The Similarities and Differences Between Glomerular vs. Non-glomerular Diagnoses on Intelligence and Executive Functions in Pediatric Chronic Kidney Disease: A Brief Report.

Pediatric chronic kidney disease (CKD) appears to be a heterogeneous group of conditions, but this heterogeneity has not been explored with respect to its impact on neurocognitive functioning. This study investigated the neurocognitive functioning of those with glomerular (G) vs. non-glomerular (NG) diagnoses. Data from the North American CKiD Study were employed and the current study included 1,003 children and adolescents with mild to moderate CKD. The G Group included 260 participants (median age = 14.7 years) and the NG Group included 743 individuals (median age = 9.0 years). Neurocognitive measures assessed IQ, inhibitory control, attention regulation, problem solving, working memory, and overall executive functioning. Data from all visits were included in the linear mixed model analyses. After adjusting for sociodemographic and CKD-related covariates, results indicated no differences between the diagnostic groups on measures of IQ, problem solving, working memory, and attention regulation. There was a trend for the G group to receive better parent ratings on their overall executive functions (p < 0.07), with a small effect size being present. Additionally, there was a significant G group X hypertension interaction (p < 0.003) for inhibitory control, indicating that those with both a G diagnosis and hypertension performed more poorly than the NG group with hypertension. These findings suggest that the separation of G vs. NG CKD produced minimal, but specific group differences were observed. Ongoing examination of the heterogeneity of pediatric CKD on neurocognition, perhaps at a different time point in disease progression or using a different model, appears warranted.

A reassessment of soluble urokinase-type plasminogen activator receptor in glomerular disease.

It has been suggested that soluble urokinase receptor (suPAR) is a causative circulating factor for and a biomarker of focal and segmental glomerulosclerosis (FSGS). Here we undertook validation of these assumptions in both mouse and human models. Injection of recombinant suPAR in wild-type mice did not induce proteinuria within 24 h. Moreover, a disease phenotype was not seen in an inducible transgenic mouse model that maintained elevated suPAR concentrations for 6 weeks. Plasma and urine suPAR concentrations were evaluated as clinical biomarkers in 241 patients with glomerular disease from the prospective, longitudinal multicenter observational NEPTUNE cohort. The serum suPAR concentration at baseline inversely correlated with estimated glomerular filtration rate (eGFR) and the urine suPAR/creatinine ratio positively correlated with the urine protein/creatinine ratio. After adjusting for eGFR and urine protein, neither the serum nor urine suPAR level was an independent predictor of FSGS histopathology. A multivariable mixed-effects model of longitudinal data evaluated the association between the change in serum suPAR concentration from baseline with eGFR. After adjusting for baseline suPAR concentration, age, gender, proteinuria, and time, the change in suPAR from baseline was associated with eGFR, but this association was not different for patients with FSGS as compared with other diagnoses. Thus these results do not support a pathological role for suPAR in FSGS.

Current treatment of atypical hemolytic uremic syndrome.

Tremendous advances have been made in understanding the pathogenesis of atypical Hemolytic Uremic Syndrome (aHUS), an extremely rare disease. Insights into the molecular biology of aHUS resulted in rapid advances in treatment with eculizumab (Soliris(®), Alexion Pharmaceuticals Inc.). Historically, aHUS was associated with very high rates of mortality and morbidity. Prior therapies included plasma therapy and/or liver transplantation. Although often life saving, these were imperfect and had many complications. We review the conditions included under the rubric of aHUS: S. pneumoniae HUS (SpHUS), inborn errors of metabolism, and disorders of complement regulation, emphasizing their differences and similarities. We focus on the clinical features, diagnosis, and pathogenesis, and treatment of aHUS that results from mutations in genes encoding alternative complement regulators, SpHUS and HUS associated with inborn errors of metabolism. Mutations in complement genes, or antibodies to their protein products, result in unregulated activity of the alternate complement pathway, endothelial injury, and thrombotic microangiopathy (TMA). Eculizumab is a humanized monoclonal antibody that inhibits the production of the terminal complement components C5a and the membrane attack complex (C5b-9) by binding to complement protein C5a. This blocks the proinflammatory and cytolytic effects of terminal complement activation. Eculizumab use has been reported in many case reports, and retrospective and prospective clinical trials in aHUS. There have been few serious side effects and no reports of tachphylaxis or drug resistance. The results are very encouraging and eculizumab is now recognized as the treatment of choice for aHUS.

High-dose continuous renal replacement therapy for neonatal hyperammonemia.

BACKGROUND: Infants with hyperammonemia can present with nonspecific findings so ordering an ammonia level requires a high index of suspicion. Renal replacement therapy (RRT) should be considered for ammonia concentrations of >400 µmol/L since medical therapy will not rapidly clear ammonia. However, the optimal RRT prescription for neonatal hyperammonemia remains unknown. Hemodialysis and continuous renal replacement therapy (CRRT) are both effective, with differing risks and benefits. CASE-DIAGNOSIS/TREATMENT: We present the cases of two neonates with hyperammonemia who were later diagnosed with ornithine transcarbamylase deficiency and received high-dose CRRT. Using dialysis/replacement flow rates of 8,000 mL/h/1.73 m(2) (1,000 mL/h or fourfold higher than the typical rate used for acute kidney injury) the ammonia decreased to <400 µmol/L within 3 h of initiating CRRT and to <100 µmol/L within 10 h. CONCLUSIONS: We propose a CRRT treatment algorithm to rapidly decrease the ammonia level using collaboration between the emergency department and departments of genetics, critical care, surgery/interventional radiology, and nephrology.

Update on Streptococcus pneumoniae associated hemolytic uremic syndrome.

PURPOSE OF REVIEW: Streptococcus pneumoniae associated hemolytic uremic syndrome (SpHUS) is defined by the occurrence of acute hemolytic anemia, thrombocytopenia and acute kidney injury in a patient with a S. pneumoniae infection. We review the pathophysiology, clinical course, treatment and prognosis for SpHUS. We also describe an expanded classification system that uses additional diagnostic criteria to identify more patients with a high likelihood of having SpHUS. RECENT FINDINGS: SpHUS often may be underdiagnosed because of overlapping features with disseminated intravascular coagulation (DIC) and the lack of strict diagnostic criteria. The epidemiology has changed with the emergence of different pneumococcal serotypes as newer pneumococcal vaccines have been introduced. SUMMARY: SpHUS accounts for 5-15% of all HUS cases. The majority of SpHUS patients have pneumonia and a low mortality rate in contrast to those with meningitis, who have a more severe clinical course. Although the pathogenesis of SpHUS remains unknown, the Thomsen-Friedenreich antigen seems to play a central role. S. pneumoniae produces neuraminidase, thereby exposing the Thomsen-Friedenreich antigen on the surface of cell membranes. Thomsen-Friedenreich antigen exposure can result in hemolysis and direct endothelial injury leading to HUS phenotype. Early identification of these patients is critical so that fresh frozen plasma may be avoided.

Long-term outcomes of Shiga toxin hemolytic uremic syndrome.

Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) is an important cause of acute kidney injury (AKI). The outcomes of STEC HUS have improved, and the acute mortality rate in children is 1-4%. About 70% of patients recover completely from the acute episode and the remainder have varying degrees of sequelae. Only a few retrospective studies have reviewed these patients over long periods. Methodological flaws include a lack of strict definitions, changing modes of treatment, ascertainment bias and loss of subjects to follow-up. The kidneys bear the brunt of the long-term damage: proteinuria (15-30% of cases); hypertension (5-15%); chronic kidney disease (CKD; 9-18%); and end-stage kidney disease (ESKD; 3%). A smaller number have extra-renal sequelae: colonic strictures, cholelithiasis, diabetes mellitus or brain injury. Most renal sequelae are minor abnormalities, such as treatable hypertension and/or variable proteinuria. Most of the patients who progress to ESKD do not recover normal renal function after the acute episode. Length of anuria (more than 10 days) and prolonged dialysis are the most important risk factors for a poor acute and long-term renal outcome. After the acute episode all patients must be followed for at least 5 years, and severely affected patients should be followed indefinitely if there is proteinuria, hypertension or a reduced glomerular filtration rate (GFR).

Spirituality, social support, and survival in hemodialysis patients.

BACKGROUND AND OBJECTIVES: No studies have evaluated the relationship among spirituality, social support, and survival in patients with ESRD. This study assessed whether spirituality was an independent predictor of survival in dialysis patients with ESRD after controlling for age, diabetes, albumin, and social support. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 166 patients who had ESRD and were treated with hemodialysis completed questionnaires on psychosocial variables, quality of life, and religious and spiritual beliefs. The religious variables were categorized into three scores on a 0 to 20 scale (low to high levels): Spirituality, religious involvement, and religion as coping. Social support was assessed using the Multidimensional Scale for Perceived Social Support. Analyses were also performed including and excluding patients with HIV infection. Religious variables were categorized on the basis of means, medians, and tertiles. RESULTS: In analyses that used religious variables, only the responses on the spirituality scale split at the mean were associated with survival. The association of other religious variables with survival did not reach significance. Social support correlated with spirituality, religion as coping, and religious involvement measures. Only social support and age were associated with survival when controlling for diabetes, albumin concentration, HIV infection, and spirituality. CONCLUSIONS: These data suggest that the effects of spirituality may be mediated by social support. Larger, multicenter, prospective studies that use well-validated tools to measure religiosity and spirituality are needed to determine whether there is an independent association of spirituality variables with survival in patients with ESRD.