Two Qatari siblings with cystic fibrosis and apparent mineralocorticoid excess.

Cystic fibrosis (CF) and apparent mineralocorticoid excess (AME) syndrome are both autosomal recessive disorders that result from mutations of specific identified genes for each condition. CF is caused by defects in the Cystic fibrosis trans membrane conductance regulator (CFTR) gene which encodes for a protein that functions as a chloride channel and regulates the flow of other ions across the apical surface of epithelial cells. AME is due to the deficiency of 11ß-hydroxysteroid dehydrogenase type 2 enzyme (11ßHSD2), which is responsible for the peripheral inactivation of cortisol to cortisone. Cortisol excess stimulates the mineralocoritoid receptors (MR) resulting in intense sodium retention, hypokalemia and hypertension. We report on a consanguineous Arab family, in which two sibs inherited both CF and AME. Gene testing for AME revealed previously unreported mutation in the 11ßHSD2 gene. This report draws attention to the importance of recognizing the possibility of two recessive disorders in the same child in complex consanguineous families. Moreover, it provides a unique opportunity to highlight the implications of the coexistence of two genetic disorders on patient care and genetic counseling of the family.

Two-dose daclizumab induction in pediatric renal transplantation.

DCZ, an IL-2 receptor antagonist, has been widely used for induction therapy in pediatric and adult solid organ transplantation. Originally, it was recommended as a five-dose regimen; however, fewer doses may be efficacious and less costly for prevention of rejection. There is limited experience with the use of fewer doses in pediatric renal transplantation. We retrospectively reviewed the outcomes of 26 primary pediatric renal transplants performed at a single center between June 2004 and May 2007 receiving induction therapy with two-dose DCZ (1.5 mg/kg preoperatively and day seven post-transplant). Maintenance immunosuppression included tacrolimus, MMF, and prednisone in all patients. Forty-six percent were African American and 92% were deceased-donor transplants. After a mean follow-up of 17.8 +/- 7.5 months, acute rejection was noted in 11.5% and graft survival was 92.3%. CMV infection occurred in 11.5%, but no case of BK nephropathy or post-transplant lymphoproliferative disorder was observed. Our preliminary results suggest that induction therapy with two-dose DCZ was convenient, economical, and effective in preventing rejection episodes without an increase in adverse events or hospital stay. Larger randomized clinical trials with longer duration of follow-up are needed to more fully validate the use of this regimen in pediatric renal transplantation.

Membranous glomerulonephritis: treatment response and outcome in children.

The aim of this study was to characterize clinical features, treatment response, and outcome of idiopathic membranous glomerulonephritis (MGN) in a single-center cohort of children. A retrospective review of biopsy-proven idiopathic MGN in 12 children (mean age 11.9 years) was undertaken. Presentation was nephrotic syndrome (NS) (75%), hematuria/proteinuria (17%), and asymptomatic proteinuria (8%). Ten patients (83%) with NS and nephrotic range proteinuria (NRP) were treated with prednisone, and two patients with non-NRP were not treated with immunosuppressive medications. Steroid response in the treated patients was complete (10%), partial (40%), and absent (50%), respectively. Oral cyclophosphamide was used in seven patients of whom five were steroid resistant, one was steroid dependent, and one was partially responsive. At the mean follow up of 27 months, outcome parameters included an estimated glomerular filtration rate of 128 cc/min per 1.73 m(2), albumin of 4.2 gm/dL, and a urine protein/creatinine ratio of 0.87 [median 0.16 (range 0.02-6.52)]. Remission was complete in 75% of the patients and partial in 17%. One patient (8%) with chronic kidney disease (stage 2) was unresponsive to therapy. Complete remission was significantly associated with the absence of chronic histological changes (p = 0.03). In conclusion, children with NS and/or NRP associated with MGN appear to have a good prognosis when treated with a combination of corticosteroids and cyclophosphamide.

Ceftriaxone induced hemolysis complicated by acute renal failure.

Over the last decade, second and third generation cephalosporins have been the most common drugs causing hemolytic anemia (HA). Of these cases, 20% have been attributed to ceftriaxone. The clinical presentation of ceftriaxone-induced HA is usually abrupt with sudden onset of pallor, tachypnea, cardio-respiratory arrest and shock. Acute renal failure (ARF) has been reported in 41% of such cases with a high fatality rate. We report a pediatric patient with ARF complicating ceftriaxone-induced HA who survived. Ceftriaxone is a commonly used drug, and early recognition of HA and institution of supportive care, including dialysis is likely to improve the outcome.

Intravenous immunoglobulin, HLA allele typing and HLAMatchmaker facilitate successful transplantation in highly sensitized pediatric renal allograft recipients.

The use of intravenous immunoglobulin (IVIG) in sensitized transplant candidates has resulted in reduced HLA antibody levels and shorter transplant wait times. In addition, the HLAMatchmaker program has been used to identify acceptable mismatches to permit transplantation in highly sensitized patients. We used IVIG desensitization in conjunction with high resolution HLA allele typing and HLAMatchmaker grading of donor offers to facilitate successful transplantation in two highly sensitized children who were awaiting second renal transplants. Both patients lost their initial transplant in <10 days to accelerated acute rejection, and were on dialysis for an average of 50 months with high panel reactive antibody (PRA) levels. They were started on monthly IVIG infusions (2 g/kg/dose). Within one wk following their third and fifth IVIG doses, both patients received a crossmatch compatible, deceased donor renal transplant selected by HLAMatchmaker as a suitable donor offer. Both patients remain rejection free with excellent renal function 19 and 15 months post-transplant, respectively. In conclusion, combining IVIG therapy and donor selection by HLA humoral epitope matching permitted successful transplantation of two highly sensitized children. Further studies in larger numbers of patients with longer follow-up are needed to determine the individual role played by, and relative importance of each component of this combined strategy.

Calciphylaxis in pediatric end-stage renal disease.

Calciphylaxis is a rare, but life-threatening complication of end-stage renal disease (ESRD) that has been reported mostly in adult patients. The exact etiology is unknown, but the disease is commonly associated with a high calcium-phosphorus product and elevated levels of parathyroid hormone (PTH). We herein review the published reports on calciphylaxis in ESRD patients less than 18 years old and report the case of a patient with severe calciphylaxis who presented with lower extremity pain, muscle tenderness and difficulty in walking. The serum PTH was low, and the calcium-phosphorus product was normal. The diagnosis of calciphylaxis was confirmed by a muscle biopsy. Treatment with low calcium peritoneal dialysate and substitution of calcium-based phosphorus binders with sevelamer (Renagel) was unsuccessful. The patient's clinical condition progressed to extensive soft tissue calcification and ulcerating skin lesions. Nine months after the onset of symptoms, the patient died of cardiopulmonary arrest.

The death domain of kidney ankyrin interacts with Fas and promotes Fas-mediated cell death in renal epithelia.

Ankyrins are a ubiquitously expressed family of conserved proteins that mediate the linkage of integral membrane proteins such as transporters and channels with the underlying cytoskeleton. Ankyrins possess a conserved death domain, the functional significance of which has remained puzzling. In this study, the death domain of AnkG190, the isoform of ankyrin expressed in kidney tubules, was used as bait in a yeast two-hybrid screen to identify interacting partners. One of these interactions was with the proapoptotic molecule Fas. This was confirmed by coimmunoprecipitation, colocalization, and glutathione S-transferase pull-down assays in cultured renal epithelial (MDCK) cells. Site-directed mutagenesis of a conserved arginine (R1496 in AnkG190), previously shown to be critical for the binding of Fas (R234 in Fas) to FADD, abolished the interaction of ankyrin's death domain with Fas. Overexpression of constructs containing ankyrin's death domain promoted Fas-mediated apoptosis in MDCK cells. The linkage between ankyrin and Fas was confirmed in vivo in mouse kidney tubule cells by coimmunoprecipitation and colocalization. In an established mouse model of renal ischemia-reperfusion injury characterized by apoptotic tubule cell death, the expression of both ankyrin and Fas was markedly induced, and the interaction between these molecules remained intact. The results identify a novel tethering interaction between ankyrin and Fas in kidney epithelia and suggest that AnkG190 may play a role as an adapter molecule in renal tubule cell death.

Renal papillary necrosis induced by naproxen.

A 17-year-old healthy girl was admitted to our hospital with diffuse abdominal pain and decreased oral intake of about 11 days duration. About a week prior to admission, she had taken naproxen, 250 mg four times a day for 4 days. Physical examination was normal except for diffuse abdominal tenderness on deep palpation. Investigations revealed high serum BUN (42 mg/dl) and creatinine (4.0 mg/dl). Serum electrolytes and complement (C3, C4) levels and urinalysis were normal. Antinuclear-antibody and anti-dsDNA were negative. Kidney biopsy revealed renal papillary necrosis, acute tubular necrosis, and focal interstitial nephritis. A diagnosis of nonoliguric acute renal failure due to naproxen nephrotoxicity was made. She received intravenous hydration, and oral steroids, which was gradually discontinued in 3 months. A follow-up at 4 months revealed normal renal function with a serum creatinine of 1.1 mg/dl, BUN 7 mg/dl, and normal urinalysis. The report highlights a need for caution while using naproxen or any other nonsteroidal anti-inflammatory drugs, even for a short duration.