Focal segmental glomerulosclerosis and proteinuria associated with Myo1E mutations: novel variants and histological phenotype analysis.

BACKGROUND: Pathogenic mutations in the non-muscle single-headed myosin, myosin 1E (Myo1e), are a rare cause of pediatric focal segmental glomerulosclerosis (FSGS). These mutations are biallelic, to date only reported as homozygous variants in consanguineous families. Myo1e regulates the actin cytoskeleton dynamics and cell adhesion, which are especially important for podocyte functions. METHODS: DNA and RNA sequencing were used to identify novel MYO1E variants associated with FSGS. We studied the effects of these variants on the localization of Myo1e in kidney sections. We then analyzed the clinical and histological observations of all known pathogenic MYO1E variants. RESULTS: We identified a patient compound heterozygote for two novel variants in MYO1E and a patient homozygous for a deletion of exon 19. Computer modeling predicted these variants to be disruptive. In both patients, Myo1e was mislocalized. As a rule, pathogenic MYO1E variants map to the Myo1e motor and neck domain and are most often associated with steroid-resistant nephrotic syndrome in children 1-11 years of age, leading to kidney failure in 4-10 years in a subset of patients. The ultrastructural features are the podocyte damage and striking diffuse and global Alport-like glomerular basement membrane (GBM) abnormalities. CONCLUSIONS: We hypothesize that MYO1E mutations lead to disruption of the function of podocyte contractile actin cables resulting in abnormalities of the podocytes and the GBM and dysfunction of the glomerular filtration barrier. The characteristic clinicopathological data can help to tentatively differentiate this condition from other genetic podocytopathies and Alport syndrome until genetic testing is done. A higher resolution version of the Graphical abstract is available as Supplementary information.

Omentectomy reduces the need for peritoneal dialysis catheter revision in children: a study from the Pediatric Nephrology Research Consortium.

BACKGROUND: There are no multi-center studies examining omentectomy and peritoneal dialysis (PD) catheter revision in the pediatric dialysis population. METHODS: We performed a retrospective study at eight centers within the Pediatric Nephrology Research Consortium (PNRC). Data review included all incident tunneled PD catheters placed between 1/1/2011 and 12/31/2016 in pediatric stage 5 chronic kidney disease (CKD 5) patients. The primary outcome was the need for catheter revision and/or replacement. Multivariable logistic regression was performed to evaluate predictors for catheter revision/replacement. RESULTS: Data from 184 children (62.5% male; median age 7.4 years) were analyzed. Omentectomy was completed in 63.6% (n = 117). Revision/replacement occurred in 34.2% (n = 63); median time to revision/replacement was 38.5 days after insertion. PD catheter revision/replacement catheter occurred in 23.9% who underwent omentectomy versus 52.2% without omentectomy (p = 0.0005). Children ≥ 6 years at the time of catheter insertion experienced fewer revisions/replacements (18.2% age ≥ 6 vs. 56.5% age < 6 years, p <0.001). After adjusting for covariates, omentectomy reduced the need for revision by 63%; revision was 3.66 times more likely in those < 6 years of age. CONCLUSIONS: This multi-center study demonstrates that omentectomy at the time of PD catheter insertion in pediatric patients is strongly associated with reduced likelihood of PD catheter revision. Omentectomy should be considered at the time of PD catheter insertion, especially in young children who are at high risk for PD catheter malfunction. A higher resolution version of the Graphical abstract is available as Supplementary information.

Neonatal kidney size and function in preterm infants: what is a true estimate of glomerular filtration rate?

OBJECTIVES: To distinguish between cystatin C (CysC) and creatinine (Cr) as markers of estimated glomerular filtration rate (eGFR) in preterm infants and to correlate eGFR with total kidney volume (TKV) as a surrogate of nephron mass. STUDY DESIGN: Sixty preterm (<37 weeks' gestational age [GA]) and 40 term infants were enrolled at birth. Serum Cr and CysC levels were assessed during the first week of life. Renal ultrasounds were performed to assess kidney dimensions with calculation of the TKV as a surrogate of nephron mass. Six equations derived from reference inulin, iohexol, and iothalamate clearance studies were used to calculate eGFR. Multiple regression analysis was applied to assess the relative impact of neonatal measures on eGFR, including TKV, GA, and mean arterial pressure (MAP). RESULTS: Renal lengths correlated with GA and were within the reference values for intrauterine measurements. Estimation equations for glomerular filtration rate (GFR) based on Cr, CysC, and combined CysC + Cr demonstrated that Cr-based equations consistently underestimated GFR, whereas CysC and combined equations were more consistent with referenced inulin clearance studies. Term infants demonstrated significantly better eGFR than preterm infants. TKV, GA, and MAP correlated positively with eGFR, although only MAP and GA remained significant when adjusted for other covariates. CONCLUSIONS: Primary determinants of eGFR in preterm infants are GA and MAP. The CysC level is a superior biomarker to serum Cr in the assessment of GFR in premature infants.

Capillary rarefaction: an early marker of microvascular disease in young hemodialysis patients.

BACKGROUND: Pediatric patients with chronic kidney disease (CKD) are at increased risk of early cardiovascular disease and premature death. Abnormalities in microvascular structure and function may presage end-organ damage including vascular calcification and myocardial ischemia associated with disordered mineral metabolism. Early detection of microvascular rarefaction (reduced density of capillaries) may identify at-risk patients and prompt timely therapeutic interventions. Our objective was to study capillary rarefaction in pediatric hemodialysis (HD) patients and to determine possible associations with mineral metabolism and cardiac risk biomarkers. METHODS: Capillary density (CD) was measured by nailfold capillaroscopy in 19 pediatric HD patients and 20 healthy controls. Demographic and biochemical markers were collected at entry and 6-month follow-up. RESULTS: CD was significantly decreased in HD patients compared with controls with a deficit of 24 and 31% at baseline and subsequent follow-up. Maximal CD correlated significantly with intact parathyroid hormone (iPTH) (r = -0.45; P = 0.005), serum calcium (r = -0.38; P = 0.02) and 25(OH) vitamin D levels (r = +0.36; P = 0.03) in HD patients. Capillary functional measures were similar to controls. By multivariate analysis, the primary negative determinants of CD were African American race and hyperparathyroidism; whereas, glomerular disease had a positive influence on capillary rarefaction (R (2) = 64.2% variance; P = 0.001). CONCLUSION: Pediatric HD patients demonstrate a 'structural deficit' in CD but show preserved 'functional integrity'. Capillary rarefaction, an early risk factor of incipient vascular calcification, was strongly associated with biomarkers of altered mineral metabolism. Further studies are warranted to determine the impact of optimizing blood pressure and metabolic control on changes in capillary rarefaction in young CKD patients.

Therapeutic plasma exchange in familial hemophagocytic lymphohistiocytosis.

Familial hemophagocytic lymphohistiocytosis is a rare, life-threatening disorder characterized by impaired cytotoxicity, hypercytokinemia and immune-mediated organ injury. We report a 7-week-old male of consanguineous parents who presented with fever, pancytopenia and multi-organ failure. Elevated inflammatory markers and hypercytokinemia led to the diagnosis of familial hemophagocytic lymphohistiocytosis, which was confirmed with genetic testing. With the fulminant multiorgan failure, therapeutic plasma exchange was instituted, using the Prismaflex® platform, followed by standard chemo-immunotherapy. There was dramatic reversal of the multi-organ failure and stabilization of the coagulopathy with this neo-adjuvant therapy. Thereafter, he was maintained in clinical remission with chemo-immunotherapy for 3 mo while awaiting stem cell transplantation.