Novel homozygous OSGEP gene pathogenic variants in two unrelated patients with Galloway-Mowat syndrome: case report and review of the literature.

BACKGROUND: Galloway-Mowat syndrome (GAMOS) is a rare autosomal recessive disorder characterized by early-onset nephrotic syndrome and microcephaly with brain anomalies. WDR73 pathogenic variants were described as the first genetic cause of GAMOS and, very recently, four novel causative genes, OSGEP, LAGE3, TP53RK, and TPRKB, have been identified. CASE PRESENTATION: We present the clinical and genetic characteristics of two unrelated infants with clinical suspicion of GAMOS who were born from consanguineous parents. Both patients showed a similar clinical presentation, with early-onset nephrotic syndrome, microcephaly, brain atrophy, developmental delay, axial hypotonia, and early fatality. We identified two novel likely disease-causing variants in the OSGEP gene. These two cases, in conjunction with the findings of a literature review, indicate that OSGEP pathogenic variants are associated with an earlier onset of nephrotic syndrome and shorter life expectancy than WDR73 pathogenic variants. CONCLUSIONS: Our findings expand the spectrum of pathogenic variants in the OSGEP gene and, taken in conjunction with the results of the literature review, suggest that the OSGEP gene should be considered the main known monogenic cause of GAMOS. Early genetic diagnosis of GAMOS is of paramount importance for genetic counseling and family planning.

Mortality among United States aerospace materials manufacturing workers.

OBJECTIVES: To evaluate long-term mortality rates among aerospace material manufacturing workers as follow-up to an earlier observed excess of nephritis/nephrosis. METHODS: Subjects were 2020 workers ever employed in the facility during 1963-2014. Vital status through 2014 was determined for all subjects and cause of death for 99.2% of 492 deaths. We computed standard mortality ratios (SMR) and internal relative risks. RESULTS: SMRs for nephritis/nephrosis were unremarkable. We observed statistically significant elevated SMRs for kidney cancer among all workers and for the category "other lymphatic hematopoietic tissue cancer" (4/5 deaths from multiple myeloma) among long-term workers with potential plant exposure. CONCLUSIONS: We found no evidence of elevated mortality rates for nephritis/nephrosis. Study limitations precluded robust evaluation of whether the elevated rates for kidney cancer and other lymphatic hematopoietic tissue cancer were related to occupational factors at the study site. Our findings for these two cancers warrant continued mortality follow-up.

Reduction of circulating endothelial progenitor cell level is associated with contrast-induced nephropathy in patients undergoing percutaneous coronary and peripheral interventions.

OBJECTIVES: Reduced number and impaired function of circulating endothelial progenitor cells (EPCs) in patients with chronic kidney disease have been reported. However, there is little data about the association between circulating EPC levels and risk of contrast-induced nephropathy (CIN). The aim of this study was to investigate the relationship between circulating EPCs and CIN in patients after angiography. METHODS AND RESULTS: A total of 77 consecutive patients undergoing elective percutaneous coronary intervention (PCI) and percutaneous transluminal angioplasty (PTA) were enrolled. Flow cytometry with quantification of EPC markers (defined as CD34+, CD34+KDR+, and CD34+KDR+CD133+) in peripheral blood samples was used to assess EPC number before the procedure. CIN was defined as an absolute increase ≧0.5 mg/dl or a relative increase ≧25% in the serum creatinine level at 48 hours after the procedure. Eighteen (24%) of the study subjects developed CIN. Circulating EPC levels were significantly lower in patients who developed CIN than in those without CIN (CD34+KDR+, 4.11±2.59 vs. 9.25±6.30 cells/105 events, P<0.001). The incidence of CIN was significantly greater in patients in the lowest EPC tertile (CD34+KDR+; from lowest to highest, 52%, 15%, and 4%, P<0.001). Using univariate logistic regression, circulating EPC number (CD34+KDR+) was a significant negative predictor for development of CIN (odds ratio 0.69, 95% CI 0.54-0.87, P = 0.002). Over a two-year follow-up, patients with CIN had a higher incidence of major adverse cardiovascular events including myocardial infarction, stroke, revascularization of treated vessels, and death (66.7% vs. 25.4%, P = 0.004) than did patients without CIN. CONCLUSIONS: Decreased EPC level is associated with a greater risk of CIN, which may explain part of the pathophysiology of CIN and the poor prognosis in CIN patients.

Relationship between urinary cadmium and mortality in habitants of a cadmium-polluted area: a 22-year follow-up study in Japan.

BACKGROUND: Several studies have suggested that the exposure to cadmium (Cd) increased mortalities from renal diseases, cardiovascular diseases and malignant neoplasm, including lung cancer and prostate cancer among inhabitants living in Cd-polluted areas and factory workers. This study aimed to assess the influence of environmental exposure to Cd on long term outcome of inhabitants living in an area polluted by Cd. METHODS: A 22-year follow-up study was conducted with 3119 inhabitants (1403 men and 1716 women) living in the Cd polluted Kakehashi River basin in Japan. The subjects were divided into 4 groups according to the amount of urinary Cd level (< 3.0 µg/g creatinine (Cr), 3.0 - 4.9 µg/g Cr, 5.0 - 9.9 µg/g Cr, and ≥ 10.0 µg/g Cr). Mortality was calculated by the person-years method. Hazards ratios (HR) and 95% confidence intervals (CI) were assessed by the Cox's proportional hazard model. RESULTS: Compared with urinary Cd < 3.0 µg/g Cr group, the HR of 5.0 - 9.9 µg/g Cr and ≥ 10.0 µg/g Cr groups were significantly increased after adjustment for age in both sexes: 1.24 (95%CI 1.01 - 1.51) and 1.48 (95%CI 1.17 - 1.90) for men; 1.64 (95%CI 1.17 - 2.28) and 1.78 (95%CI 1.27 - 2.50) for women. The most frequent cause of death was malignant neoplasm in men and cardiovascular diseases in women. The significant increase in mortality risk for cardiovascular diseases was observed in the subjects with ≥ 10 µg/g Cr in both sexes: 1.79 for men (95%CI 1.02 - 3.12) and 2.38 for women (95%CI 1.11 - 5.07). When the subjects were divided into 2 categories (< 20 µg/g Cr and ≥ 20 µg/g Cr), the HR of the urinary Cd ≥ 20 µg/g Cr group for nephritis and nephrosis were 4.82 (95%CI 1.07 - 21.61) in men and 7.92 (95%CI 1.77 - 35.33) in women, respectively. The significant increase was not observed for malignant neoplasm. CONCLUSION: These results suggest a dose-response relationship between Cd body burden and mortality for cardiovascular diseases, cerebrovascular diseases and nephritis and nephrosis.

Focal segmental glomerulosclerosis in nephrotic adults: presentation, prognosis, and response to therapy of the histologic variants.

The histopathologic diagnosis of primary focal segmental glomerulosclerosis (FSGS) has come to include a number of histologic lesions (variants), but the prognostic significance of these discrete lesions is controversial because published information regarding the presentation, course, and response to treatment is limited. A retrospective analysis was conducted of 87 nephrotic adult patients with biopsy-proven primary FSGS. Patients were categorized on the basis of histologic criteria into those with a classic scar (36 patients), the cellular or collapsing lesion (40 patients), or the tip lesion (11 patients) of FSGS to evaluate differences in presentation, response to therapy, and clinical outcomes. The clinical features at biopsy were similar among the three groups with the exception that patients with the tip lesion were older and patients with the collapsing lesion had more severe proteinuria. Over the course of follow-up, 63% of patients treated attained remission and the response to steroid therapy was similar among the groups (classic scar 53% versus collapsing lesion 64% versus tip lesion 78%; P = 0.45). The overall renal survival was significantly better for patients who entered remission compared with patients who did not enter remission (92% versus 33% at 10 yr; P < 0.0001). The renal survival at 10 yr for patients who entered remission was similar among the three groups (classic scar 100% versus tip lesion 100% versus collapsing lesion 80%; P = 0.61). In patients who did not enter remission, the renal survival at 10 yr was significantly worse for patients with collapsing lesion and tip lesion (classic scar 49% versus tip lesion 25% versus collapsing lesion 21%; P = 0.002). In conclusion, the prognosis for nephrotic FSGS patients who enter remission is excellent regardless of the histologic lesion. Because the remission rate after treatment is similar among patients with the histologic variants, response to therapy cannot be predicted on the basis of histology alone. Thus, nephrotic patients with primary FSGS should receive a trial of therapy irrespective of the histologic lesion when not contraindicated.

Mortality from nephritis and nephrosis in the fibreglass manufacturing industry.

OBJECTIVES: To investigate the question of whether there is an association between exposure to silica or respirable glass fibre and mortality from nephritis or nephrosis among workers in fibrous glass wool manufacturing facilities. METHODS: A case-control study with cases and controls derived from the Owens Corning mortality surveillance system. Two case-control analyses were carried out, one where the cases are defined with nephritis or nephrosis as the underlying cause of death and one where cases are defined as those where nephritis or nephrosis is either the underlying or a contributing cause of death. RESULTS: There is no consistent relation between respirable fibres or respirable silica and nephritis or nephrosis when the analysis is based either on underlying cause only or on underlying plus contributing cause of death. None of the sociodemographic variables considered suggests an increased risk when considering both underlying and contributing cause of death. CONCLUSIONS: These data would seem to support the contention that the most accurate picture of renal disease will be gained from the use of all information on the death certificate and not only the underlying cause. For these data, all odds ratios (ORs) for respirable fibres and silica based on both underlying and contributing cause of death are < 1 with the exception of the highest exposure to silica which is slightly > 1 (OR = 1.04). Although these results do not prove that there is no association between nephritis and nephrosis and exposure to fibreglass or silica in the fibreglass manufacturing environment, they do not support the assertion that such an association exists.

Analysis of mortality from nephritis and nephrosis among nickel-cadmium battery workers.

Mortality from nephritis and nephrosis (and other diseases of the genitourinary system) experienced by a study cohort of 3,025 nickel-cadmium battery workers was investigated. Observed (O) numbers of deaths from these diseases for the period 1946 through 1981 were compared with those that might be expected (E) to occur on the basis of rates of mortality for the general population of England and Wales (nephritis and nephrosis, International Classification of Diseases, eighth revision [ICD 8th] Code No. 580-584; E = 5.49, O = 10: all disease of the genitourinary system (noncancers), ICD 8th 580-629; E = 11.50, O = 17). These differences were not statistically significant at the 5% level. When the estimated cadmium exposures of those who died from these causes were compared with those of all matching survivors using the method of regression models in life-tables, no statistically significant association was found between occupational exposure to cadmium and mortality from these diseases. A separate analysis was made of the mortality experience of 39 workers with cadmium nephropathy.

A breeding study to control chronic progressive nephrosis in rats.

Breeder male Sprague-Dawley rats were categorized as potential low and high protein excretors at 4 months of age. The average selection values of these two groups were 0.59 and 1.75 mg/ml, respectively. Paris of females were mated to these males in two breeding cycles in the fashion of a diallele cross. The heritability index based on protein excretion values of 263 male offspring at 6 months of age from both cycles of high and low excretor males was 0.526 with approximate variance of 0.0668. Significantly different (p less than 0.01) survival distributions were shown. The mean and median survival times of the high excretor offspring were 611.1 and 652 days, respectively, compared to 651.4 and 680.5 days, respectively, in low excretor offspring. The proportion of offspring with marked chronic progressive nephrosis was significantly greater (p less than 0.01) in the high excretor group, both prior to and after 700 days of age, than that of offspring in the low excretor group. The selection of low excretor males for breeding stock appears to offer a practical basis for minimizing the total expression of chronic progressive nephrosis in this strain of rat.

Mortality and autopsy rate from urogenital diseases in Finland in 1955-1973.

Mortality from various urogenital diseases including the malignant neoplasms of the genito-urinary system and the breast in Finland in 1955-1973 was studied. Only minor changes were found in the total death rate of all these diseases between 1955 and 1973. However, the age-specific death rates of the nephritis-nephrosis group decreased both among males and females. Also mortality from all other urogenital diseases than malignant neoplasms decreased among elderly and middle-aged people. Mortality from malignant neoplasms of the breast increased slightly among elderly women and that of the prostate among elderly men. The autopsy rate of the deaths due to all other urogenital diseases (33.5% in 1973) than malignant neoplasms (27.4%) was of the same order as that recorded for all natural deaths (33.2%) in Finland between 1963 and 1973. Many types of malignant urogenital neoplasms remained significantly under-autopsied. The highest autopsy rates of the single urogenital diseases were recorded for acute nephritis and unqualified nephritis; the respective national rates were 90 and 71%, in 1973. These rates exceeded highly significantly the mean national autopsy rate of all deaths which was 38.2%.

Recent trends in the mortality rate from renal disease in children and young adults in New York City.

Analysis has shown that the over-all death rate from renal disease for residents of New York City under 25 years of age has declined from 4.6 per 100,000 in 1950 to 2.3 per 100,000 in 1970. Nephritis and nephrosis was the major disease category accounting for this decrease in deaths. A similar trend was found for the United States as a whole. Other causes of renal disease did not manifest consistent changes in death rates. The decline in deaths from nephritis and nephrosis could not be ascribed solely to changing diagnostic habits or terminology. A possible alternative explanation is a change in the natural history of these diseases. Data of this type might be useful as an index to future trends in the mortality rate from renal diseases and as one basis for projections of potential future needs for dialysis and renal transplantation. Using 1965 data, we estimate the number of such potential candidates in New York City would have been 9 per 1,000,000 for the 5 to 14 year age group and 23 per 1,000,000 for the 15 to 24 year age group. There are significant limitations of projections based on such data. These estimates of potential candidates for chronic dialysis or renal transplantation are the first available for children in the United States.

Distribution of hypertension and renal disease in Oregon.

Expecting to find agreement between the geographic distribution of hypertension and renal disease, we developed regional mortality rates for 1950-72 and prevalence rates for a Selective Service cohort born in 1939-41 and examined during 1957-69. For this purpose the State's counties were grouped into eight geographically homogeneous regions. The general decline in hypertension mortality was most pronounced in Portland, Oregon's major urban center. However, the decline halted during 1968-72 in the southern Cascade region which has become an area of relatively higher risk within the State. During these 23 years nephritis mortality fell, kidney infection mortality was stable, and both syndromes showed peak mortality in other, different regions of the State. The geographic pattern of hypertension prevalence among the draftee cohort resembled the 1963-67 hypertension mortality pattern, but more recent morbidity data are needed to confirm the southern Cascade region's recent change to a high-risk area. Of 529 draftees with diagnosed hypertension, only 35 percent of the cases were previously known, only 7 percent has had any previous treatment, and only 7 percent were associated with known renal conditions. Among 521 registrants with a history of renal disorders, the prevalence of hypertension was increased for all categories of renal disease but was significantly high only for those with a history of glomerulonephritis. To date in Oregon we have found no evidence that renal disorders are major determinants of hypertension morbidity or mortality.