C3 Glomerulopathy and Related Disorders in Children: Etiology-Phenotype Correlation and Outcomes.

BACKGROUND AND OBJECTIVES: Membranoproliferative GN and C3 glomerulopathy are rare and overlapping disorders associated with dysregulation of the alternative complement pathway. Specific etiologic data for pediatric membranoproliferative GN/C3 glomerulopathy are lacking, and outcome data are based on retrospective studies without etiologic data. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 80 prevalent pediatric patients with membranoproliferative GN/C3 glomerulopathy underwent detailed phenotyping and long-term follow-up within the National Registry of Rare Kidney Diseases (RaDaR). Risk factors for kidney survival were determined using a Cox proportional hazards model. Kidney and transplant graft survival was determined using the Kaplan-Meier method. RESULTS: Central histology review determined 39 patients with C3 glomerulopathy, 31 with immune-complex membranoproliferative GN, and ten with immune-complex GN. Patients were aged 2-15 (median, 9; interquartile range, 7-11) years. Median complement C3 and C4 levels were 0.31 g/L and 0.14 g/L, respectively; acquired (anticomplement autoantibodies) or genetic alternative pathway abnormalities were detected in 46% and 9% of patients, respectively, across all groups, including those with immune-complex GN. Median follow-up was 5.18 (interquartile range, 2.13-8.08) years. Eleven patients (14%) progressed to kidney failure, with nine transplants performed in eight patients, two of which failed due to recurrent disease. Presence of >50% crescents on the initial biopsy specimen was the sole variable associated with kidney failure in multivariable analysis (hazard ratio, 6.2; 95% confidence interval, 1.05 to 36.6; P<0.05). Three distinct C3 glomerulopathy prognostic groups were identified according to presenting eGFR and >50% crescents on the initial biopsy specimen. CONCLUSIONS: Crescentic disease was a key risk factor associated with kidney failure in a national cohort of pediatric patients with membranoproliferative GN/C3 glomerulopathy and immune-complex GN. Presenting eGFR and crescentic disease help define prognostic groups in pediatric C3 glomerulopathy. Acquired abnormalities of the alternative pathway were commonly identified but not a risk factor for kidney failure.

Large-Scale Whole-Genome Sequencing Reveals the Genetic Architecture of Primary Membranoproliferative GN and C3 Glomerulopathy.

BACKGROUND: Primary membranoproliferative GN, including complement 3 (C3) glomerulopathy, is a rare, untreatable kidney disease characterized by glomerular complement deposition. Complement gene mutations can cause familial C3 glomerulopathy, and studies have reported rare variants in complement genes in nonfamilial primary membranoproliferative GN. METHODS: We analyzed whole-genome sequence data from 165 primary membranoproliferative GN cases and 10,250 individuals without the condition (controls) as part of the National Institutes of Health Research BioResource-Rare Diseases Study. We examined copy number, rare, and common variants. RESULTS: Our analysis included 146 primary membranoproliferative GN cases and 6442 controls who were unrelated and of European ancestry. We observed no significant enrichment of rare variants in candidate genes (genes encoding components of the complement alternative pathway and other genes associated with the related disease atypical hemolytic uremic syndrome; 6.8% in cases versus 5.9% in controls) or exome-wide. However, a significant common variant locus was identified at 6p21.32 (rs35406322) (P=3.29×10-8; odds ratio [OR], 1.93; 95% confidence interval [95% CI], 1.53 to 2.44), overlapping the HLA locus. Imputation of HLA types mapped this signal to a haplotype incorporating DQA1*05:01, DQB1*02:01, and DRB1*03:01 (P=1.21×10-8; OR, 2.19; 95% CI, 1.66 to 2.89). This finding was replicated by analysis of HLA serotypes in 338 individuals with membranoproliferative GN and 15,614 individuals with nonimmune renal failure. CONCLUSIONS: We found that HLA type, but not rare complement gene variation, is associated with primary membranoproliferative GN. These findings challenge the paradigm of complement gene mutations typically causing primary membranoproliferative GN and implicate an underlying autoimmune mechanism in most cases.

Hyperspectral mapping-combining cathodoluminescence and X-ray collection in an electron microprobe.

An optical spectrometer has been integrated into a JEOL 8900R electron microprobe, which allows simultaneous collection of light, X-ray, and electron signals. The cathodoluminescence signal is collected from a monocular eyepiece, which is integrated into the electron optics of the electron microprobe. The optical acquisition is synchronized with the stage motion. X-ray lines of major elements are collected using an energy dispersive spectrometer, X-ray lines of minor elements are collected using wavelength dispersive spectrometers, and the secondary and backscattered electron signals are collected using standard detectors. In mapping mode of operation the different signals are collected at each pixel with map sizes typically ranging from 1 million to 10 million pixels. This represents a significant amount of data from which the major correlations and associations in the map can be determined. Summing over a small number of channels and examining only a subset of the complete wavelength range are the strategies that have been developed to reduce the size of the data handled. The application of this mapping technique is demonstrated with two examples, zircons and refractory bricks. Zircons with various degrees of metamictization have been characterized, and inclusions differentiated using a combination of cathodoluminescence and X-ray maps. Examination of refractory bricks reveals subtle chemical changes in the spinel grains.

Decreased postpartum use of oral pain medication after a single dose of epidural morphine.

BACKGROUND: Pain after vaginal delivery may result from episiotomy, perineal laceration, or uterine involution. Many women have indwelling epidural catheters in place at delivery. We hypothesized that a small dose of epidural morphine would be an effective strategy for postpartum analgesia. METHODS: Eighty-one healthy parturients receiving epidural analgesia for labor were enrolled. Patients were randomized in double-blind fashion to 1 of 3 groups: all groups received a 4-mL volume of epidural solution consisting of saline (group 1, control), 1 mg (group 2), or 2 mg morphine (group 3) after vaginal delivery. During the first 24 hours postpartum, patients were evaluated for the amount of oral pain medication requested; visual analog scale scores for pain at rest and with movement; satisfaction with postpartum pain treatment; and opioid side effects including nausea, pruritus, urinary retention, and respiratory depression. RESULTS: Patients who received 2 mg of epidural morphine used an average of 0.7 (0-1, interquartile range) opioid-containing pain pills (acetaminophen with codeine or oxycodone) compared with 1.2 (0-2) in the 1-mg group and 1.9 (0-3) in the control group ( P = .07). There was a statistically significant difference in oral drug usage between those who received epidural morphine and those who did not ( P < .03). There were no differences in side effects except that at 12 hours postpartum there was an increase in Foley catheterization in the 1-mg morphine group ( P = .007). CONCLUSIONS: These results suggest that epidural morphine decreases the need for oral pain medication in the first 24 hours postpartum. No significant dose-dependent side effects were found.

Primary hyperoxaluria type 2 in children.

The primary hyperoxalurias (PH1 and PH2) are rare defects of oxalate overproduction. There are only 24 reported cases of PH2, which is characterized by raised urine oxalate and L-glycerate. We describe 13 previously unreported children with PH2, representing the largest single-centre cohort in the world. DNA samples were tested for a common mutation and four other documented mutations in the gene encoding the enzyme glyoxylate reductase/hydroxypyruvate reductase (GRHPR). Two of the five kindred showed homozygosity for two different mutations in the GRHPR gene. The genetic defect was not identified in the other three families. The median age at diagnosis of PH2 was 1.7 years. Five children presented with nephrolithiasis between 0.8 and 9 years. Haematuria was common, but urinary tract infection and nephrocalcinosis were not. All had normal renal function at diagnosis, and only 1 patient had a significant decline in glomerular filtration rate. We conclude that all children with nephrolithiasis secondary to hyperoxaluria should have urinary glycerate measured, as PH2 may be more prevalent than currently estimated. DNA mutational analysis may be useful in supporting the diagnosis.