SUMMARYThe syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatremia. We describe two infants whose clinical and laboratory evaluations were consistent with the presence of SIADH, yet who had undetectable arginine vasopressin (AVP) levels. We hypothesized that they had gain-of-function mutations in the V2 vasopressin receptor (V2R). DNA sequencing of each patient's V2R gene (AVPR2) identified missense mutations in both, with resultant changes in codon 137 from arginine to cysteine or leucine. These novel mutations cause constitutive activation of the receptor and are the likely cause of the patients' SIADH-like clinical picture, which we have termed "nephrogenic syndrome of inappropriate antidiuresis."Fluid homeostasis depends on proper water intake, governed by an intact thirst mechanism, and on urinary excretion of free water, mediated by appropriate secretion of arginine vasopressin (AVP) (also known as antidiuretic hormone). 1 AVP exerts its antidiuretic action by binding to the V2 vasopressin receptor (V2R), a G protein-coupled receptor, on the basolateral membrane of epithelial cells in the collecting duct of the kidney. Ligand binding activates the V2R, stimulating adenylate cyclase by means of G s proteins. The resulting increase in intracellular cyclic AMP (cAMP) promotes shuttling of intracellular vesicles containing the water channel aquaporin-2 to the apical membrane of the collecting-duct cells, thereby increasing water permeability and inducing antidiuresis.Clinical disorders of water balance are common, and alterations in many steps of this pathway have been described. 1 Urinary concentrating defects associated with diabetes insipidus may result from a deficiency of AVP or from nephrogenic causes, such as Xlinked, inactivating mutations in the V2R or autosomal recessive or autosomal dominant lesions in aquaporin-2. 2 Conversely, the syndrome of inappropriate antidiuretic hormone secretion (SIADH) manifests as an inability to excrete a free water load, with inappropriately concentrated urine and resultant hyponatremia, hypo-osmolality, and We describe two unrelated male infants whose clinical presentation was consistent with the presence of chronic SIADH but who had undetectable AVP levels. We postulated that novel activating mutations of the V2R might account for their unique presentation. Evaluation revealed novel activating mutations of the V2R leading to what we term "nephrogenic syndrome of inappropriate antidiuresis" (NSIAD). HHS Public Access CASE REPORTSPatient 1 presented at 3 months of age with irritability, and Patient 2 presented at 2.5 months of age with two generalized seizures. Both children had had unremarkable early neonatal courses. Both were exclusively bottle-fed formula (7 mmol of sodium per liter). Both infants had mild systolic hypertension with otherwise normal physical examinations. Initial laboratory evaluations demonstrated hyponatremia with normal serum levels of potassium and bicarbonate (Table 1). Both children had serum hypo-o...

Monitoring of renal graft status through peripheral blood (PB) rather than invasive biopsy is important as it will lessen the risk of infection and other stresses, while reducing the costs of rejection diagnosis. Blood gene biomarker panels were discovered by microarrays at a single center and subsequently validated and cross-validated by QPCR in gthe NIH SNSO1 randomized study from 12 US pediatric transplant programs. A total of 367 unique human PB samples, each paired with a graft biopsy for centralized, blinded phenotype classification, were analyzed (115 acute rejection (AR), 180 stable and 72 other causes of graft injury). Of the differentially expressed genes by microarray, Q-PCR analysis of a five gene-set (DUSP1, PBEF1, PSEN1, MAPK9 and NKTR) classified AR with high accuracy. A logistic regression model was built on independent training-set (n=47) and validated on independent test-set (n=198)samples, discriminating AR from STA with 91% sensitivity and 94% specificity and AR from all other non-AR phenotypes with 91% sensitivity and 90% specificity. The 5-gene set can diagnose AR potentially avoiding the need for invasive renal biopsy. These data support the conduct of a prospective study to validate the clinical predictive utility of this diagnostic tool.

To determine whether steroid avoidance in pediatric kidney transplantation is safe and efficacious, a randomized, multicenter trial was performed in 12 pediatric kidney transplant centers. One hundred thirty children receiving primary kidney transplants were randomized to steroid‐free (SF) or steroid‐based (SB) immunosuppression, with concomitant tacrolimus, mycophenolate and standard dose daclizumab (SB group) or extended dose daclizumab (SF group). Follow‐up was 3 years posttransplant. Standardized height Z‐score change after 3 years follow‐up was –0.99 ± 2.20 in SF versus –0.93 ± 1.11 in SB; p = 0.825. In subgroup analysis, recipients under 5 years of age showed improved linear growth with SF compared to SB treatment (change in standardized height Z‐score at 3 years –0.43 ± 1.15 vs. –1.07 ± 1.14; p = 0.019). There were no differences in the rates of biopsy‐proven acute rejection at 3 years after transplantation (16.7% in SF vs. 17.1% in SB; p = 0.94). Patient survival was 100% in both arms; graft survival was 95% in the SF and 90% in the SB arms (p = 0.30) at 3 years follow‐up. Over the 3 year follow‐up period, the SF group showed lower systolic BP (p = 0.017) and lower cholesterol levels (p = 0.034). In conclusion, complete steroid avoidance is safe and effective in unsensitized children receiving primary kidney transplants.

Neonates with a presumptive diagnosis of end-stage renal disease may initiate long-term dialysis during the first month of life with outcomes comparable to those of patients who initiate dialysis later in infancy.