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Interventions for Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura: A Systematic Review of Randomized Controlled Trials

BACKGROUND Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are related conditions with similar clinical features of variable severity. The objective of this systematic review is to evaluate the benefits and harms of available interventions for HUS and TTP. SELECTION CRITERIA FOR STUDIES MEDLINE (1966 to June 2006), EMBASE (1980 to June 2006), the Cochrane Central Register, conference proceedings, and reference lists were searched to find randomized controlled trials (RCTs) of any intervention for HUS or TTP in patients of all ages selected for inclusion for this systematic review. INTERVENTIONS Trials that compared an intervention with placebo, an intervention with supportive therapy, or one or more different interventions for HUS or TTP. OUTCOMES For TTP trials, failure of remission at 2 weeks or less and at 1 month or longer, all-cause mortality rate, and relapse rate. For HUS trials, all-cause mortality, chronic reduced kidney function, and persistent proteinuria or hypertension at last follow-up. RESULTS For TTP in adults, we found 6 RCTs of 331 patients. Two trials compared plasma infusion with plasma exchange using fresh frozen plasma and showed failure of remission at 2 weeks (2 trials, 140 patients; relative risk, 2.87; 95% confidence interval, 1.41 to 5.84), and all-cause mortality (relative risk, 1.91; 95% confidence interval, 1.09 to 3.33) occurred more frequently in the plasma infusion group. Three trials compared plasma exchange using cryosupernatant plasma with plasma exchange using fresh frozen plasma, and a meta-analysis of these trials showed no difference. Seven RCTs in 476 young children with postdiarrheal HUS have been conducted. None of the evaluated interventions (fresh frozen plasma transfusion, heparin with or without urokinase or dipyridamole, Shiga toxin-binding protein, and steroid) were superior to supportive therapy alone for any outcomes. LIMITATIONS Limitations of this review include the small number and suboptimal quality of reporting of included trials, possibility of publication bias, small number of participants with atypical HUS, and failure to report results for patients with atypical and typical HUS separately. CONCLUSIONS No additional therapy has been shown to increase efficacy over plasma exchange for TTP. No intervention has been shown to be superior to supportive therapy in patients with postdiarrheal HUS.

Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene

Purpose:To investigate the utility of whole-exome sequencing (WES) to define a molecular diagnosis for patients clinically diagnosed with congenital anomalies of kidney and urinary tract (CAKUT).Methods:WES was performed in 62 families with CAKUT. WES data were analyzed for single-nucleotide variants (SNVs) in 35 known CAKUT genes, putatively deleterious sequence changes in new candidate genes, and potentially disease-associated copy-number variants (CNVs).Results:In approximately 5% of families, pathogenic SNVs were identified in PAX2, HNF1B, and EYA1. Observed phenotypes in these families expand the current understanding about the role of these genes in CAKUT. Four pathogenic CNVs were also identified using two CNV detection tools. In addition, we found one deleterious de novo SNV in FOXP1 among the 62 families with CAKUT. The clinical database of the Baylor Miraca Genetics laboratory was queried and seven additional unrelated individuals with novel de novo SNVs in FOXP1 were identified. Six of these eight individuals with FOXP1 SNVs have syndromic urinary tract defects, implicating this gene in urinary tract development.Conclusion:We conclude that WES can be used to identify molecular etiology (SNVs, CNVs) in a subset of individuals with CAKUT. WES can also help identify novel CAKUT genes.Genet Med 19 4, 412–420.

Patient EducationMedical Nutrition Therapy for Pediatric Kidney Stone Prevention, Part One

Intended Audience: Pediatrics; Nephrology Outpatient Clinic; Children With Kidney Stones RENAL STONE DISEASE, or nephrolithiasis, is a major health concern associated with significant pain, morbidity, and medical cost. Recurrent nephrolithiasis can lead to chronic kidney disease, as well as increased risk of related conditions such as cardiovascular disease and fracture. The incidence of nephrolithiasis appears to be increasing among US children in recent decades. Moreover, the health and economic burden of nephrolithiasis may be heightened in children who have increased rates of metabolic abnormalities, resulting in recurrent nephrolithiasis, leading to increased risk for developing end-stage renal disease. The majority of children (up to 95%) with nephrolithiasis have at least one metabolic abnormality that will likely require a combination of dietary and pharmacological therapy. Most common metabolic abnormalities are hypercalciuria and hypocitraturia, either isolated or co-occurring; other metabolic abnormalities include hyperuricosuria, hyperoxaluria, and cystinuria. Although studies that focus on pediatric populations are scarce, extrapolations from adult research suggest that the increasing rates of nephrolithiasis are related to shifting dietary norms, such as the widespread consumption of processed and fast foods, diets high in sodium and animal protein, and the decline in the consumption of fruits, vegetables, and calcium-rich foods.

Medical Nutrition Therapy for Pediatric Kidney Stone Prevention, Part Two

Intended Audience: Pediatric Patients, Nephrology Outpatient Clinic Patients, Pediatric Kidney Stone Clinic Patients THEARTICLETHAT follows represents the second in a three-part series of handouts intended to provide a comprehensive nutrition education tool for the prevention of pediatric nephrolithiasis. The dietary recommendations presented in the handouts are described in the following along with the evidence-based rational and application in the clinical setting.

Outcomes of two-drug maintenance immunosuppression for pediatric renal transplantation: 10-yr follow-up in a single center

Minimizing IS to reduce side effects without compromising long‐term renal transplant survival is the goal of all IS protocols. We conducted a retrospective study of pediatric renal transplants performed August 1988 to July 2008 and treated with two‐drug maintenance therapy by one of three protocols: prednisone/cyclosporine without induction (SB) or with daclizumab induction (SBI), or tacrolimus/mycophenolate with daclizumab induction (SF). Kaplan–Meier survival curves were used to determine graft and patient survival at one, three, five, and 10 yr. Associations between graft survival and patient/transplant characteristics were determined using log‐rank test and CPH model adjusting for treatment group. About 208 patients were included in the analysis (96 SB, 97 SBI, 15 SF; 148 DD, 60 LD, 37 pre‐emptive). Overall graft and patient survival at one, three, five, and 10 yr were similar to the previously published results of pediatric renal transplants in similar years treated predominantly with three‐drug maintenance therapy (https://web.emmes.com/study/ped/annlrept/2010). Only biopsy‐proven TG was significantly associated with worse graft survival (HR 11.5, 95% CI: 3.4, 38.7). Malignancy rate was low (2.4%) with little PTLD (0.5%). Few opportunistic or other infections occurred (<5% patients). Minimizing IS to a two‐drug maintenance regimen had no adverse effect on long‐term transplant outcome and had low malignancy and infection rates.

Persistent Cat Scratch Disease Requiring Surgical Excision in a Patient With MPGN

We present the case of a 13-year-old immunosuppressed patient with unrelenting cat scratch disease despite 9 months of antibiotic therapy. The patient was being treated with mycophenolate and prednisone for membranoproliferative glomerulonephritis (type 1) diagnosed 13 months before the onset of cat scratch disease. Cat scratch disease was suspected due to epitrochlear lymphadenitis and an inoculation papule on the ipsilateral thumb, and the diagnosis was confirmed by the use of acute and convalescent titers positive for Bartonella henselae. The patient experienced prolonged lymphadenitis despite azithromycin and rifampin therapy, and she developed a draining sinus tract ∼4 months after initial inoculation while receiving antibiotics. Acute exacerbation of the primary supratrochlear node prompted incision and drainage of the area, with no improvement in the disease course. Ultimately, excision of all affected nodes and the sinus tract 9 months after the initial diagnosis was required to achieve resolution. Bartonella was detected at a high level according to a polymerase chain reaction assay in the excised nodes. Persistent treatment with oral antibiotics may have prevented disseminated infection in this immunosuppressed patient. Surgical excision of affected nodes should be considered in patients with cat scratch disease that persists beyond 16 weeks.

Idiopathic membranous nephropathy in children treated with rituximab: report of two cases

BackgroundIdiopathic membranous nephropathy is an uncommon cause of nephrotic syndrome in children and can present treatment challenges. The current treatment options of steroids and cyclophosphamide, cyclosporine, or mycophenolate require prolonged treatment durations and the associated side effects may result in nonadherence in children, especially in adolescents.Case-diagnosisWe report two adolescent patients with idiopathic membranous nephropathy with nephrotic range proteinuria and elevated anti-phospholipase A2 receptor levels who did not achieve remission with steroids and were later treated with rituximab. Both patients received two doses of rituximab and responded with remission. In addition, anti-PLA2R antibody levels normalized and/or significantly improved.ConclusionsRituximab seems to be a safe and effective treatment option in children with idiopathic membranous nephropathy due to anti-PLA2R. Further studies are needed to evaluate this effectiveness.

Milky appearance of peritoneal fluid in a neonate on peritoneal dialysis due to end-stage renal disease: Questions

A 5-week-old Caucasian male infant was born at 37 weeks and 3 days of gestation, with a birth weight of 3.375 kg and a pre-natal diagnosis of lower urinary tract obstruction with normal amniotic fluid. The post-natal ultrasound [day of life (DOL) 1] was consistent with a diagnosis of bilateral cystic renal dysplasia. The initial serum creatinine (Cr) level was 1.34 mg/dL at birth. A voiding cystourethrogram on DOL 3 identified dilated posterior urethra and right vesicoureteral reflux. On DOL 6, the infant underwent diagnostic cystoscopy which showed a congenital bulbar urethra stricture without valves and dilation of the stricture; a peritoneal dialysis (PD) catheter (39 cm single cuff curled) was put in place at this time. Due to the non-oliguric nature of the infant’s renal failure, the PD catheter was allowed to heal prior to use. Continuous manual PD (Gesco AG, Wuppertal, Germany) was started on DOL 12 when the Cr level peaked at 6.69 mg/dL, with hourly cycles and a fill volume of 10 mL/kg (30 ml) using 1.5% Dianeal solution; average ultrafiltration ranged from 90 to 170 mL/day. His neonatal course was further complicated by the development of Escherichia coli urosepsis on DOL 18 with bacteremia and cerebrospinal fluid pleocytosis which was treated with intravenously administered ceftriaxone for a total of 21 days. He received expressed breast milk (380 mL) + Similac PM 60/40 10 kcal/oz. + Duocal 3 kcal/oz. + 1.2 g Beneprotein/100 mL (Diet 1) to limit electrolyte content due to end-stage renal disease while providing adequate nutrition for growth at 100 kcal/kg/day and volume 100 mL/kg/day. He tolerated feeds well while on the Gesco PD system and showed good interval weight gain. The fill volume was adjusted by 5 mL/kg every 1–2 weeks to achieve the eventual target of 40 mL/kg fill volume. On DOL 34, at which time the infant had been receiving PD on the Gesco PD system for approximately 3 weeks, and 48 h after the fill volume had been increased to 60 mL (15 mL/kg), his peritoneal fluid turned milky in appearance (Fig. 1).

Deficiency of complement factor H-related proteins and autoantibody-positive hemolytic uremic syndrome in an infant with combined partial deficiencies and autoantibodies to complement factor H and ADAMTS13

ABSTRACT A 3-month-old male infant developed an extremely severe episode of atypical hemolytic uremic syndrome (aHUS) associated with partial deficiencies of full-length complement factor H (FH; ∼15% of infant normal) and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) (39% of normal) and autoantibodies reactive with both proteins. His FH and ADAMTS13 genes were normal, indicating that the partial deficiencies were acquired, probably as the result of autoantibodies against full-length FH and ADAMTS13. The child also had a homozygous deletion of the complement factor H–related (CFHR)3–CFHR1 portion in the complement factor H (CFH) gene cluster. He therefore had deficiency of CFHR proteins and autoantibody-positive hemolytic uremic syndrome (DEAP-HUS) with an unusual early onset associated with a partial deficiency of ADAMTS13 and an anti-ADAMTS13 autoantibody. His clinical episode of aHUS responded to plasma infusion and subsequent treatment with mycophenolate and rituximab. We believe that this is the first report of DEAP-HUS in an infant with partial deficiencies in both ADAMTS13 and full-length FH acquired in association with autoantibodies to both proteins.

A case of gross hematuria with flank pain in a 16-year-old boy: Questions

A 16-year-old Caucasian boy presented with intermittent gross hematuria for 3 months and an episode of bilateral flank pain 2 weeks before the clinic visit. He had no history of trauma, dysuria, frequency, urinary tract infections or passage of kidney stones. Initial workup showed normal serum creatinine of 0.7 mg/dL, normal complete blood count, normal C3, negative antinuclear antibody (ANA), and negative urine culture. Urine analysis showed 1+ blood with 51–100 red blood cells (RBC)/hpf, no RBC casts, crystals or protein. Urine calcium/Cr ratio was 0.19 mg/mg and urine protein/Cr ratio 0.14 mg/mg. Doppler renal ultrasound (RUS) performed at a local hospital showed normal renal artery blood flow. The right and left kidneys measured 11.1 cm and 11.2 cm respectively and there was no evidence of mass, hydronephrosis or stones, and the bladder was normal. His medical history was significant for HLA-B27 ankylosing spondylitis for which he was followed by rheumatology on Humira 40 mg SQ every 7 days. His family history was significant as his mother had had ankylosing spondylitis and kidney stones. Physical examination showed a healthy appearing male with normal blood pressure 126/74 and a body mass index 22.92 kg/m (75 % tile) in no apparent distress and unremarkable examination without any flank tenderness, rash or lower extremity edema. Because there was a family history of stones, he was advised to hydrate a minimum of 3 L/day and to monitor for recurrence of symptoms. The patient returned for follow-up 4 months later and reported intermittent episodes of gross hematuria at baseball practice, with no episodes of flank pain or proteinuria (was doing urine dipsticks at home). Evaluation was unremarkable except for microscopic hematuria, hence continued observation was planned. Four months later, he was seen at another hospital’s emergency room with severe left-sided flank pain associated with vomiting, gross hematuria, and with the passage of blood clots. Spiral computed tomography (CT) did not show any stones and he was sent home after a few hours of observation as the symptoms resolved with hydration and analgesia. The next day a CT angiography of the abdomen The answers to these questions can be found at http://dx.doi.org/10.1007 /s00467-016-3521-3