Background and objectives: Acute kidney injury (AKI) is a frequent complication of cardiopulmonary bypass (CPB). Serum creatinine (SCr), the current standard, is an inadequate marker for AKI since a delay occurs before SCr rises. Biomarkers that are sensitive and rapidly measurable could allow early intervention and improve patient outcomes. We investigated the value of serum cystatin C as an early biomarker for AKI after pediatric CPB.Design, setting, participants, & measurements: We analyzed data from 374 prospectively enrolled children undergoing CPB. Serum samples were obtained before and at 2, 12, and 24 hours after CPB. Cystatin C was quantified by nephelometry. The primary outcome was AKI, defined as a >50% increase in SCr. Secondary outcomes included severity and duration of AKI, hospital length of stay, and mortality. A multivariable stepwise logistic regression analysis was used to assess predictors of AKI.Results: One hundred nineteen patients (32%) developed AKI using SCr criteria. Serum cystatin C concentrations were significantly increased in AKI patients at 12 hours after CPB (P < 0.0001) and remained elevated at 24 hours (P < 0.0001). Maximal sensitivity and specificity for prediction of AKI occurred at a 12-hour cystatin C cut-off of 1.16 mg/L. The 12-hour cystatin C strongly correlated with severity and duration of AKI as well as length of hospital stay. In multivariable analysis, 12-hour cystatin C remained a powerful independent predictor of AKI.Conclusion: Serum cystatin C is an early predictive biomarker for AKI and its clinical outcomes after pediatric CPB.

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Pierson syndrome is an autosomal recessive disorder comprising congenital nephrotic syndrome with diffuse mesangial sclerosis and distinct eye abnormalities with microcoria reported as the most prominent clinical feature. LAMB2 mutations leading to lack of laminin beta2 were identified as the molecular cause underlying Pierson syndrome. Although LAMB2 is known to be expressed in the neuromuscular system, and defects of the neuromuscular junctions had been found in laminin beta2-deficient mice, no consistent neurological phenotype has been described clinically in murine or human laminin beta2-deficiency before. This is likely due to the early lethality from renal failure. Here we provide a detailed description of neurological manifestations and development in four patients affected by Pierson syndrome, who survived until the age of 1.3-4.8 years owing to renal replacement therapy. Severe muscular hypotonia, psychomotor retardation, and blindness were present in three patients harboring truncating mutations on both LAMB2 alleles. These symptoms were not attributable to complications of chronic renal failure, thus representing a primary feature of the genetic disorder. Alterations in skeletal muscle tissue from one case were compatible with a chronic denervating process. One affected girl, however, exhibited a milder course of renal disease, normal development, and preserved vision, presumably owing to some residual LAMB2 function. Our findings indicate that severe neurodevelopmental deficits have to be considered as part of Pierson syndrome, at least in the presence of biallelic functional null mutations (complete lack of laminin beta2). This is an important issue in the counseling of parents of an affected newborn or infant.

Pierson syndrome is a congenital nephrotic syndrome with ocular and neurological defects caused by mutations in LAMB2 , the gene encoding the basement membrane protein laminin β2 (Lamβ2). It is the kidney glomerular basement membrane (GBM) that is defective in Pierson syndrome, as Lamβ2 is a component of laminin-521 (LM-521; α5β2γ1), the major laminin in the mature GBM. In both Pierson syndrome and the Lamb2 −/− mouse model for this disease, laminin β1 (Lamβ1), a structurally similar homolog of Lamβ2, is marginally increased in the GBM, but it fails to fully compensate for the loss of Lamβ2, leading to the filtration barrier defects and nephrotic syndrome. Here we generated several lines of Lamβ1 transgenic mice and used them to show that podocyte-specific Lamβ1 expression in Lamb2 −/− mice abrogates the development of nephrotic syndrome, correlating with a greatly extended lifespan. In addition, the more Lamβ1 was expressed, the less urinary albumin was excreted. Transgenic Lamβ1 expression increased the level of Lamα5 in the GBM of rescued mice, consistent with the desired increased deposition of laminin-511 (α5β1γ1) trimers. Ultrastructural analysis revealed occasional knob-like subepithelial GBM thickening but intact podocyte foot processes in aged rescued mice. These results suggest the possibility that up-regulation of LAMB1 in podocytes, should it become achievable, would likely lessen the severity of nephrotic syndrome in patients carrying LAMB2 mutations.

On the basis of strong research evidence, the prevalence of poststreptococcal glomerulonephritis (PSGN) is decreasing worldwide, although it still remains the leading cause of glomerulonephritis in children. The overall decrease in prevalence of PSGN has been mainly driven by a significant decrease in pyoderma seen in the last half-century, such that postpharyngitic PSGN is most commonly seen in developed nations. On the basis of primarily consensus because of a lack of relevant clinical studies, the latency period between streptococcal infection and the development of nephritis is a hallmark of PSGN, with this period lasting 1 to 2 weeks with pharyngeal infections or 2 to 6 weeks with skin infections. Concurrent infectious and nephritis symptoms should elicit further suspicion of other causes of glomerulonephritis. On the basis of expert opinion, PSGN is one of a handful of nephritic disorders with hypocomplementemia (low C3 level). The decrease in C3 is found in more than 90% of PSGN cases and is typically seen earlier than an increase in antistreptolysin O titers. Measuring C3 and C4 may also be helpful in the evaluation of other causes of acute nephritis. On the basis of primarily consensus because of a lack of relevantclinical studies, the main sequelae of PSGN (hypertension, edema,gross hematuria, and impaired renal function) are greatest in thefirst 7 to 10 days of disease. Therefore, this period requires themost vigilance for adverse effects. On the basis of some research evidence and consensus, the most effective treatment of hypertension and edema in PSGN is loop or thiazide diuretics, which may also address hyperkalemia. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may be effective in hypertension control but carry the risk of hyperkalemia and temporarily impairing recovery of renal function. On the basis of some research evidence and consensus, the prognosis for PSGN, even long term, is good. Despite being the most prevalent of the childhood glomerulonephritides, it often does not cause chronic kidney disease, but persistent microscopic hematuria and proteinuria may be seen in less than 10% of patients.

MMF is commonly prescribed following kidney transplantation, yet its use is complicated by leukopenia. Understanding the genetics mediating this risk will help clinicians administer MMF safely. We evaluated 284 patients under 21 years of age for incidence and time course of MMF-related leukopenia and performed a candidate gene association study comparing the frequency of 26 SNPs between cases with MMF-related leukopenia and controls. We matched cases by induction, steroid duration, race, center, and age. We also evaluated the impact of induction and SNPs on time to leukopenia in all cases. Sixty-eight (24%) patients had MMF-related leukopenia, of which 59 consented for genotyping and 38 were matched with controls. Among matched pairs, no SNPs were associated with leukopenia. With non-depleting induction, UGT2B7-900A>G (rs7438135) was associated with increased risk of MMF-related leukopenia (P = .038). Time to leukopenia did not differ between patients by induction agent, but 2 SNPs (rs2228075, rs2278294) in IMPDH1 were associated with increased time to leukopenia. MMF-related leukopenia is common after transplantation. UGT2B7 may influence leukopenia risk especially in patients without lymphocyte-depleting induction. IMPDH1 may influence time course of leukopenia after transplant.

We describe a child with familial hypocalciuric hypercalcemia (FHH) in whom the hypercalcemia seemed to interfere with tissue healing after tympanoplasty. Consequently, he was placed on cinacalcet (30 mg/day), changed after 2 weeks to 60 mg/day. The treatment resulted in a decrease in serum parathyroid hormone (PTH) from 148 to 32 pg/mL (normal 7-75) and ionized calcium from 1.48 to 1.23 mmol/L (1.13-1.34), as well as successful healing of the revised surgical scar. Over the 12-month treatment period no complications were noted. We conclude that cinacalcet may be considered a new, and currently the only, tool in treating children with symptomatic FHH.

In this report, we describe a newborn infant who presented with congenital nephrotic syndrome and renal insufficiency, as well as bilateral microcoria. This constellation of findings is a hallmark of Pierson syndrome, a newly recognized genetic disorder that is caused by a deficiency of beta2 laminin in the basement membrane. Our patient demonstrated classic histopathologic findings of Pierson syndrome on renal biopsy, including absence of beta2 laminin on immunofluorescent staining, and genetic testing confirmed the diagnosis. We conclude that Pierson syndrome should be included in the differential diagnosis for congenital nephrotic syndrome, especially in patients with ocular abnormalities.