Sparsentan versus Irbesartan in Focal Segmental Glomerulosclerosis.

BACKGROUND: An unmet need exists for focal segmental glomerulosclerosis (FSGS) treatment. In an 8-week, phase 2 trial, sparsentan, a dual endothelin-angiotensin receptor antagonist, reduced proteinuria in patients with FSGS. The efficacy and safety of longer-term treatment with sparsentan for FSGS are unknown. METHODS: In this phase 3 trial, we enrolled patients with FSGS (without known secondary causes) who were 8 to 75 years of age; patients were randomly assigned to receive sparsentan or irbesartan (active control) for 108 weeks. The surrogate efficacy end point assessed at the prespecified interim analysis at 36 weeks was the FSGS partial remission of proteinuria end point (defined as a urinary protein-to-creatinine ratio of ≤1.5 [with protein and creatinine both measured in grams] and a >40% reduction in the ratio from baseline). The primary efficacy end point was the estimated glomerular filtration rate (eGFR) slope at the time of the final analysis. The change in eGFR from baseline to 4 weeks after the end of treatment (week 112) was a secondary end point. Safety was also evaluated. RESULTS: A total of 371 patients underwent randomization: 184 were assigned to receive sparsentan and 187 to receive irbesartan. At 36 weeks, the percentage of patients with partial remission of proteinuria was 42.0% in the sparsentan group and 26.0% in the irbesartan group (P = 0.009), a response that was sustained through 108 weeks. At the time of the final analysis at week 108, there were no significant between-group differences in the eGFR slope; the between-group difference in total slope (day 1 to week 108) was 0.3 ml per minute per 1.73 m2 of body-surface area per year (95% confidence interval [CI], -1.7 to 2.4), and the between-group difference in the slope from week 6 to week 108 (i.e., chronic slope) was 0.9 ml per minute per 1.73 m2 per year (95% CI, -1.3 to 3.0). The mean change in eGFR from baseline to week 112 was -10.4 ml per minute per 1.73 m2 with sparsentan and -12.1 ml per minute per 1.73 m2 with irbesartan (difference, 1.8 ml per minute per 1.73 m2; 95% CI, -1.4 to 4.9). Sparsentan and irbesartan had similar safety profiles, and the frequency of adverse events was similar in the two groups. CONCLUSIONS: Among patients with FSGS, there were no significant between-group differences in eGFR slope at 108 weeks, despite a greater reduction in proteinuria with sparsentan than with irbesartan. (Funded by Travere Therapeutics; DUPLEX ClinicalTrials.gov number, NCT03493685.).

CMV-associated collapsing focal segmental glomerulosclerosis after kidney transplant in a pediatric patient.

BACKGROUND: Cytomegalovirus (CMV) is a significant cause of morbidity among immunocompromised patients who have undergone kidney transplantation and is known to rarely induce collapsing focal segmental glomerulosclerosis (FSGS) among adults. METHODS: We present the first reported case of CMV-induced collapsing FSGS in a pediatric patient after kidney transplant. RESULTS: Our patient underwent a deceased donor kidney transplant due to end-stage renal disease secondary to lupus nephritis. Approximately 4 months after transplantation, he developed signs of worsening kidney function in the setting of CMV viremia and was found to have collapsing features of FSGS on kidney transplant biopsy. He was managed with a prompt escalation of antiviral therapy along with a reduction of immunosuppression and recovered without significant complication. At follow-up, he continued to have undetectable CMV titers, creatinine within normal limits, and no significant proteinuria. CONCLUSION: This report demonstrates CMV as a cause of collapsing FSGS and should be considered among pediatric transplant recipients who present with acute kidney injury, as should early assessment of APOL1 genetic status in both donor and recipient.

COL4A gene variants are common in children with hematuria and a family history of kidney disease.

BACKGROUND: Inherited kidney diseases are a common cause of chronic kidney disease (CKD) in children. Identification of a monogenic cause of CKD is more common in children than in adults. This study evaluated the diagnostic yield and phenotypic spectrum of children who received genetic testing through the KIDNEYCODE sponsored genetic testing program. METHODS: Unrelated children < 18 years of age who received panel testing through the KIDNEYCODE sponsored genetic testing program from September 2019 through August 2021 were included (N = 832). Eligible children met at least one of the following clinician-reported criteria: estimated GFR ≤ 90 ml/min/1.73 m2, hematuria, a family history of kidney disease, or suspected or biopsy confirmed Alport syndrome or focal segmental glomerulosclerosis (FSGS) in the tested individual or family member. RESULTS: A positive genetic diagnosis was observed in 234 children (28.1%, 95% CI [25.2-31.4%]) in genes associated with Alport syndrome (N = 213), FSGS (N = 9), or other disorders (N = 12). Among children with a family history of kidney disease, 30.8% had a positive genetic diagnosis. Among those with hematuria and a family history of CKD, the genetic diagnostic rate increased to 40.4%. CONCLUSIONS: Children with hematuria and a family history of CKD have a high likelihood of being diagnosed with a monogenic cause of kidney disease, identified through KIDNEYCODE panel testing, particularly COL4A variants. Early genetic diagnosis can be valuable in targeting appropriate therapy and identification of other at-risk family members. A higher resolution version of the Graphical abstract is available as Supplementary information.

Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease.

Fibromuscular dysplasia (FMD) is a heterogeneous group of non-atherosclerotic and non-inflammatory arterial diseases that primarily involves the renal and cerebrovascular arteries. Grange syndrome is an autosomal-recessive condition characterized by severe and early-onset vascular disease similar to FMD and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Exome-sequencing analysis of DNA from three affected siblings with Grange syndrome identified compound heterozygous nonsense variants in YY1AP1, and homozygous nonsense or frameshift YY1AP1 variants were subsequently identified in additional unrelated probands with Grange syndrome. YY1AP1 encodes yin yang 1 (YY1)-associated protein 1 and is an activator of the YY1 transcription factor. We determined that YY1AP1 localizes to the nucleus and is a component of the INO80 chromatin remodeling complex, which is responsible for transcriptional regulation, DNA repair, and replication. Molecular studies revealed that loss of YY1AP1 in vascular smooth muscle cells leads to cell cycle arrest with decreased proliferation and increased levels of the cell cycle regulator p21/WAF/CDKN1A and disrupts TGF-ß-driven differentiation of smooth muscle cells. Identification of YY1AP1 mutations as a cause of FMD indicates that this condition can result from underlying genetic variants that significantly alter the phenotype of vascular smooth muscle cells.

DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients with FSGS.

BACKGROUND: We evaluated and compared the effects of sparsentan, a dual endothelin type A (ETA) and angiotensin II type 1 receptor antagonist, with those of the angiotensin II type 1 receptor antagonist irbesartan in patients with primary FSGS. METHODS: In this phase 2, randomized, double-blind, active-control Efficacy and Safety of Sparsentan (RE-021), a Dual Endothelin Receptor and Angiotensin Receptor Blocker, in Patients with Focal Segmental Glomerulosclerosis (FSGS): A Randomized, Double-blind, Active-Control, Dose-Escalation Study (DUET), patients aged 8-75 years with biopsy-proven FSGS, eGFR>30 ml/min per 1.73 m2, and urinary protein-to-creatinine ratio (UP/C) ≥1.0 g/g received sparsentan (200, 400, or 800 mg/d) or irbesartan (300 mg/d) for 8 weeks, followed by open-label sparsentan only. End points at week 8 were reduction from baseline in UP/C (primary) and proportion of patients achieving FSGS partial remission end point (FPRE) (UP/C: ≤1.5 g/g and >40% reduction [secondary]). RESULTS: Of 109 patients randomized, 96 received study drugs and had baseline and week 8 UP/C measurements. Sparsentan-treated patients had greater reductions in UP/C than irbesartan-treated patients did when all doses (45% versus 19%; P=0.006) or the 400 and 800 mg doses (47% versus 19%; P=0.01) were pooled for analysis. The FSGS partial remission end point was achieved in 28% of sparsentan-treated and 9% of irbesartan-treated patients (P=0.04). After 8 weeks of treatment, BP was reduced with sparsentan but not irbesartan, and eGFR was stable with both treatments. Overall, the incidence of adverse events was similar between groups. Hypotension and edema were more common among sparsentan-treated patients but did not result in study withdrawals. CONCLUSIONS: Patients with FSGS achieved significantly greater reductions in proteinuria after 8 weeks of sparsentan versus irbesartan. Sparsentan was safe and well tolerated.

Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is caused by alternative complement pathway dysregulation, leading to systemic thrombotic microangiopathy (TMA) and severe end-organ damage. Based on 2 prospective studies in mostly adults and retrospective data in children, eculizumab, a terminal complement inhibitor, is approved for aHUS treatment. Here we prospectively evaluated efficacy and safety of weight-based dosing of eculizumab in eligible pediatric patients with aHUS in an open-label phase II study. The primary end point was complete TMA response by 26 weeks. Twenty-two patients (aged 5 months-17 years) were treated; 16 were newly diagnosed, 12 had no prior plasma exchange/infusion during current TMA symptomatology, 11 received baseline dialysis and 2 had prior renal transplants. By week 26, 14 achieved a complete TMA response, 18 achieved hematologic normalization, and 16 had 25% or better improvement in serum creatinine. Plasma exchange/infusion was discontinued in all, and 9 of the 11 patients who required dialysis at baseline discontinued, whereas none initiated new dialysis. Eculizumab was well tolerated; no deaths or meningococcal infections occurred. Bone marrow failure, wrist fracture, and acute respiratory failure were reported as unrelated severe adverse events. Thus, our findings establish the efficacy and safety of eculizumab for pediatric patients with aHUS and are consistent with proposed immediate eculizumab initiation following diagnosis in children.

The KIDNEYCODE Program: Diagnostic Yield and Clinical Features of Individuals with CKD.

Background: Despite increasing recognition that CKD may have underlyi ng genetic causes, genetic testing remains limited. This study evaluated the diagnostic yield and phenotypic spectrum of CKD in individuals tested through the KIDNEYCODE sponsored genetic testing program. Methods: Unrelated individuals who received panel testing (17 genes) through the KIDNEYCODE sponsored genetic testing program were included. Individuals had to meet at least one of the following eligibility criteria: eGFR ≤90 ml/min per 1.73m2 and hematuria or a family history of kidney disease; or suspected/biopsy-confirmed Alport syndrome or FSGS in tested individuals or relatives. Results: Among 859 individuals, 234 (27%) had molecular diagnoses in genes associated with Alport syndrome (n=209), FSGS (n=12), polycystic kidney disease (n=6), and other disorders (n=8). Among those with positive findings in a COL4A gene, the majority were in COL4A5 (n=157, 72 hemizygous male and 85 heterozygous female individuals). A positive family history of CKD, regardless of whether clinical features were reported, was more predictive of a positive finding than was the presence of clinical features alone. For the 248 individuals who had kidney biopsies, a molecular diagnosis was returned for 49 individuals (20%). Most (n=41) individuals had a molecular diagnosis in a COL4A gene, 25 of whom had a previous Alport syndrome clinical diagnosis, and the remaining 16 had previous clinical diagnoses including FSGS (n=2), thin basement membrane disease (n=9), and hematuria (n=1). In total, 491 individuals had a previous clinical diagnosis, 148 (30%) of whom received a molecular diagnosis, the majority (89%, n=131) of which were concordant. Conclusions: Although skewed to identify individuals with Alport syndrome, these findings support the need to improve access to genetic testing for patients with CKD-particularly in the context of family history of kidney disease, hematuria, and hearing loss.

Adrenocorticotropic hormone therapy for the treatment of idiopathic nephrotic syndrome in children and young adults: a systematic review of early clinical studies with contemporary relevance.

Adrenocorticotropic hormone (ACTH) as a treatment for proteinuria due to nephrotic syndrome (NS) has re-emerged over the last decade. Current clinical data are primarily limited to adults with treatment-resistant NS. Largely unknown to today's clinicians is the existence of early clinical studies, following ACTH's introduction in the late 1940s, showing sustained proteinuria response in idiopathic NS in predominantly pediatric, treatment-naïve patients. Before ACTH, patients suffered severe edema and high mortality rates with no reliable or safe treatment. ACTH dramatically altered NS management, initially through recognition of diuresis effects and then through sustained proteinuria remission. This review synthesizes early clinical literature to inform current NS patient management. We undertook a MEDLINE search using MeSH terms "adrenocorticotropic hormone" and "nephrotic syndrome," with limits 1945-1965 and English. Sixty papers totaling 1137 patients were found; 14 studies (9 short-term, five long-term, N = 419 patients) met inclusion criteria. Studies were divided into two groups: short-term (≤28 days) and long-term (>5 weeks; short-term initial daily treatment followed by long-term intermittent)ACTH therapy and results were aggregated. An initial response, defined as a diuresis, occurred in 74 % of patients/treatment courses across nine short-term ACTH studies. Analyzed in eight of these studies, proteinuria response occurred in 56 % of patients/treatment courses. Across five long-term ACTH studies, proteinuria response was shown in 71 % of patients and was sustained up to 4.7 years following treatment. The inventory and re-evaluation of early clinical data broadens the evidence base of clinical experiences with ACTH for implementation of current treatment strategies and aiding the design of future studies.

The efficacy and safety of valsartan in obese and non-obese pediatric hypertensive patients.

This post hoc analysis assessed the efficacy and tolerability of valsartan for the treatment of hypertension in obese vs non-obese children and adolescents. After a 1-week antihypertensive washout period, 142 obese and 119 non-obese hypertensive children and adolescents aged 6 to 16 years were randomized to 2 weeks of once-daily treatment with valsartan 10 to 20 mg, 40 to 80 mg, or 80 to 160 mg, followed by re-randomization to either valsartan or placebo for an additional 2 weeks. Patients could continue to receive valsartan during an optional 52-week, open-label extension. Valsartan resulted in statistically significant (P<.05) and clinically relevant reductions in mean sitting blood pressure (BP), ranging from approximately 7/4 mm Hg (valsartan 10-20 mg) to 13/9 mm Hg (valsartan 80-160 mg) in both obese and non-obese patients. BP control was achieved in 44% of obese and 56% of non-obese patients. Following re-randomization, non-obese patients experienced an increase in BP during placebo treatment, albeit levels remained below baseline, whereas BP reductions were maintained in valsartan recipients (P<.05). The most frequent adverse events during the open-label phase were headache and fever. Valsartan provides similar antihypertensive efficacy in obese and non-obese hypertensive children and adolescents, with good tolerability in both patient populations.

A new case of Grange syndrome without cardiac findings.

Grange syndrome comprises arterial stenoses with hypertension, brachysyndactyly, bone fragility, learning disability, and cardiac defects. To date, we know of two reported families with five affected individuals. We report on one of the youngest cases, in a third family, a 3-year-old girl with brachysyndactyly, renal artery stenosis with hypertension, and bone fragility. She does not have apparent cardiac disease, suggesting cardiac anomalies may not be an obligatory finding in this syndrome.

Fulminant recurrence of atypical hemolytic uremic syndrome during a calcineurin inhibitor-free immunosuppression regimen.

Recurrence of hemolytic uremic syndrome (HUS) after kidney transplantation is frequent, occurring almost exclusively in patients with atypical HUS, which is not caused by Escherichia coli gastroenteritis and in which diarrhea is absent. Calcineurin inhibitors are associated with recurrence of HUS. In two children who underwent living donor kidney transplantation for atypical HUS, we pre-emptively employed sirolimus in a calcineurin inhibitor-free immunosuppression regimen. Both children had excellent early graft function, yet both developed severe recurrent disease and subsequently lost their grafts. Avoidance of calcineurin inhibitors did not prevent recurrence of severe HUS and graft loss. Transplantation for severe atypical HUS remains problematic.