sickle nephropathy reduces urinary protein excretion and normalizes serum albumin. Hydroxyurea therapy may further normalize the urine protein/creatinine ratio. Combination therapy should be tested prospectively in children with sickle nephropathy.

HLA-DQA1 and PLCG2 Are Candidate Risk Loci for Childhood-Onset Steroid-Sensitive Nephrotic Syndrome

Steroid-sensitive nephrotic syndrome (SSNS) accounts for >80% of cases of nephrotic syndrome in childhood. However, the etiology and pathogenesis of SSNS remain obscure. Hypothesizing that coding variation may underlie SSNS risk, we conducted an exome array association study of SSNS. We enrolled a discovery set of 363 persons (214 South Asian children with SSNS and 149 controls) and genotyped them using the Illumina HumanExome Beadchip. Four common single nucleotide polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants that were tested (odds ratio, 2.11; 95% confidence interval, 1.56 to 2.86; P=1.68×10(-6) (Fisher exact test). Two of these SNPs-the missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1-were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and ≤589 controls; P=1.42×10(-17)). In the rare variant gene set-based analysis, the best signal was found in PLCG2 (P=7.825×10(-5)). In conclusion, this exome array study identified HLA-DQA1 and PLCG2 missense coding variants as candidate loci for SSNS. The finding of a MHC class II locus underlying SSNS risk suggests a major role for immune response in the pathogenesis of SSNS.

Interleukin-2 receptor expression in peripheral blood lymphocytes from systemic lupus erythematosus patients: Relationship to clinical activity

Deficient interleukin-2 (IL-2) production and other T-cell dysfunctions have been demonstrated in active systemic lupus erythematosus (SLE). The generation of IL-2 receptors is known to be important to the growth and differentiation of T and B lymphocytes. This study investigated IL-2 receptor expression in peripheral blood lymphocytes (PBL) from patients with active and inactive SLE. PBL from 27 SLE patients, diagnosed by revised ARA criteria, were assayed for IL-2 receptor expression, IL-2 and immunoglobulin (Ig) production. PBL from SLE patients with active disease spontaneously expressed increased numbers of IL-2 receptors compared to those with inactive disease (P less than 0.01) and normal donors (P less than 0.01). There was no significant increase in IL-2 receptors expression in PBL from active SLE patients in response to mitogenic stimulation with PHA compared to inactive SLE patients and normal donors. There was negligible IL-2 production in response to mitogenic stimulation and increased spontaneous IgG production by PBL from active SLE patients compared to normal donors (P less than 0.001). Purified B cells isolated from active SLE patients showed significant spontaneous IL-2 receptor expression when compared to spontaneous IL-2 receptor expression by normal B cells (P = 0.005). Therefore, in addition to derangements in Ig and IL-2 production, the level of spontaneous expression of IL-2 receptors may represent a cellular indicator of disease activity, and hence, may be a useful parameter in monitoring disease activity in SLE patients. The significance of the increased IL-2 receptor expression on B cells of active SLE patients is unknown, but may represent a marker of polyclonal activation of these cells.

Efficacy of Antibiotic Prophylaxis in Children with Vesicoureteral Reflux: Systematic Review and Meta-Analysis

PURPOSE Controversy exists regarding the use of continuous antibiotic prophylaxis vs observation in the management of children with vesicoureteral reflux. The reported effectiveness of continuous antibiotic prophylaxis in children with reflux varies widely. We determined whether the aggregated evidence supports use of continuous antibiotic prophylaxis in children with vesicoureteral reflux. MATERIALS AND METHODS We searched the Cochrane Controlled Trials Register, clinicaltrials.gov, MEDLINE(®), EMBASE(®), Google Scholar and recently presented meeting abstracts for reports in any language. Bibliographies of included studies were then hand searched for any missed articles. The study protocol was prospectively registered at PROSPERO (No. CRD42014009639). Reports were assessed and data abstracted in duplicate, with differences resolved by consensus. Risk of bias was assessed using standardized instruments. RESULTS We identified 1,547 studies, of which 8 are included in the meta-analysis. Pooled results demonstrated that continuous antibiotic prophylaxis significantly reduced the risk of recurrent febrile or symptomatic urinary tract infection (pooled OR 0.63, 95% CI 0.42-0.96) but, if urinary tract infection occurred, increased the risk of antibiotic resistant organism (pooled OR 8.75, 95% CI 3.52-21.73). A decrease in new renal scarring was not associated with continuous antibiotic prophylaxis use. Adverse events were similar between the 2 groups. Significant heterogeneity existed between studies (I(2) 50%, p = 0.03), specifically between those trials with significant risk of bias (eg unclear protocol descriptions and/or lack of blinding). CONCLUSIONS Compared to no treatment, continuous antibiotic prophylaxis significantly reduced the risk of febrile and symptomatic urinary tract infections in children with vesicoureteral reflux, although it increased the risk of infection due to antibiotic resistant bacteria. Continuous antibiotic prophylaxis did not significantly impact the occurrence of new renal scarring or reported adverse events.

Variability in phenotype induced by the podocin variant R229Q plus a single pathogenic mutation

Background Mutations in podocin (NPHS2) are the most common cause of childhood onset autosomal recessive steroid-resistant nephrotic syndrome (SRNS). The disease is characterized by early-onset proteinuria, resistance to immunosuppressive therapy and rapid progression to end-stage renal disease. Compound heterozygous changes involving the podocin variant R229Q combined with another pathogenic mutation have been associated with a mild phenotype with disease onset often in adulthood. Methods We screened 19 families with early-onset SRNS for mutations in NPHS2 and WT1 and identified four disease-causing mutations (three in NPHS2 and one in WT1) prior to planned whole-exome sequencing. Results We describe two families with three individuals presenting in childhood who are compound heterozygous for R229Q and one other pathogenic NPHS2 mutation, either L327F or A297V. One child presented at age 4 years (A297V plus R229Q) and the other two at age 13 (L327F plus R229Q), one with steadily deteriorating renal function. Conclusions These cases highlight the phenotypic variability associated with the NPHS2 R229Q variant plus pathogenic mutation. Individuals may present with early aggressive disease.

Appearance of immune complex glomerulonephritis following the onset of type I diabetes mellitus in a child

Renal disease is a frequent late complication of type I diabetes mellitus, occurring almost entirely in adult patients. Typical diabetic nephropathy is characterized by proteinuria, and by the histological lesions of mesangial expansion and basement membrane thickening. We report an interesting case of a 3-year-old boy who developed immune complex glomerulonephritis with nephrotic syndrome 2 months after the onset of insulin-dependent diabetes mellitus.

Essentials of Nephrology

Abstract The basic functions of the kidney are to maintain fluid and electrolyte homeostasis and metabolism. Renal disease requires the practitioner to be vigilant about fluid homeostasis, acid-base balance, electrolyte management, choice of anesthetics, and potential complications. This requires a thorough understanding of the excretory and fluid homeostatic functions of the kidney, particularly in the neonate and younger child. If not managed assiduously, perioperative renal dysfunction can deteriorate into renal failure or multiorgan system failure resulting in significant morbidity or mortality. The anesthesia provider must understand renal physiology, appropriate preoperative preparation, intraoperative management, and postoperative care of the child with renal disease.