Homocysteine, B vitamins, and vascular-access thrombosis in patients treated with hemodialysis.

To evaluate whether increased plasma homocysteine concentrations (hyperhomocysteinemia) are associated with thrombosis of arteriovenous (AV) grafts, we determined plasma homocysteine, plasma and erythrocyte folate, plasma vitamin B12, and vitamin B6 (pyridoxal-5'-phosphate [PLP]) in 48 patients (45 black patients and three white patients) with end-stage renal disease who received hemodialysis. 5,10-Methylenetetrahydrofolate reductase (MTHFR) genotypes were also analyzed. The patients were divided into two groups, including a thrombosis-prone group with frequent graft loss (n = 24) and a control group with prolonged graft survival who were matched by age and duration of dialysis (n = 24). Hyperhomocysteinemia (>15 micromol/L) was found in 42 patients. There were no significant differences in all values, including the concentrations of homocysteine and vitamins between the two groups. Based on plasma folate and PLP concentrations, over 70% of patients appeared to have inadequate folate and/or vitamin B6 nutriture. Plasma homocysteine concentrations showed significant negative correlations with plasma and erythrocyte folate, and plasma vitamin B12 in all patients combined, whereas no significant correlation was found between plasma PLP and homocysteine concentrations. Among 48 patients, the heterozygous mutation (Val/Ala) of MTHFR was found only in three patients, two of whom belonged to the thrombosis-prone group and one to the control group, and there were no individuals with homozygous thermolabile mutation (Val/Val). All three white patients had Ala/Ala genotype, and 3 in 45 black patients (6.7%) were heterozygotes (Val/Ala).

Dominantly transmitted glomerulocystic kidney disease: a distinct genetic entity.

Glomerulocystic kidney disease (GCKD) is a relatively rare condition with both a sporadic and familial occurrence. Pathologically, GCKD is characterized by cystic dilatation of Bowman's space and the initial proximal convoluted tubule. As a heritable disorder, GCKD has primarily been recognized in infants with a family history of classic, autosomal dominant polycystic kidney disease (ADPKD). Dominantly transmitted GCKD associated with either hypoplastic or normal-sized kidneys has also been reported in older children and adults. A large, three-generation African-American family with familial GCKD is characterized. Of the 20 individuals available for study, seven affected individuals were identified by renal sonogram or renal histopathology. GCKD in this family segregates as an autosomal dominant trait as evidenced by its apparent transmission from a father to his sons. A set of directed linkage strategies indicates that the distinctive GCKD phenotype in this family results from a dominantly acting mutation that disrupts a genetic locus distinct from the ADPKD loci, PKD1 and PKD2, as well the human homologue of mouse jcpk mutation, a newly described murine GCKD. These analyses are the first known genetic studies conducted in a family with heritable GCKD and post-infantile age of onset.

Homocysteine and folate concentrations in blood from patients treated with hemodialysis.

Plasma homocysteine and plasma and erythrocyte folate concentrations before and after hemodialysis were measured in 31 patients with ESRD. Homocysteine and folate were measured by HPLC-fluorometric and microbiological methods, respectively. The mean plasma homocysteine level declined from 36.8 to 24.2 mumol/L during hemodialysis, indicating that homocysteine can be partly removed by hemodialysis (P < 0.0001). Mean plasma folate concentration before hemodialysis was 46.4 nmol/L and decreased to 25.9 nmol/L after hemodialysis (P < 0.0001), whereas mean erythrocyte folate concentration did not change (1295 and 1385 nmol/L before and after hemodialysis, respectively). Plasma folate concentrations showed a significant negative correlation with homocysteine concentrations before and after hemodialysis (r = -0.53, P < 0.003, and r = -0.59, P < 0.001, respectively). Furthermore, there were significant negative correlations between plasma homocysteine and erythrocyte folate concentrations both before (r = -0.60, P < 0.0005) and after hemodialysis (r = -0.49, P < 0.005). All patients had homocysteine concentrations over 12.0 mumol/L before hemodialysis, and only three had homocysteine concentrations lower than 12.0 mumol/L after hemodialysis. Although significant correlations existed between homocysteine and folate concentrations, the majority of the patients in this study appeared to have adequate folate nutriture as assessed by blood folate concentrations. It remains to be determined whether patients with ESRD have an altered homocysteine metabolism.

Genetic association of 11 beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) flanking microsatellites with essential hypertension in blacks.

11 beta-Hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) specifically modulates access of the mineralocorticoid aldosterone to the kidney mineralocorticoid type 1 receptors in a physiological environment in which there is a molar excess of cortisol. Cortisol and aldosterone have similar affinities for mineralocorticoid receptors. Mechanistically, 11 beta-HSD2 converts cortisol to cortisone. The other known isoform, 11 beta-HSD1, not only catalyzes the cortisol to cortisone reaction but also the reverse reaction, making it unlikely to play an important role in modulating the access of aldosterone to mineralocorticoid receptors. Mutations in the HSD11B2 gene (both exonic and intronic) have been demonstrated to cause reduced activity of this enzyme in the syndrome of apparent mineralocorticoid excess, a rare autosomal recessive disorder. We hypothesized that this locus is also involved in the etiology of essential hypertension. To test this locus and flanking chromosomal regions for allelic association and genetic linkage to essential hypertension, it is necessary to have informative genetic markers. To this end, we have refined the localization of 11 beta-HSD2 to 16q22.1. We genotyped subjects using the nearest flanking microsatellites (D16S301 and D16S496). We conducted an association study using black subjects with hypertensive end-stage renal disease, black normotensive control subjects, and black and white individuals from the general population. We used chi 2 analysis and Fisher's exact test to test for association with these candidate gene markers. No significant association was found between D16S301 and hypertension. However, a positive association with hypertension was found at the D16S496 microsatellite locus (chi 2 = 6.98, df = 1, P < or = .008). Our data suggest that HSD11B2 is associated with hypertension in our black subjects with hypertensive end-stage renal disease. The 16q22.1 chromosome region potentially harbors a candidate gene for essential hypertension. Confirmation of our findings in another independently ascertained group of hypertensive subjects will provide a basis for proceeding with sib-pair linkage analyses.

Possible mediators in hypertension: renal factors.

Hypertension is more prevalent and more severe in African Americans compared with whites. Evidence is presented that support an important role of the kidney in the excess incidence of hypertension in this population group. There are quantitative differences in renal physiology between hypertensive African Americans and whites, the most dominant of which is an increased renal vascular resistance in African Americans that might be structural or functional. This increased renal vascular resistance might represent an underlying primary renal disease that has remained concealed among the spectrum of diseases referred to as benign nephrosclerosis. The answer(s) to this intriguing question will provide a better understanding of the kidney as a mediator and/or target of hypertension.

Rapid renal deterioration secondary to oxalate in a patient with diabetic gastroenteropathy.

We report the case of a white woman with insulin-dependent diabetes for 12 years who had rapid deterioration in renal function over a 7-month period. A renal biopsy showed widespread deposition of a polarizing crystalline material consistent with calcium oxalate. Fat malabsorption due to diabetic diarrhea was first documented 5 years earlier when renal function was normal. Chronic malabsorption can lead to chronic interstitial nephritis secondary to oxalate deposition, but rarely leads to acute deterioration in renal function. This entity should be considered in individuals with steatorrhea and no other cause for their renal failure.

Tetrodotoxin protects against acute ischemic renal failure in the rat.

Tetrodotoxin has been reported to cause prolonged systemic hypotension without resultant ischemic damage. We tested its ability to protect the kidney during 60 minutes of warm ischemia in uninephrectomized rats. Protection was observed when tetrodotoxin was given intravenously at two microgram./kg. and four microgram./kg. as assessed by serial plasma blood urea nitrogen and creatinine measurements over two weeks. Tetrodotoxin was protective when given immediately before or immediately after the ischemic period. The renal protection of tetrodotoxin was not due to its effects on renal nerves as renal denervation did not protect the kidney from the ischemic damage. The renal protective effects of four microgram. tetrodotoxin/kg. were similar to those of four mg. captopril/kg. but the combination of the two was paradoxically without effect. We tested whether tetrodotoxin and captopril chemically antagonized each other, but in the presence of tetrodotoxin, captopril was still a potent inhibitor of the conversion of angiotensin I to angiotensin II. These results indicate that tetrodotoxin could be useful in elucidating the sequence of events associated with ischemic-reperfusion renal injury and in identifying ways of preserving renal function during renal surgery.

Ureteral obstruction due to blood clot following percutaneous renal biopsy: resolution with intraureteral streptokinase.

The nonsurgical approach to unilateral ureteral obstruction due to impaction of a blood clot is described. A patient with the nephrotic syndrome secondary to minimal change disease had gross hematuria and acute renal failure following percutaneous renal biopsy. After he responded to prednisone therapy, clot obstruction developed at the site of the percutaneous biopsied kidney, which was treated with intracaliceal infusion of streptokinase via a ureteral catheter. Complete resolution of the clot and the urinary tract obstruction was accomplished within 3 days. This approach appears to be the treatment of choice in upper urinary tract obstruction secondary to blood clots when simple ureteral catheter drainage is ineffective.

Vitamin-A-induced hypercalcemia: response to corticosteroids.

Hypercalcemia caused by vitamin A toxicity and its prompt response to prednisone is described. Diagnosis was difficult in this 16-year-old patient because she denied recent ingestion of vitamin A and was thought to be bulimic. Intravenous fluids and loop diuretics lowered the serum calcium and ameliorated the symptoms of nausea and vomiting temporarily. During the 10 days of this therapy the serum calcium never fell below 11.5 mg/dl. Oral prednisone was then started and produced a prompt and lasting reduction of the serum calcium to normal. Physicians should be aware of this complication in teenagers who use vitamin A for cosmetic purposes and in patients who habitually overuse vitamin preparations.

Renal disease and syphilis: a report of nephrotic syndrome with minimal change disease.

A case of nephrotic syndrome and acute renal failure in a 74-year-old man with latent syphilis is described. A renal biopsy demonstrated focal global sclerosis in three of nine glomeruli, however, the remaining glomeruli revealed typical lesions of minimal change disease. Previous reports of renal involvement in syphilis have described membranous glomerulonephritis, mesangial and endothelial cell proliferative glomerulonephritis, and, recently, rapidly progressive glomerulonephritis. The proteinuria and renal failure resolved after penicillin therapy alone. This response strongly suggested that there was a causal relationship between the syphilis and the nephrotic syndrome. This is the first report of such a relationship.

Incidental bilateral adrenal calcification.

incidental bilateral adrenal calcification was detected in a man during evaluation for low back pain. He had been born a double footling breech at home, and probably had bilateral adrenal hemorrhage. He now has normal adrenal function. This case is discussed, and the literature is reviewed.

The value of whole lung tomography in the early detection of metastatic disease in patients with renal cell carcinoma and testicular tumors.

The value of whole lung tomography was compared to chest x-rays in patients with renal cell carcinoma and germ cell testicular tumors. We studied 83 patients with testicular tumors and 34 with renal cell carcinoma. At least 1 metastatic lesion was present on whole lung tomography in 11 of 64 patients (17 per cent) with testicular tumors and 2 of 21 (10 per cent) with renal cell carcinoma who had negative chest x-rays. Of the patients with a solitary lesion on the chest x-ray 3 of 10 (30 per cent) with testicular tumor and 5 of 11 (45 per cent) with renal cell carcinoma had multiple metastatic lesions on whole lung tomograms. Falsely positive chest x-rays were noted in 6 of 15 patients (40 per cent) with renal cell carcinoma and 6 of 16 (37 per cent) with testis tumor. These falsely positive results were caused by overlapping shadows, vessels or granulomas.

Expression of A and B tissue isoantigens in benign and malignant lesions of the breast.

AB isoantigens are widely distributed in human tissues and loss of AB isoantigen expression has been shown to be an early marker for carcinomatous transformation in some tissues. We therefore applied the Specific Red Cell Adherence Reaction (SRCA) for detection and localization of AB isoantigens in tissue to the study of benign and malignant proliferative lesions of the breast. Twenty-nine lesions in 19 patients were studied. AB isoantigen expression in normal breast tissue was found to be largely confined to the mammary duct system. Loss of AB isoantigen expression was a consistent feature of intraductal carcinoma (3 of 3 cases). Proliferative lesions associated with fibrocystic disease also demonstrated varying degrees of isoantigen loss (simple cystic disease, 3 of 8 cases; intraductal hyperplasia, 6 of 7 cases; sclerosing adenosis, 4 of 4 cases; and intraductal papillomatosis, 7 of 7 cases negative for isoantigen). In contrast to other systems, loss of AB isoantigen expression in the breast appears to be a consistent marker of apparently benign proliferative duct lesions associated with fibrocystic disease, as well as duct carcinoma. The early loss of AB isoantigen expression in these histologically benign lesions supports a possible link between fibrocystic disease and mammary carcinoma. In contrast to other tissues, loss of AB isoantigen expression in proliferative breast lesions is not necessarily evidence of malignancy.

Pressure effects of urinary reflux studied with renal autotransplantation and pyelocystostomy.

The pressure effects of urinary reflux on renal structure and function were studied using a canine model in which the kidney was autotransplanted to the iliac fossa and the urine drained through a pyelocystostomy. This provided grade III reflux of urine (distention of the renal pelvis and calyces). A control group of nonrefluxing animals with the ureter and ureterovesical valve intact was studied in an identical fashion, and all animals were observed for one year. The reflux of sterile urine was not associated with any impairment of the inulin clearance or transport maximum of para-aminohippuric acid. There were no histologic abnormalities of glomeruli, tubules, or interstitium noted in the animals exposed to sterile reflux, nor were any differences found between the study and control groups. The transmission of bladder pressures into the renal pelvis and calyces during reflux is considered an unimportant factor in explaining the renal damage noted from sterile reflux of short duration in adults. The pyelocystostomy provides a satisfactory means of urinary drainage, and may be used effectively to study the properties of urinary reflex.

Abnormal seminiferous tubule cells associated with choriocarcinoma: immunoperoxidase study.

A case is presented of widely metastatic choriocarinoma, associated with an intratubular proliferation of atypical germ cells in the testis and a minute adult cystic teratoma. Immunoperoxidase study of the intratubular germ cells did not confirm their trophoblastic origin. Intratubular proliferation of undifferentiated germ cells may be associated with choriocarcinoma.