Histologic and Clinical Factors Associated with Kidney Outcomes in IgA Vasculitis Nephritis.

BACKGROUND: Nephritis is a common manifestation of IgA vasculitis and is morphologically indistinguishable from IgA nephropathy. While MEST-C scores are predictive of kidney outcomes in IgA nephropathy, their value in IgA vasculitis nephritis has not been investigated in large multiethnic cohorts. METHODS: Biopsies from 262 children and 99 adults with IgA vasculitis nephritis ( N =361) from 23 centers in North America, Europe, and Asia were independently scored by three pathologists. MEST-C scores were assessed for correlation with eGFR/proteinuria at biopsy. Because most patients ( N =309, 86%) received immunosuppression, risk factors for outcomes were evaluated in this group using latent class mixed models to identify classes of eGFR trajectories over a median follow-up of 2.7 years (interquartile range, 1.2-5.1). Clinical and histologic parameters associated with each class were determined using logistic regression. RESULTS: M, E, T, and C scores were correlated with either eGFR or proteinuria at biopsy. Two classes were identified by latent class mixed model, one with initial improvement in eGFR followed by a late decline (class 1, N =91) and another with stable eGFR (class 2, N =218). Class 1 was associated with a higher risk of an established kidney outcome (time to ≥30% decline in eGFR or kidney failure; hazard ratio, 5.84; 95% confidence interval, 2.37 to 14.4). Among MEST-C scores, only E1 was associated with class 1 by multivariable analysis. Other factors associated with class 1 were age 18 years and younger, male sex, lower eGFR at biopsy, and extrarenal noncutaneous disease. Fibrous crescents without active changes were associated with class 2. CONCLUSIONS: Kidney outcome in patients with biopsied IgA vasculitis nephritis treated with immunosuppression was determined by clinical risk factors and endocapillary hypercellularity (E1) and fibrous crescents, which are features that are not part of the International Study of Diseases of Children classification.

Pediatric Minimal Change Disease and AKI following the Pfizer-BioNTech COVID-19 Vaccine: causal or incidental correlation?

The global coronavirus 2019 (COVID-19) pandemic required vaccination even in children to reduce infection. We report on the development of acute kidney injury (AKI) and minimal change disease (MCD) nephrotic syndrome (NS), shortly after the first injection BNT162b2 COVID-19 vaccine (Pfizer-BioNTech). A 12-year-old previously healthy boy was referred to our hospital with complaints of peripheral edema and nephrotic range proteinuria. Nine days earlier he had received his first injection BNT162b2 COVID-19 vaccine (Pfizer-BioNTech). Seven days after injection, he developed leg edema, which rapidly progressed to anasarca with significant weight gain. On admission, serum creatinine was 1.3 mg/dL and 24-hour urinary protein excretion was 4 grams with fluid overload. As kidney function continued to decline over the next days, empirical steroid treatment and renal replacement therapy with ultrafiltration were started and kidney biopsy was performed. Seven days after steroid therapy, kidney function began to improve, gradually returning to normal. The association of MCD, nephrotic syndrome and AKI hasn't been previously described following the Pfizer-BioNTech COVID-19 vaccine in pediatric population, but this triad has been reported in adults. We need further similar case reports to establish the real incidence of this possible vaccine side effect.

Laparoscopic or Robotic Deroofing Guided by Indocyanine Green Fluorescence and Perirenal Fat Tissue Wadding Technique of Pediatric Simple Renal Cysts.

Purpose: To present the outcomes of the laparoscopic and robotic treatment of pediatric simple renal cysts with two novel modifications: the indocyanine green (ICG) fluorescence and the perirenal fat tissue wadding technique. Methods: Between 2012 and 2019, 13 patients with solitary renal cysts were treated through minimally invasive approach. Preoperative work-up included ultrasonography and computed tomography or magnetic resonance. A cyst deroofing was performed in all cases. In the last 3 cases, the ICG fluorescence technique enabled a clear identification and safe puncture of the cyst dome. Five cysts were filled with perirenal fat tissue after deroofing. Results: Thirteen patients (9 boys) were treated through laparoscopic (6 patients), retroperitoneoscopic (3 patients), or robotic approach (4 patients). Median age was 8 years (5-15 years). The median cyst size was 70 mm (42-160 mm). Eight cysts were located in the right kidney. All cysts were progressive and symptomatic. Thirteen cysts (100%) were graded as type II according to the Bosniak classification. No conversion was recorded. The median operative time for laparoscopy was 50 minutes (35-90 minutes) and 85 minutes for robotics (65-120 minutes) including surgical and docking time. No intraoperative complications occurred. The median hospital stay was 2 days (36-96 hours). No residual liquid was detected on follow-up after deroofing and fat tissue wadding technique. Conclusions: Cyst deroofing is an effective and durable treatment for symptomatic simple renal cysts. Robotics enables excellent tissue dissection and ergonomics. The perirenal fat tissue wadding of the cyst seems to reduce the recurrence rate. The ICG fluorescence technique allows for better identification of the cyst and safer surgical procedure.

An Ex Vivo Test of Complement Activation on Endothelium for Individualized Eculizumab Therapy in Hemolytic Uremic Syndrome.

RATIONALE & OBJECTIVE: Although primary atypical hemolytic uremic syndrome (aHUS) is associated with abnormalities in complement genes and antibodies to complement factor H, the role of complement in secondary aHUS remains debatable. We evaluated the usefulness of an ex vivo test to: (1) detect complement activation within the endothelium in primary and secondary aHUS, (2) differentiate active disease from remission, (3) monitor the effectiveness of eculizumab therapy, and (4) identify relapses during eculizumab dosage tapering and after discontinuation of treatment. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 121 patients with primary aHUS and 28 with secondary aHUS. Serum samples were collected during acute episodes, following remission, and during eculizumab treatment and were assessed using a serum-induced ex vivo C5b-9 endothelial deposition test. RESULTS: Serum-induced C5b-9 deposition on cultured microvascular endothelium was quantified by calculating the endothelial area covered by C5b-9 staining; values were expressed as percentage of C5b-9 deposits induced by a serum pool from healthy controls. Testing with adenosine diphosphate-activated endothelium demonstrated elevated C5b-9 deposits for all untreated patients with aHUS independent of disease activity, while testing with unstimulated endothelium demonstrated deposits only in active disease. Similar findings were observed in secondary aHUS. Serum-induced C5b-9 deposits on activated and unstimulated endothelium normalized during eculizumab treatment. 96% (22/23) of patients receiving eculizumab at extended 3- or 4-week dosing intervals demonstrated normal C5b-9 deposits on activated endothelium, despite most patients having CH50Eq (serum complement activity) > 20 UEq/mL, indicating that adequate complement control was achieved even with incomplete blockade of circulating C5. During eculizumab dosage tapering or after treatment discontinuation, all patients experiencing relapses versus only 6% (1/17) of those in stable remission had elevated C5b-9 deposits on unstimulated endothelium. LIMITATIONS: The C5b-9 endothelial deposition test can be performed in only specialized laboratories. Findings on eculizumab dosage tapering need to be confirmed with longitudinal monitoring of C5b-9 deposition. CONCLUSIONS: The C5b-9 endothelial deposition assay may represent an advance in our ability to monitor aHUS activity and individualize therapy.

Role of color Doppler ultrasound in the early diagnosis of a major complication after percutaneous renal biopsy: two case reports.

Percutaneous renal biopsy (PRB) is an important procedure in the diagnostic and prognostic evaluation of renal disorders. Despite the relative simplicity, it can be a possible cause of iatrogenic renovascular injury. We describe two cases of iatrogenic pseudoaneurysm, a major post-biopsy complication, in two pediatric patients with persistent micro- and macro-hematuria, promptly diagnosed using color Doppler ultrasound, confirmed with renal arteriography and treated with embolization.

The Italian Society for Pediatric Nephrology (SINePe) consensus document on the management of nephrotic syndrome in children: Part I - Diagnosis and treatment of the first episode and the first relapse.

This consensus document is aimed at providing an updated, multidisciplinary overview on the diagnosis and treatment of pediatric nephrotic syndrome (NS) at first presentation. It is the first consensus document of its kind to be produced by all the pediatric nephrology centres in Italy, in line with what is already present in other countries such as France, Germany and the USA. It is based on the current knowledge surrounding the symptomatic and steroid treatment of NS, with a view to providing the basis for a separate consensus document on the treatment of relapses. NS is one of the most common pediatric glomerular diseases, with an incidence of around 2-7 cases per 100000 children per year. Corticosteroids are the mainstay of treatment, but the optimal therapeutic regimen for managing childhood idiopathic NS is still under debate. In Italy, shared treatment guidelines were lacking and, consequently, the choice of steroid regimen was based on the clinical expertise of each individual unit. On the basis of the 2015 Cochrane systematic review, KDIGO Guidelines and more recent data from the literature, this working group, with the contribution of all the pediatric nephrology centres in Italy and on the behalf of the Italian Society of Pediatric Nephrology, has produced a shared steroid protocol that will be useful for National Health System hospitals and pediatricians. Investigations at initial presentation and the principal causes of NS to be screened are suggested. In the early phase of the disease, symptomatic treatment is also important as many severe complications can occur which are either directly related to the pathophysiology of the underlying NS or to the steroid treatment itself. To date, very few studies have been published on the prophylaxis and treatment of these early complications, while recommendations are either lacking or conflicting. This consensus provides indications for the prevention, early recognition and treatment of these complications (management of edema and hypovolemia, therapy and prophylaxis of infections and thromboembolic events). Finally, recommendations about the clinical definition of steroid resistance and its initial diagnostic management, as well as indications for renal biopsy are provided.

Outcome of childhood-onset full-house nephropathy.

BACKGROUND: Patients with full-house nephropathy (FHN) present renal lesions that are indistinguishable from those of lupus nephritis (LN) but lack the systemic features necessary to meet diagnostic criteria for systemic lupus erithematosus (SLE). Some have been reported to develop a delayed SLE with time. The clinical outcome of children having FHN without SLE has never been reported. METHODS: Children with biopsy-proven FHN were selected after excluding SLE cases by the absence of America College of Rheumatology criteria. The proportion of patients with complete (proteinuria <0.5 g/day) or partial remission (proteinuria ≤50% from baseline), relapse (estimated glomerular filtration rate <25% and/or proteinuria ≥50% from baseline) and progression to Stage III chronic kidney disease (CKD) was described according to age and gender groups with the Kaplan-Meier curve and compared with the Log-rank test. Entity of treatment was summarized by a score at induction (0-6 months) and maintenance (6-18 months). Cox-regression model was performed to test predictors of remission, relapse and progression to CKD. RESULTS: Among 42 patients (28 pre-pubertal) who met the inclusion criteria, 39 (92.9%) achieved partial and 32 (76.2%) complete remission of nephropathy over 2.78 and 7.51 months of follow-up. At 10 years, the probability of progressing to CKD was 4.8%. Of those achieving remission, 18% had a renal flare mainly within 4 years after remission. Pre-pubertal males achieved complete remission more frequently than other patients but often relapsed; pre-pubertal females were treated more aggressively. Cox-regression analysis did not find independent predictors of remission or relapse. CONCLUSIONS: The outcome of the patients with FHN we investigated was encouraging. Recurrences are limited to the first 4 years following diagnosis, allowing progressive withdrawal of immunosuppression in patients achieving remission. Evaluation of risk factors for adverse outcome is necessary especially in pre-pubertal children.

MYO1E mutations and childhood familial focal segmental glomerulosclerosis.

BACKGROUND: Focal segmental glomerulosclerosis is a kidney disease that is manifested as the nephrotic syndrome. It is often resistant to glucocorticoid therapy and progresses to end-stage renal disease in 50 to 70% of patients. Genetic studies have shown that familial focal segmental glomerulosclerosis is a disease of the podocytes, which are major components of the glomerular filtration barrier. However, the molecular cause in over half the cases of primary focal segmental glomerulosclerosis is unknown, and effective treatments have been elusive. METHODS: We performed whole-genome linkage analysis followed by high-throughput sequencing of the positive-linkage area in a family with autosomal recessive focal segmental glomerulosclerosis (index family) and sequenced a newly discovered gene in 52 unrelated patients with focal segmental glomerulosclerosis. Immunohistochemical studies were performed on human kidney-biopsy specimens and cultured podocytes. Expression studies in vitro were performed to characterize the functional consequences of the mutations identified. RESULTS: We identified two mutations (A159P and Y695X) in MYO1E, which encodes a nonmuscle class I myosin, myosin 1E (Myo1E). The mutations in MYO1E segregated with focal segmental glomerulosclerosis in two independent pedigrees (the index family and Family 2). Patients were homozygous for the mutations and did not have a response to glucocorticoid therapy. Electron microscopy showed thickening and disorganization of the glomerular basement membrane. Normal expression of Myo1E was documented in control human kidney-biopsy specimens in vivo and in glomerular podocytes in vitro. Transfection studies revealed abnormal subcellular localization and function of the A159P-Myo1E mutant. The Y695X mutation causes loss of calmodulin binding and of the tail domains of Myo1E. CONCLUSIONS: MYO1E mutations are associated with childhood-onset, glucocorticoid-resistant focal segmental glomerulosclerosis. Our data provide evidence of a role of Myo1E in podocyte function and the consequent integrity of the glomerular filtration barrier.