Eberhard Kuwertz-Bröking

Mutations in CYP24A1 and Idiopathic Infantile Hypercalcemia

BACKGROUND Vitamin D supplementation for the prevention of rickets is one of the oldest and most effective prophylactic measures in medicine, having virtually eradicated rickets in North America. Given the potentially toxic effects of vitamin D, the recommendations for the optimal dose are still debated, in part owing to the increased incidence of idiopathic infantile hypercalcemia in Britain in the 1950s during a period of high vitamin D supplementation in fortified milk products. We investigated the molecular basis of idiopathic infantile hypercalcemia, which is characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis. METHODS We used a candidate-gene approach in a cohort of familial cases of typical idiopathic infantile hypercalcemia with suspected autosomal recessive inheritance. Identified mutations in the vitamin D-metabolizing enzyme CYP24A1 were evaluated with the use of a mammalian expression system. RESULTS Sequence analysis of CYP24A1, which encodes 25-hydroxyvitamin D 24-hydroxylase, the key enzyme of 1,25-dihydroxyvitamin D(3) degradation, revealed recessive mutations in six affected children. In addition, CYP24A1 mutations were identified in a second cohort of infants in whom severe hypercalcemia had developed after bolus prophylaxis with vitamin D. Functional characterization revealed a complete loss of function in all CYP24A1 mutations. CONCLUSIONS The presence of CYP24A1 mutations explains the increased sensitivity to vitamin D in patients with idiopathic infantile hypercalcemia and is a genetic risk factor for the development of symptomatic hypercalcemia that may be triggered by vitamin D prophylaxis in otherwise apparently healthy infants.

Mutations in the Human Laminin β2 (LAMB2) Gene and the Associated Phenotypic Spectrum

Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin β2, which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease‐causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin β2 function is the molecular basis of Pierson syndrome. Although truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N‐terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist. Hum Mutat 31:992–1002, 2010.

Immunosuppression and Renal Outcome in Congenital and Pediatric Steroid-Resistant Nephrotic Syndrome

BACKGROUND AND OBJECTIVES Mutations in podocyte genes are associated with steroid-resistant nephrotic syndrome (SRNS), mostly affecting younger age groups. To date, it is unclear whether these patients benefit from intensified immunosuppression with cyclosporine A (CsA). The aim of this study was to evaluate the influence of podocyte gene defects in congenital nephrotic syndrome (CNS) and pediatric SRNS on the efficacy of CsA therapy and preservation of renal function. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS Genotyping was performed in 91 CNS/SRNS patients, irrespective of age at manifestation or response to CsA. RESULTS Mutations were identified in 52% of families (11 NPHS1, 17 NPHS2, 11 WT1, 1 LAMB2, 3 TRPC6). Sixty-eight percent of patients with nongenetic SRNS responded to CsA, most of them achieved complete remission. In contrast, none of the patients with genetic CNS/SRNS experienced a complete remission and only two (17%) achieved a partial response, both affected by a WT1 mutation. Preservation of renal function was significantly better in children with nongenetic disease after a mean follow-up time of 8.6 years (ESRD in 29% versus 71%). CONCLUSIONS The mutation detection rate in our population was high (52%). Most patients with genetic CNS/SRNS did not benefit from CsA with significantly lower response rates compared with nongenetic patients and showed rapid progression to end-stage renal failure. These data strongly support the idea not to expose CNS/SRNS patients with inherited defects related to podocyte function to intensified immunosuppression with CsA.

Extracorporeal Shock Wave Lithotripsy in Children

Objectives: Extracorporeal shock wave lithotripsy (ESWL) is effective and safe for the treatment of upper urinary tract calculi in adults. Some speculations concerning possible damages from ESWL on the growing kidney have been raised. Methods: From January 1990 to December 1998, 64 children (30 girls and 34 boys; 8 months to 15 years old, mean 5.6 years) with a total of 83 stones of the upper urinary tract were treated by ESWL (Lithostar). Preoperative evaluation included history, physical examination, routine blood tests, urinalysis, urine culture, intravenous urography and optional renal scintigraphy. The impulse rate per treatment varied from 750 to 4,000 (mean 2,996). After acute treatment, routine follow–up included renal ultrasound, blood pressure controls, laboratory tests and eventually plain film X–ray. Results: Successful fragmentation of the stones was achieved in all patients. In 54% the patients were free of stones treated at the time of discharge. At 3 months after treatment radiographic studies showed no residual fragments in 80% of the treated children. 83% of the treated stones were cleared entirely. The remaining fragments were clinically insignificant. An average of 2.5 ESWL treatments per child in general anesthesia were required. Stone analysis showed 20 calcium oxalate, 38 calcium phosphate, 12 struvite, 2 uric acid and 9 cystine calculi. Ureteral stents were placed in 43%. No significant urinary infection was seen under antibiotic prophylaxis. Only 3 children showed a recurrence (1 × cystinuria with low compliance and 2 × struvite). There was no case of renal scarring. No change in renal function or blood pressure was found compared to the preoperativ values. Hematuria and proteinuria disappeared in all children who were free of stones. Renal ultrasound revealed no growth difference between treated and untreated renal units. Conclusions: In childhood, ESWL is an efficacious and safe treatment of stones of the upper urinary tract. The long–term follow–up after ESWL with a second–generation lithotriptor did not show any signs of damage to the growing kidney. Sometimes repeated ESWL treatments are justified by the low rate of complications.

CLDN16 Genotype Predicts Renal Decline in Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive tubular disorder caused by CLDN16 mutations. CLDN16 encodes the renal tight junction protein claudin-16, which is important for the paracellular reabsorption of calcium and magnesium in the thick ascending limb of Henle’s loop. That FHHNC is frequently associated with progressive renal failure suggests additional roles for claudin-16 in the maintenance of tight junction integrity. An investigation of 32 patients with FHHNC and 17 different mutations was previously reported; here, the analysis is expanded to 39 additional patients and 12 new mutations. Expression studies revealed that five of the12 new mutations led to partial loss of claudin-16 function and the remaining seven led to complete loss of function. The 23 patients who had mutations resulting in complete loss of function of both alleles were significantly younger at the onset of symptoms than the 46 patients who had at least one mutant allele providing partial function (2.2 versus 5.6 years; P _ 0.01). In addition, those with complete loss of function had a more rapid decline in GFR (7.3 versus 2.9 ml/min per 1.72 m2/y; P _ 0.01), leading to 54% requiring renal replacement therapy by age 15 compared with 20% of those with residual function (P _0.05). These data suggest that residual function of claudin-16 may delay the progression of renal failure in FHHN

Combined C3b and factor B autoantibodies and MPGN type II.

This letter describes two unrelated patients with membranoproliferative glomerulonephritis type 2 and autoantibodies to the two individual components of C3 convertase, factor B and C3. These autoantibodies enhance C3 convertase activity, probably leading to nephritis.

New Treatment Options for Bartter's Syndrome

To the Editor: Bartters syndrome is a major cause of congenital salt wasting. As a consequence of abnormal salt reabsorption in the thick ascending limb of Henles loop due to mutations in the lum...

Accelerated kidney transplant rejection and hypertensive encephalopathy in a pediatric patient associated with antibodies against angiotensin type 1 receptor and HLA class II.

This work was supported by the University of Nebraska Medical Center Research Support Fund. J.T.L. has received money for support from Merck & Co., Inc. to study sitagliptin in a subsequent study. All other authors declare no conflicts of interest. Address correspondence to: James T. Lane, M.D., Division of Endocrinology and Diabetes, Department of Internal Medicine, Harold Hamm Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, 1000 N. Lincoln Blvd., Suite 2900, Oklahoma City, OK 73104-3252. E-mail: james-lane@ouhsc.edu J.T.L. participated in the design, and implementation of the study, participated in the recruitment and clinical care of patients, completed data acquisition, statistical analysis, and manuscript preparation. D.E.O. participated in statistical analysis, data acquisition, and review of the manuscript. C.E.H participated in the recruitment of patients, clinical follow-up within the clinical research center, data acquisition, and review of the manuscript. D.S.C. participated in the design of the study and review of the manuscript. L.E.W. performed renal transplants and administered clinical care. R.B.S. performed renal transplants, administered clinical care, participated in the design and implementation of the study, recruited patients, and reviewed the manuscript. Received 21 July 2011. Accepted 24 August 2011. Copyright

Renal Fanconi syndrome: first sign of partial respiratory chain complex IV deficiency.

Abstract A 2-year-old boy who developed hypophosphatemic rickets without signs of muscular weakness or neurological disturbances is presented. Biochemical findings included hypophosphatemia, metabolic acidosis, hypouricemia, hyperphosphaturia, severe glucosuria, generalized hyperaminoaciduria, hypercalciuria, proteinuria with elevated excretion of IgG, transferrin, albumin and high levels of α-1-microglobulin. Urine concentration capacity and creatinine clearance were normal. Lactaturia without elevated levels of plasma lactate and a high urinary excretion of β-hydroxybutyrate were suggestive for mitochondriopathy. Partial deficiency of cytochrome c oxidase (complex IV of the respiratory chain) was found in skeletal muscle. A renal biopsy specimen demonstrated enlarged mitochondria with abnormal arborization and disorientation of the cristae in the proximal tubular cells. Reduced activity of mitochondrial cytochrome c oxidase in tubular cells could be demonstrated by ultracytochemistry. In conclusion, rickets due to the renal Fanconi syndrome can be the first clinical sign of mitochondrial cytopathies without extrarenal symptoms. Elevated excretion of lactate and ketone bodies in urine may serve as a diagnostic marker.

Diagnostik bei konnatalen Dilatationen der Harnwege

ZusammenfassungHintergrund. Durch prä- und postnatales sonographisches Screening werden bei annähernd jedem 100. Kind Nieren- oder Harnwegsfehlbildungen erkannt. Meist besteht das Bild einer ureteropelvinen Stenose oder eines Megaureters. Diagnostik. Besonders in diesen Fällen ist für die Therapieentscheidung die Differenzierung zwischen einer korrekturbedürftigen Obstruktion und einer Harnwegsdilatation ohne Auswirkung auf die Nierenfunktion essenziell. Beurteilungskriterien für die Einschätzung der Harntransportstörung sind die Nierenbeckenkelchdilatation mit ihrer zeitlichen Dynamik bei Verlaufskontrollen, der Nuklidabfluss im Diureseszintigramm und die seitengetrennte Nierenfunktion. Indikation, Durchführung und Bewertung der Diagnostik sind bislang uneinheitlich. Standardisierung. Zur Vergleichbarkeit von Untersuchungsbefunden und insbesondere zur Planung prospektiver randomisierter Therapiestudien ist jedoch eine Standardisierung erforderlich. Die APN beauftragte daher eine Arbeitsgruppe, einen Konsens über diagnostische Strategien für konnatale Harnwegsdilatationen zu erreichen. Die Erarbeitung der endgültigen Fassung erfolgte in Kooperation mit dem Arbeitskreis Kinderurologie der Deutschen Gesellschaft für Urologie und mit der Arbeitsgemeinschaft für Kinderurologie in der Deutschen Gesellschaft für Kinderchirurgie unter fachlicher Beratung durch führende Kinderadiologen und Nuklearmediziner. Die wesentlichen Ergebnisse werden vorgestellt.AbstractBackground. Anomalies of the urinary tract are detected by ultrasound screening in one out of one hundred newborns. In most cases, dilatations of the upper urinary tract result from ureteropelvic junction obstruction or a primary megaureter. Diagnosis. Especially in these cases, it is essential to differentiate between an obstruction defined as a stenosis potentially leading to progressive parenchymal damage from a dilatation without any consequences for renal function. Main criteria for the assessment of urinary transport are ultrasound examinations to observe the dilatation of the collecting system, washout of the tracer during diuresis renography and the split renal function. Standardization. Standards for investigation procedures are required to ensure comparability of treatment concepts and especially for prospective randomized studies planned for the future. A consensus concerning basic diagnostic strategies has been elaborated by a task force group consisting of members of the “Arbeitsgemeinschaft für Pädiatrische Nephrologie” in cooperation with the “Arbeitskreis Kinderurologie” in the German Society of Urology and the “Kinderurologische Arbeitsgemeinschaft” in the German Society of Pediatric Surgery with advice from leading pediatric radiologists and specialists in pediatric nuclear medicine. The main contents of this consensus are reported.