DEVELOPING THERAPIES FOR C3G: REPORT OF THE KIDNEY HEALTH INITIATIVE C3G TRIAL ENDPOINTS WORK GROUP.

Randomized clinical trials are underway to evaluate the efficacy of novel agents targeting the alternative complement pathway in patients with C3G, a rare glomerular disease. The Kidney Health Initiative (KHI) convened a panel of experts in C3G to: (1) assess the data supporting the use of the prespecified trial endpoints as measures of clinical benefit; and (2) opine on efficacy findings they would consider compelling as treatment(s) for C3G in native kidneys. Two subpanels of the C3G Trial Endpoints Work group reviewed the available evidence and uncertainties for the association between the three prespecified endpoints -- (1) proteinuria; (2) estimated glomerular filtration rate (eGFR); and (3) histopathology -- and anticipated outcomes. The full work group provided feedback on the summaries provided by the subpanels and on what potential treatment effects on the proposed endpoints they would consider compelling to support evidence of an investigational product's effectiveness for treating C3G. Members of the full work group agreed with the characterization of the data, the evidence, and uncertainties, supporting the endpoints. Given the limitations of the available data, the workgroup was unable to define a minimum threshold for change in any of the endpoints that might be considered clinically meaningful. The workgroup concluded that a favorable treatment effect on all three endpoints would provide convincing evidence of efficacy in the setting of a therapy that targeted the complement pathway. A therapy might be considered effective in the absence of complete alignment in all three endpoints if there was meaningful lowering of proteinuria and stabilization or improvement in eGFR. The panel unanimously supported efforts to foster data sharing between academic and industry partners to address the gaps in the current knowledge identified by the review of the endpoints in the aforementioned trials.

Carotid Artery Flow Time Measured by Point-of-Care Ultrasound Correlates with Volume Changes in Pediatric Hemodialysis Patients.

Carotid artery flow time corrected for heart rate (CFTc) correlates with intravascular volume changes in adults but has not been studied adequately in the pediatric population. We studied how fluid status changes correlate with CFTc in pediatric patients undergoing hemodialysis. This prospective observational study involved pediatric patients aged 5-18 y undergoing chronic hemodialysis at a tertiary care children's hospital in the United States. We measured CFTc by point-of-care ultrasound before and after each hemodialysis session, including passive leg raise. One hundred sixty-eight CFTc measurements were obtained from a total of 21 patient encounters. Post-dialysis CFTc decreased by 21.7 ms (95% confidence interval: 12.3-31.0) (p < 0.001). Pre- and post-dialysis ∆CFTc measurements were proportionally correlated with volume removed in dialysis adjusted for weight (mL/kg) (R2 = 0.224, p = 0.03). There was no significant change in mean CFTc with passive leg raise before or after hemodialysis. In children on hemodialysis, changes in CFTc were moderately correlated with decrease in intravascular volume after hemodialysis.

Dialysis disequilibrium syndrome prevention and management.

The dialysis disequilibrium syndrome (DDS) is a clinical constellation of neurologic symptoms and signs occurring during or shortly following dialysis, especially when dialysis is first initiated. It is a diagnosis of exclusion occurring in those that are uremic and hyperosmolar, in whom rapid correction with renal replacement therapy leads to cerebral edema and raised intracranial pressure with resultant clinical neurologic manifestations. DDS is most commonly described in association with hemodialysis but can occur in patients with acute kidney injury requiring continuous renal replacement therapy (CRRT). To date, it has not been described in association with peritoneal dialysis. The syndrome is uncommon and becoming rarer, so performing randomized controlled trials to evaluate the effectiveness of potential therapies is almost impossible. This also makes studying the pathophysiology in humans challenging. It is associated with mortality but is also preventable, so identification of patients at risk, preventive measures, early recognition and prompt management of DDS will minimize morbidity and mortality associated with this syndrome. While the focus of this review is the prevention and management of DDS, there will be an emphasis on what is known about the pathophysiology because it strongly impacts the prevention and management strategies.

Pleural and pericardial effusion: A manifestation of SVC syndrome in a child on chronic hemodialysis.

Central venous catheter is commonly utilized as a hemodialysis access in the pediatric population. Long-standing central venous catheters can be complicated by superior vena cava (SVC) stenosis and thrombosis that can rarely present as pleural effusions. We report a case of a 5-year-old boy on chronic hemodialysis who presented with combined pleural and pericardial effusions, which was secondary to catheter induced SVC stenosis. Both the pleural effusion and the pericardial effusion in this patient subsequently improved with the relief of SVC stenosis. This case report highlights the serious complications of SVC stenosis associated with long-standing central venous catheters which is an under-recognized problem in the pediatric population.

Renal and urological diseases of the newborn neonatal acute kidney injury.

Survival of critically ill neonates in the intensive care unit has improved over the past decades reflecting improvements in obstetric, delivery room and neonatal intensive care, however, morbidity remains significant. Acute kidney injury is a common occurrence in these neonates and despite improved understanding of the pathophysiology and management of acute kidney injury in full term and preterm infants, the mortality remains as high as 61%. Furthermore, there is growing evidence that despite recovery from the acute injury, these infants are at risk for developing hypertension and chronic kidney disease later in life. Emphasis on improving our capability to detect renal insult and injury early, before renal failure occurs, and identification of novel therapeutic agents to prevent and treat acute kidney injury may impact mortality and morbidity. This review focuses on our current knowledge of acute kidney injury in the newborn, approaches to investigating and managing this complication and what future trends in this field may bring.

Assessment of glomerular and tubular function.

At birth, GFR and tubular function of neonates is compromised as compared to older children and adults. These functions are even less developed in premature infants. These facts have a direct bearing on drug dosing, fluid and electrolyte administration, and maintenance of acid-base balance in neonates. Although many detailed methods of assessing renal functions have been provided in this article, laboratory and radiologic studies available in most healthcare facilities are often sufficient to provide a clinically relevant data in most patients, including neonates.

Dialysis disequilibrium syndrome occurring during continuous renal replacement therapy.

The dialysis disequilibrium syndrome (DDS) is characterized by progressive neurological symptoms and signs attributable to cerebral edema that occurs due to fluid shifts into the brain following a relatively rapid decrease in serum osmolality during hemodialysis (HD). Since continuous renal replacement therapy (CRRT) is less efficient at solute clearance than intermittent HD, it seems logical that this mode of therapy is less likely to cause DDS. This entity has not been previously reported to occur with this modality. Here, we report two cases of DDS associated with CRRT that provide insights into its pathophysiological mechanisms and suggest strategies for its prevention.

Novel mutations in NPHP4 in a consanguineous family with histological findings of focal segmental glomerulosclerosis.

Nephronophthisis is a form of autosomal recessive hereditary cystic kidney disease that typically progresses to end-stage renal disease by early adulthood. Conversely, focal segmental glomerulosclerosis is a histological glomerular phenotype that can be familial, primary (idiopathic), or secondary to a multitude of pathological processes affecting the kidney, including such tubulointerstitial diseases as nephronophthisis. Mutations in 6 distinct nephronophthisis genes have been described to date. We describe a consanguineous Filipino family with 2 novel sequence variants in the NPHP4 gene. Affected individuals presented with end-stage renal disease and histological features of focal segmental glomerulosclerosis on biopsy. They also had atypical radiological findings, making the clinical diagnosis of the genetic syndrome difficult. Furthermore, although ocular abnormalities and hearing loss were described previously, this is the first report of hepatic disease in patients with mutations in NPHP4. The diagnosis of nephronophthisis was made by means of mutational analysis of the NPHP4 gene after isolation of a region of homozygosity in affected individuals by using whole-genome single-nucleotide polymorphism analysis. Because establishment of the correct diagnosis has implications for therapeutic interventions, prognosis, and, in the case of heritable diseases, appropriate genetic counseling for affected individuals and their families, this report emphasizes the importance of obtaining meticulous clinical information, considering alternative diagnoses, and, when possible, performing genetic evaluation to confirm the diagnosis. We outline an approach to patients with hereditary kidney disease, focusing specifically on the molecular genetic techniques available to evaluate such families and determine a chromosomal region of interest and, subsequently, the diagnosis.