The Clinical Utility of Genetic Testing in the Diagnosis and Management of Adults with Chronic Kidney Disease.

SIGNIFICANCE STATEMENT: Accurate diagnosis of a patient's underlying cause of CKD can influence management and ultimately overall health. The single-arm, interventional, prospective Renasight Clinical Application, Review, and Evaluation study assessed the utility of genetic testing with a 385 gene kidney disease panel on the diagnosis and management of 1623 patients with CKD. Among 20.8% of patients who had positive genetic findings, half resulted in a new or reclassified diagnosis. In addition, a change in management because of genetic testing was reported for 90.7% of patients with positive findings, including treatment changes in 32.9%. These findings demonstrate that genetic testing has a significant effect on both CKD diagnosis and management. BACKGROUND: Genetic testing in CKD has recently been shown to have diagnostic utility with many predicted implications for clinical management, but its effect on management has not been prospectively evaluated. METHODS: Renasight Clinical Application, Review, and Evaluation RenaCARE (ClinicalTrials.gov NCT05846113 ) is a single-arm, interventional, prospective, multicenter study that evaluated the utility of genetic testing with a broad, 385 gene panel (the Renasight TM test) on the diagnosis and management of adult patients with CKD recruited from 31 US-based community and academic medical centers. Patient medical history and clinical CKD diagnosis were collected at enrollment. Physician responses to questionnaires regarding patient disease categorization and management were collected before genetic testing and 1 month after the return of test results. Changes in CKD diagnosis and management after genetic testing were assessed. RESULTS: Of 1623 patients with CKD in 13 predefined clinical disease categories (ages, 18-96; median, 55 years), 20.8% ( n =338) had positive genetic findings spanning 54 genes. Positive genetic findings provided a new diagnosis or reclassified a prior diagnosis in 48.8% of those patients. Physicians reported that genetic results altered the management of 90.7% of patients with a positive genetic finding, including changes in treatment plan, which were reported in 32.9% of these patients. CONCLUSIONS: Genetic testing with a CKD-focused 385 gene panel substantially refined clinical diagnoses and had widespread implications for clinical management, including appropriate treatment strategies. These data support the utility of broader integration of panels of genetic tests into the clinical care paradigm for patients with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov, NCT05846113 .

Steroid Responsive Atypical Hemolytic Uremic Syndrome Triggered by Influenza B Infection.

Atypical hemolytic uremic syndrome (aHUS) is characterized by uncontrolled complement activation leading to thrombotic microangiopathy and severe end-organ damage. The most common trigger for an episode of aHUS in the background of genetic deregulation of the alternative complement pathway is systemic infection. There are only 4 reported cases of aHUS triggered by influenza B thus far. Current accepted therapies for aHUS include plasma exchange and eculizumab. We describe a unique patient with aHUS with a rare membrane cofactor protein mutation triggered by influenza B infection, who achieved complete remission with treatment with high-dose corticosteroids after failure of plasmapheresis.

Bortezomib in the treatment of antibody-mediated rejection in pediatric kidney transplant recipients: A multicenter Midwest Pediatric Nephrology Consortium study.

Antibody-mediated rejection leads to allograft loss after kidney transplantation. Bortezomib has been used in adults for the reversal of antibody-mediated rejection; however, pediatric data are limited. This retrospective study was conducted in collaboration with the Midwest Pediatric Nephrology Consortium. Pediatric kidney transplant recipients who received bortezomib for biopsy-proven antibody-mediated rejection between 2008 and 2015 were included. The objective was to characterize the use of bortezomib in pediatric kidney transplant recipients. Thirty-three patients received bortezomib for antibody-mediated rejection at nine pediatric kidney transplant centers. Ninety percent of patients received intravenous immunoglobulin, 78% received plasmapheresis, and 78% received rituximab. After a median follow-up of 15 months, 65% of patients had a functioning graft. The estimated glomerular filtration rate improved or stabilized in 61% and 36% of patients at 3 and 12 months post-bortezomib, respectively. The estimated glomerular filtration rate at diagnosis significantly predicted estimated glomerular filtration rate at 12 months after adjusting for chronic histologic changes (P .001). Fifty-six percent of patients showed an at least 25% reduction in the mean fluorescence intensity of the immune-dominant donor-specific antibody, 1-3 months after the first dose of bortezomib. Non-life-threatening side effects were documented in 21 of 33 patients. Pediatric kidney transplant recipients tolerated bortezomib without life-threatening side effects. Bortezomib may stabilize estimated glomerular filtration rate for 3-6 months in pediatric kidney transplant recipients with antibody-mediated rejection.

Townes-Brocks Syndrome Revealed by Kidney Gene Panel Testing.

Introduction: Townes-Brocks syndrome (TBS), a rare autosomal dominant genetic condition associated with SALL1 (Spalt like Transcription Factor 1), is reported to be present in 1:238,000 individuals in the general population. TBS is characterized by the triad of anorectal malformations, dysplastic ears, with or without hearing impairment, and hand or thumb anomalies. Although kidney involvement is less common in TBS, the disease can progress to kidney failure. Here, we sought to characterize the incidence of SALL1 variants in individuals undergoing broad-based genetic testing with a kidney gene panel and to quantify the presence of (extra)renal features. Methods: A retrospective analysis of the genetic data from a 385-gene panel identified cases with a pathogenic (P) or likely pathogenic (LP) variant in SALL1. Data including age, features, and disease progression were collected. Results: Of 35,044 samples, P or LP variants in SALL1 were identified in 22, yielding a prevalence of 1:1592 among patients tested for monogenic kidney disease, and 1:342 among cases identified with a monogenic kidney disease. Among this cohort, the median patient age was 23 years (range: 3 months-62 years) with chronic kidney disease (CKD) reported in 91% (20/22) of cases. Reported kidney features included renal agenesis/hypoplasia (7/22; 32%), focal segmental glomerulosclerosis (4/22; 18%), and kidney cysts (3/22; 14%). Confirmed extrarenal features included hearing loss and/or ear features (7/22; 32%), anorectal malformations (6/22; 27%) and hand or thumb abnormalities (4/22; 18%). Three patients (3/22; 14%) had both a priori TBS diagnoses and the traditional "triad." Conclusion: Traditionally, a molecular diagnosis was ascertained primarily in individuals presenting with cardinal features of TBS; therefore, individuals with mild or atypical presentations were often overlooked clinically. Our findings reveal that SALL1 P/LP variants could be a consequential contributor to monogenic kidney disease.

Pericardial Effusion Causing Cardiac Tamponade in a 10-Year-Old Male.

A 10-year-old male with a past medical history of premature pubarche, mild persistent asthma, and eczema presented to the emergency department with progressive dyspnea and chest pain. On examination, he was found to be tachycardic and tachypneic. Chest radiograph demonstrated cardiomegaly, bilateral pleural effusions, and scattered atelectasis. Echocardiogram revealed a large pericardial effusion with right atrial collapse. The patient was admitted to the pediatric ICU for pericardiocentesis and drain placement. As he later became hypertensive and febrile, we will discuss how our patient's hospital course guided our differential diagnosis and how we arrived at a definitive diagnosis using a multidisciplinary approach.

Retrospective cohort study of individuals born with low birthweight: implications for screening practices.

BACKGROUND: Previous studies have established an association between low birthweight (LBW) and future kidney disease, but few have explored the progression of kidney dysfunction through the pediatric years leading up through adolescence and young adulthood. METHODS: To better understand the temporal effects of birthweight on kidney disease progression, we conducted a retrospective cohort study comparing the glomerular filtration rate (GFR) between LBW (<2500 grams) and normal birthweight (NBW) infants who were admitted to the neonatal intensive care unit (NICU) at our institution from 1992 to 2006. RESULTS: Age at follow-up ranged 1-26 years old. GFR was found to be significantly lower in participants born with LBW than those born with NBW, with a mean difference of 5.5 mL/min/1.73m2 (P < 0.01). These differences were found in the adolescent and young adult age group over 9 years of age, specifically in the extremely low birthweight group (ELBW) whose birthweight was less than 1000 grams. CONCLUSIONS: We recommend screening for CKD in ELBW individuals starting at the age of 9 years old, regardless of their previous medical history.

Magnesium Supplementation Shortens Hemodialysis-Associated Prolonged QT.

Hemodialysis affects myocardial depolarization and repolarization notably lengthening the QT interval. Prolonged QT, in turn, has been a reliable surrogate for higher risk of potentially lethal ventricular arrhythmias. We present an adolescent girl with end-stage kidney disease who consistently developed prolonged QT following hemodialysis sessions. Interestingly, her QT intervals were inversely correlated with her serum magnesium levels. Magnesium supplementation appeared to help reduce the QT prolongation after hemodialysis. Our case shows the potential utility of magnesium as a cardioprotective agent in hemodialysis patients. We recommend that patients undergoing hemodialysis receive frequent electrocardiograms and electrolytes monitoring for tailored electrolytes management to reduce the risk of developing potentially lethal cardiac arrhythmias.

TGF-beta signal transduction in chronic kidney disease.

Transforming growth factor (TGF)-beta is a central stimulus of the events leading to chronic progressive kidney disease, having been implicated in the regulation of cell proliferation, hypertrophy, apoptosis and fibrogenesis. The fact that it mediates these varied events suggests that multiple mechanisms play a role in determining the outcome of TGF-beta signaling. Regulation begins with the availability and activation of TGF-beta and continues through receptor expression and localization, control of the TGF-beta family-specific Smad signaling proteins, and interaction of the Smads with multiple signaling pathways extending into the nucleus. Studies of these mechanisms in kidney cells and in whole-animal experimental models, reviewed here, are beginning to provide insight into the role of TGF-beta in the pathogenesis of renal dysfunction and its potential treatment.