Discordant Phenotypes of Nephritis in Patients with X-linked Agammaglobulinemia.

PURPOSE: To define the clinical and histological characteristics of nephritis in patients with X-linked agammaglobulinemia (XLA) and their immunological profiles. METHODS: The clinical, immunological, and histological findings of nine patients with XLA and nephritis were retrospectively analyzed. RESULTS: Based on kidney histological findings, patients with XLA and nephritis could be divided into two groups, viz., chronic glomerulonephritis (CGN) and tubulointerstitial nephritis (TIN). The two groups showed different immunological profiles. Patients in the CGN group exhibited an atypical immunological profile of XLA, with pathogenic leaky B cells producing immunoglobulins that may play a role in forming immune complexes and causing immune-mediated glomerulonephritis. In contrast, patients in the TIN group exhibited a typical immunological profile of XLA, suggesting that antibody-independent/other BTK-dependent mechanisms, or immunoglobulin replacement therapy (IgRT)-related immune/nonimmune-mediated nephrotoxicity causes TIN. CONCLUSION: Nephritis occurring in patients with XLA could have links between their renal pathology and immunological status. Careful observation is recommended to detect kidney pathology in patients with XLA on IgRT.

Maternal Chronic Disease and Congenital Anomalies of the Kidney and Urinary Tract in Offspring: A Japanese Cohort Study.

RATIONALE & OBJECTIVE: Several maternal chronic diseases have been reported as risk factors for congenital anomalies of the kidney and urinary tract (CAKUT) in offspring. However, these investigations used case-control designs, and cases with isolated genitourinary CAKUT were not distinguished from cases in which CAKUT were present with extrarenal congenital anomalies (complicated CAKUT). We examined the association of maternal diseases with isolated and complicated CAKUT in offspring using data from a prospective cohort study. STUDY DESIGN: A nationwide prospective birth cohort study. SETTING & PARTICIPANTS: 100,239 children enrolled in the Japan Environment and Children's Study between January 2011 and March 2014 at 15 research centers. Physicians' diagnoses in mothers and children were collected from medical record transcripts and questionnaires. EXPOSURES: Medical histories of maternal noncommunicable diseases, including obesity, hypertension, diabetes mellitus, kidney disease, hyperthyroidism, hypothyroidism, psychiatric disease, epilepsy, cancer, and autoimmune disease. OUTCOMES: CAKUT diagnosed during the first 3 years of life, classified as isolated or complicated. ANALYTICAL APPROACH: Multivariable Poisson regression with generalized estimating equations accounting for clustering by clinical center. RESULTS: Among the 100,239 children, 560 (0.6%) had CAKUT, comprising 454 (81%) isolated and 106 (19%) complicated forms. The risk of isolated CAKUT was increased in children of mothers who experienced kidney disease (adjusted risk ratio [RR], 1.80 [95% CI, 1.12-2.91]) or cancer (RR, 2.11 [95% CI, 1.15-3.86]). Furthermore, the risk of complicated CAKUT was increased in children of mothers with diabetes mellitus (RR, 3.04 [95% CI, 1.64-5.61]). LIMITATIONS: Lack of standardization or prespecification of clinical definitions, diagnostic criteria, measurements, and testing. Genetic testing was not performed. CONCLUSIONS: Isolated CAKUTs and complicated CAKUTs were associated with different maternal diseases. The results may inform clinical management of pregnancy and highlight potential differences in the genesis of isolated and complicated forms of CAKUT.

Pulmonary vascular resistance and compliance in pulmonary blood flow alterations in children with congenital heart disease.

There is a unique hyperbolic relationship between pulmonary vascular resistance (Rp) and compliance (Cp); however, the characteristics of this coupling curve in pulmonary blood flow alterations remains unknown in children with congenital heart disease. We aimed to explore the Rp-Cp coupling and resistant-compliance (RC) time among them. We retrospectively reviewed catheterization data and calculated Rp and Cp in 217 subjects with ventricular septal defect. Median age and weight at catheterization were 2.8 (1.7-4.4) months and 4.3 (3.7-5.3) kg, respectively. Pulmonary hemodynamic parameters were as follows: mean pulmonary arterial pressure: 36 (28-43) mmHg; the amount of pulmonary blood flow (Qp): 14.2 (11.6-17.6) L/min/m2; Rp: 1.95 (1.38-2.59) Wood unit m2; Cp: 2.98 (2.42-3.88) mmHg/mL/m2; and RC time: 0.35 (0.30-0.40) s. RC time remained unchanged according to alterations in Qp (P = 0.206); however, the relationship between logarithm transformations of Rp and Cp showed more steeper according to an increase in Qp. The pulmonary circulation depends upon Cp rather than Rp according to the degree of Qp despite the constancy in RC time. We should take both Rp and Cp into consideration when evaluating the pulmonary circulation among children with congenital heart disease.

Relationship Between Pulmonary Arterial Resistance and Compliance in Patients with Down Syndrome.

This study aimed to clarify the characteristics of pulmonary arterial resistance (Rp)-compliance (Cp) coupling in individuals with Down syndrome (DS), who have increased risks of pulmonary arterial hypertension (PAH). We performed cardiac catheterization before and after corrective surgery in 85 DS infants and 85 controls with congenital heart disease and PAH. We retrospectively collected hemodynamic data and compared Rp and Cp between the groups. Age at surgery was 3.5 (2.6-4.6) months. The first and second catheterizations were performed 1 month before and after corrective surgery in both groups. Preoperative Cp in DS patients was significantly lower than that in controls [2.27 (1.62-3.0) vs. 2.50 (1.86-3.31) mL/mmHg/m2, p = 0.039], although there was no significant difference in mean pulmonary arterial pressure and Rp between the groups. Analysis of covariance revealed that the slopes of the preoperative regression lines for the logarithmic transformations of Rp and Cp were identical in DS patients and controls (p = 0.299). However, the postoperative regression line was shifted downward in DS patients after corrective surgery. Postoperative home oxygen therapy (HOT) was performed in 39 patients (36 DS patients) and multivariate logistic regression analysis revealed that postoperative HOT was significantly related to low preoperative Cp (p = 0.039) and DS (p = 0.0001). Individuals with DS have the unique pulmonary vasculature characterized with low Cp that is related to postoperative HOT.

Prenatal metal levels and congenital anomalies of the kidney and urinary tract: The Japan Environment and Children's Study.

BACKGROUND: Prenatal exposure to metal elements has been reported as a potential risk factor for congenital malformation. However, studies on the relationship with congenital anomalies of the kidney and urinary tract (CAKUT) are very scarce. METHODS: Participants of a prospective cohort from the Japan Environment and Children's Study, conducted at 15 research centers, were recruited between January 2011 and March 2014. The exposure factors were concentrations of lead (Pb), cadmium (Cd), mercury (Hg), selenium (Se), and manganese (Mn) measured from maternal whole blood in the second or third trimester. The primary outcome was CAKUT diagnosed during the first three years of life, which was classified into isolated cases and complicated cases accompanied by extrarenal congenital defects. To conduct a nested case-control design within the cohort, we selected 351 isolated cases with 1404 matched controls, and 79 complicated cases with 316 matched controls. RESULTS: A logistic regression model was used to examine the associations between individual metal concentrations and each subtype of CAKUT. A higher level of Se was associated with an increased risk of isolated CAKUT (adjusted odds ratio [95 % confidence interval]: 3.22 [1.33-7.77]). Meanwhile, higher levels of Pb and Mn were associated with a reduced risk of the complicated subtype (0.46 [0.24-0.90] and 0.33 [0.15-0.73], respectively). A Bayesian kernel machine regression model accounting for mixed effects of multiple metals further demonstrated that a higher level of Mn alone was significantly associated with a reduced occurrence of the complicated subtype. CONCLUSIONS: Using a stringent statistical approach, the present study demonstrated that a higher Mn concentration in the maternal blood was associated with a lower risk of complicated CAKUT in offspring. Further cohort and experimental studies are needed to verify the clinical impact of this finding.