Identification of a novel UMOD mutation (c.163G>A) in a Brazilian family with autosomal dominant tubulointerstitial kidney disease.

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is characterized by autosomal dominant inheritance, progressive chronic kidney disease, and a bland urinary sediment. ADTKD is most commonly caused by mutations in the UMOD gene encoding uromodulin (ADTKD-UMOD). We herein report the first confirmed case of a multi-generational Brazilian family with ADTKD-UMOD, caused by a novel heterozygous mutation (c.163G>A, GGC→AGC, p.Gly55Ser) in the UMOD gene. Of 41 family members, 22 underwent genetic analysis, with 11 individuals found to have this mutation. Three affected individuals underwent hemodialysis, one peritoneal dialysis, and one patient received a kidney transplant from a family member later found to be genetically affected. Several younger individuals affected with the mutation were also identified. Clinical characteristics included a bland urinary sediment in all tested individuals and a kidney biopsy in one individual showing tubulointerstitial fibrosis. Unlike most other reported families with ADTKD-UMOD, neither gout nor hyperuricemia was found in affected individuals. In summary, we report a novel UMOD mutation in a Brazilian family with 11 affected members, and we discuss the importance of performing genetic testing in families with inherited kidney disease of unknown cause.

Clinical and molecular characterization of a family with a dominant renin gene mutation and response to treatment with fludrocortisone.

BACKGROUND: A family was identified with autosomal dominant inheritance of anemia, polyuria, hyperuricemia, and chronic kidney disease. Mutational analysis revealed a novel heterozygous mutation c.58T > C resulting in the amino acid substitution of cysteine for arginine in the preprorenin signal sequence (p.cys20Arg) occurring in all affected members. METHODS: Effects of the identified mutation were characterized using in vitro and in vivo studies. Affected individuals were clinically characterized before and after administration of fludrocortisone. RESULTS: The mutation affects endoplasmic reticulum co-translational translocation and posttranslational processing, resulting in massive accumulation of non-glycosylated preprorenin in the cytoplasm. This affects expression of intra-renal RAS components and leads to ultrastructural damage of the kidney. Affected individuals suffered from anemia, hyperuricemia, decreased urinary concentrating ability, and progressive chronic kidney disease. Treatment with fludrocortisone in an affected 10-year-old child resulted in an increase in blood pressure and estimated glomerular filtration rate. CONCLUSIONS: A novel REN gene mutation resulted in an alteration in the amino acid sequence of the renin signal sequence and caused childhood anemia, polyuria, and kidney disease. Treatment with fludrocortisone improved renal function in an affected child. Nephrologists should consider REN mutational analysis in families with autosomal dominant inheritance of chronic kidney disease, especially if they suffer from anemia, hyperuricemia, and polyuria in childhood.

Characteristics of sudden death in hemodialysis patients.

Hemodialysis (HD) is an intermittent procedure during which large fluid and electrolyte shifts occur. We hypothesized that sudden death occurrences in HD patients are related to the timing of HD, and that they occur more frequently in the 12 h period starting with dialysis and in the 12 h period at the end of the dialysis-free weekend interval. In a retrospective study, 228 patient deaths were screened to determine if they met the criteria for sudden death. Information was obtained from clinic charts, dialysis center records, and interview of witnesses of the death event. There were 80 HD patients who met the criteria for sudden death. A bimodal distribution of death occurrences was present, with a 1.7-fold increased death risk occurring in the 12 h period starting with the dialysis procedure and a threefold increased risk of death in the 12 h before HD at the end of the weekend interval (P=0.011). Patients with sudden death had a high prevalence of congestive heart failure and coronary artery disease. Only 40% of patients experiencing sudden death were receiving beta-blockers, and the prior monthly serum potassium value was less than 4 mEq/l in 25%. Sudden death is temporally related to the HD procedure. Every other day HD could be beneficial in preventing sudden death. Careful attention to the usage of beta-blockers and to the maintenance of normal serum potassium values is indicated in HD patients at risk for sudden death.

Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy.

INTRODUCTION: Medullary cystic kidney disease 2 (MCKD2) and familial juvenile hyperuricaemic nephropathy (FJHN) are both autosomal dominant renal diseases characterised by juvenile onset of hyperuricaemia, gout, and progressive renal failure. Clinical features of both conditions vary in presence and severity. Often definitive diagnosis is possible only after significant pathology has occurred. Genetic linkage studies have localised genes for both conditions to overlapping regions of chromosome 16p11-p13. These clinical and genetic findings suggest that these conditions may be allelic. AIM: To identify the gene and associated mutation(s) responsible for FJHN and MCKD2. METHODS: Two large, multigenerational families segregating FJHN were studied by genetic linkage and haplotype analyses to sublocalise the chromosome 16p FJHN gene locus. To permit refinement of the candidate interval and localisation of candidate genes, an integrated physical and genetic map of the candidate region was developed. DNA sequencing of candidate genes was performed to detect mutations in subjects affected with FJHN (three unrelated families) and MCKD2 (one family). RESULTS: We identified four novel uromodulin (UMOD) gene mutations that segregate with the disease phenotype in three families with FJHN and in one family with MCKD2. CONCLUSION: These data provide the first direct evidence that MCKD2 and FJHN arise from mutation of the UMOD gene and are allelic disorders. UMOD is a GPI anchored glycoprotein and the most abundant protein in normal urine. We postulate that mutation of UMOD disrupts the tertiary structure of UMOD and is responsible for the clinical changes of interstitial renal disease, polyuria, and hyperuricaemia found in MCKD2 and FJHN.

Relationship between underlying renal disease and renal transplantation outcome.

The purpose of this study is to better characterize graft and patient survival posttransplantation by examining survival according to underlying renal disease for all first-time renal allograft recipients in the United Network for Organ Sharing (UNOS) registry. From 1987 through 1996, the UNOS registry collected data on 23,838 living and 67,183 cadaveric renal transplantations. This investigation included all patients undergoing their first renal transplantation for whom the underlying cause of renal failure could be identified and categorized. Gross 1- and 3-year patient and graft survival according to underlying renal disease are included. In addition, a Cox proportional hazards model was created to analyze the effect of underlying disease on graft and patient survival after adjusting for comorbid conditions, demographics, and type of renal transplant (living versus cadaveric). The association between underlying disease and graft and patient survival is shown. Amyloidosis, sickle cell anemia, scleroderma, and radiation nephritis are associated with poor graft and patient survival. The risk ratio for patient mortality was more than twice that for immunoglobulin A nephropathy for a number of conditions, including analgesic nephropathy, amyloidosis, and both forms of diabetes mellitus.

Tobacco, hypertension, and vascular disease: risk factors for renal functional decline in an older population.

BACKGROUND: A decline in renal function with age has been noted in some but not all individuals. The purpose of this study was to identify risk factors associated with a clinically significant increase in serum creatinine (of at least 0.3 mg/dL) in an older nondiabetic population. METHODS: A retrospective case-control study was performed analyzing data obtained from 4142 nondiabetic participants of the Cardiovascular Health Study Cohort, all at least 65 years of age, who had two measurements of serum creatinine performed at least three years apart. Cases were identified as participants who developed an increase in serum creatinine of at least 0.3 mg/dL, with controls including participants who did not sustain such an increase. RESULTS: There was an increase in the serum creatinine of at least 0.3 mg/dL in 2.8% of the population. In a multivariate "best-fit" model adjusted for gender, weight, black race, baseline serum creatinine, and age, the following factors were associated with an increase in serum creatinine: number of cigarettes smoked per day, systolic blood pressure, and maximum internal carotid artery intimal thickness. CONCLUSIONS: These data suggest that three very preventable or treatable conditions-hypertension, smoking, and prevalent vascular disease, which are associated with large and small vessel disease-are highly associated with clinically important changes in renal function in an older population.

Administration and pharmacokinetics of high-dose cyclophosphamide with hemodialysis support for allogeneic bone marrow transplantation in acute leukemia and end-stage renal disease.

We report a patient with pre-existing end-stage renal disease (ESRD) who underwent successful matched related donor allogeneic bone marrow transplantation for AML in second complete remission (CR2) using conditioning with high-dose cyclophosphamide (CY, 60 mg/kg/day x 2) and TBI (165 cGy twice daily x 4 days). The timing of hemodialysis after high-dose CY was extrapolated from available data on the pharmacokinetics of high-dose CY and hemodialysis clearance of conventional dose CY and its metabolites. Pharmacokinetic analyses indicated that the elimination of high-dose CY and its alkylating metabolites is impaired in ESRD but is cleared with hemodialysis. The patient's early post-transplant course was uncomplicated, and WBC and platelet engraftment occurred by day +22. Bone marrow examination on day +25 showed trilineage engraftment with no AML; cytogenetics showed 100% donor karyotype. The patient remains in remission with 100% donor karyotype at 3 years post transplant. Clinical results indicate that the administration of high-dose CY is feasible with hemodialysis support for patients with ESRD.

A case control study of proximal calciphylaxis.

The purpose of this investigation was to describe the clinical presentation of nine patients with calciphylaxis involving the proximal lower extremities or trunk and to compare the clinical characteristics of these patients with those of 347 hemodialysis patients from the same geographic area. Patients were identified primarily through a computer search of pathology records, identifying patients with the term "calciphylaxis" in the biopsy report. All patients had pathologic specimens consistent with calciphylaxis. All the calciphylaxis patients were white and were markedly obese. While two patients had markedly elevated parathyroid hormone levels, most patients did not show severe derangements of calcium phosphate metabolism compared with other dialysis patients. A logistic regression model identified body mass index and low serum albumin 3 months before diagnosis as being highly associated with a diagnosis of calciphylaxis. Diabetes mellitus and parameters of calcium-phosphate metabolism were not significantly associated with proximal calciphylaxis. These findings suggest that white race, morbid obesity, and poor nutritional status are associated with proximal calciphylaxis in dialysis patients.

Is renal revascularization in diabetic patients worthwhile?

PURPOSE: This retrospective review describes surgical management of atherosclerotic renovascular disease (RVD) in hypertensive adults with diabetes mellitus. METHODS: From July 1987 through July 1995, 54 consecutive hypertensive diabetics (mean 213/103 mm Hg; mean medications three drugs) requiring either insulin (16 patients) or oral hypoglycemic therapy (38 patients) had operative repair of atherosclerotic RVD. Renal dysfunction (serum creatinine [SCr] > or = 1.3 mg/dl) was present in 82% of patients (mean SCr 2.4 mg/dl). Associations between blood pressure and renal function response to operation and preoperative parameters were examined. Clinical characteristics, response to operation, and dialysis-free survival were compared with those of 291 nondiabetic patients. RESULTS: Four (7.4%) operative deaths occurred. Among 50 survivors blood pressure response was considered cured or improved in 72% and unchanged in 28%. Of 42 patients with renal dysfunction 40% had improved function including three patients removed from dialysis. No preoperative parameter examined demonstrated a significant association with blood pressure or renal function response. During follow-up 10 additional patient deaths occurred, and eight patients progressed to dialysis dependence. Time to death or dialysis was associated with preoperative estimates of glomerular filtration (p = 0.03) and the change in estimates of glomerular filtration after operation (p = 0.01). Compared with 291 nondiabetics, the diabetic group had no statistical difference in improved function response (40% vs 51%, p = 0.21); however, diabetics had a significantly lower rate of beneficial blood pressure response (72% vs 89%, p = 0.01) and an increased risk of dialysis or death during follow-up (p = 0.02). By multivariate analysis independent predictors of time to death or dialysis included the presence of diabetes mellitus, patient age, history of congestive heart failure, and increased serum creatinine. CONCLUSIONS: Most of the selected diabetic patients had a beneficial blood pressure response after undergoing operative repair of atherosclerotic RVD, albeit at a lower rate compared with nondiabetics. In diabetics poor renal function before and after operation was associated with progression to dialysis and death. Improved renal function after operation was associated with improved survival; however, function response to renal revascularization was difficult to predict.

Survival of patients undergoing renal replacement therapy in one center with special emphasis on racial differences.

This study compared racial differences in end-stage renal disease (ESRD) in 550 patients starting renal replacement therapy at a large academic dialysis center between January 1, 1990, and December 31, 1993, with follow-up through December 31, 1994. Patient groups were compared with respect to cause of ESRD, comorbid factors at the start of dialysis therapy, choice of modality, transplantation rate, and survival. Fifty-eight percent of the patients were white and 42% were African-American. There was a similar distribution of causes of ESRD between races. African-American patients were less likely to choose peritoneal dialysis as initial therapy (11.6% v 29.3%; P < 0.001) and were less likely to change dialysis modality. Transplantation rates were significantly different between African-American and white patients (9.3% v 27.6%; P < 0.001). African-Americans less frequently received living-related, living-nonrelated, and cadaveric renal transplants. Given differences in transplantation rates and in survival of transplanted patients versus patients on dialysis, survival analysis was performed without censoring for transplantation. A multivariate Cox proportional hazards model was formed, and the following were identified as being significant independent predictors of survival: age, race, age-race interaction, serum albumin at the start of dialysis, activity level at the start of dialysis, and presence of congestive heart failure and cancer. Age had little effect on survival among African-American patients, while it was a significant predictor of survival in white patients. In the group of patients starting dialysis before the age of 30 years, African-American patients had a significantly increased mortality risk compared with white patients. However, white patients older than 50 years had a higher mortality risk; this risk difference increased with age. Racial differences in mortality among older white patients could not be explained by differences in comorbid conditions, transplantation rates, or withdrawal from dialysis.

Case report: analgesic nephropathy: a soda and a powder.

Analgesic nephropathy has long been considered a potentially preventable cause of renal disease. Early reports were described in patients who consumed analgesics containing phenacetin. In recent data, the removal of phenacetin from analgesic preparations resulted in a reduction in analgesic-induced end stage renal disease in Europe and Australia. However, a reduction in the incidence of analgesic nephropathy has not occurred uniformly, suggesting that phenacetin is not the sole cause. Current data raise concerns regarding adverse renal effects of acetaminophen and nonsteroidal antiinflammatory drugs. Aspirin taken alone may be of least concern. The diagnosis of analgesic nephropathy is suggested in subjects with chronic renal failure, a history of daily consumption of analgesic preparations, small bumpy kidneys, and renal papillary necrosis or chronic interstitial nephritis. However, the spectrum of disease may be changing, because these agents also may increase the risk of cardiovascular disease and chronic renal disease due to nephrosclerosis, glomerulonephritis, and diabetes mellitus. Potential pathogenetic mechanisms in analgesic nephropathy include direct cellular injury induced by analgesics, prostaglandin inhibition with reduction or redistribution of renal blood flow, and interesting new concepts regarding the role of caffeine in increasing oxygen demand and reducing oxygen supply in the medulla. The primary goal of therapy is discontinuation of analgesic consumption. Because of the association between analgesic intake and uroepithelial tumors, surveillance of patients for neoplasm is suggested.

Renovascular disease in older patients beginning renal replacement therapy.

Renovascular disease (RVD) in older patients can cause progressive renal insufficiency and even end-stage renal disease (ESRD). The frequency of this clinical problem is not well defined. Renal duplex sonography (RDS) correctly identifies the presence of RVD with an overall accuracy of approximately 95%. Therefore, the purpose of this study was to utilize RDS as a noninvasive tool to identify the presence of critical RVD (> or = 60% diameter-reducing stenosis or occlusion) in patients 50 years of age or older beginning renal replacement therapy. A total of 53 consecutive participating patients were prospectively interrogated. Complete interrogations occurred in 45 of the 53 patients (85%), and 92 of the 103 kidneys (89%). Critical RVD was noted in 10 of 45 patients (22%). RVD was bilateral in 5 patients, unilateral in 5 patients, and there were 4 renal artery occlusions noted. All patients with critical RVD were white (10 of 25 white patients or 40%). Total pack years of smoking as well as associated cardiovascular and cerebrovascular conditions were greater in those patients with critical RVD compared to those without. These results indicate that RDS remains technically feasible as renal blood flow and function decline. Unsuspected RVD possibly contributory to renal insufficiency exists in a significant number of primarily white patients 50 years of age or older beginning renal replacement therapy. These patients are generally smokers with a high frequency of associated extrarenal atherosclerosis The addition of RVD as a separate category of disease causing ESRD would improve U.S. Renal Data System ESRD classification. RVD should be recognized as a cause of ESRD.

Interactions of molecules with nucleic acids. X. Covalent intercalative binding of the carcinogenic BPDE I(+) to kinked DNA.

A theoretical model is proposed for the covalent binding of (+) 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene denoted by BPDE I(+), to N2 on guanine. The DNA must kink a minimum of 39 degrees to allow proper hybrid configurations about the C10 and N2 atoms involved in bond formation and to allow stacking of the pyrene moiety with the non-bonded adjacent base pair. Conservative (same sugar puckers and glycosidic angles as in B-DNA) and non-conservative (alternating sugar puckers as in intercalation sites) conformations are found and they are proposed structures in pathways connecting B-DNA, an intercalation site, and a kink site in the formation of a covalently intercalative bound adduct of BPDE I(+) to N2 on guanine. Stereographic projections are presented for (3') and (5') binding in the DNA. Experimental data for bending of DNA by BPDE, orientation of BPDE in DNA and unwinding of superhelical DNA is explained. The structure of a covalent intercalative complex is predicted to result from the reaction. Also, an anti----syn transition of guanine results in a structure which allows the DNA to resume its overall B-form. The only change is that guanine has been rotated by 200 degrees about its glycosidic bond so that the BPDE I(+) is bound in the major groove. The latter step may allow the DNA to be stored with an adduct which may produce an error in the genetic code.