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E A Friedman

Publications and source records attributed to E A Friedman.

At least 37 records · Page 2Linked to original sources
PubMed1999

Steps in integrin beta1-chain glycosylation mediated by TGFbeta1 signaling through Ras.

Ras is activated by transforming growth factor beta (TGFbeta) in several cell types, but the biological consequences of this activation are largely unknown. We now show that ras mediates two stages in integrin beta1-chain maturation: 1) glycosylation of the 86-kD core peptide, which is a TGFbeta1-independent process, and 2) TGFbeta1-mediated conversion of the 115-kD beta1 integrin precursor into the mature 130-kD form. HD3 colon epithelial cells maintain elevated levels of integrin alpha2beta1 heterodimers, strong binding to collagen I, and autocrine regulation by TGFbeta1, which converts beta1 integrin into the mature cell surface form. Each of three HD3 cell clones that stably express dominant negative ras (N17ras) exhibited abnormal glycosylation of the integrin beta1-chain, decreased cell surface expression of the mature integrin beta1, and impaired binding to collagen and laminin. Autocrine levels of TGFbeta were not altered by expression of N17ras. The aberrant glycosylation of the integrin beta1-chain was reversed by antisense oligonucleotides specific to the DNA sequence encoding the rasS17N mutation. Glycosylation of the 86-kD core peptide was delayed in the N17ras transfectants, but was not altered by either the addition of TGFbeta1 or inhibition of autocrine TGFbeta1. In contrast, conversion of the partially glycosylated beta1 integrin precursor into the mature 130-kD isoform was accelerated by exogenous TGFbeta1 and blocked by neutralizing antibody to autocrine TGFbeta1 in control cell lines. Neither effect was seen in the N17ras transfectants, indicating that TGFbeta1 modulates integrin beta1-chain maturation by activating ras proteins. Cell fractionation studies demonstrated that this conversion takes place within the Golgi.

Animals↗
PubMed1999

Delayed referral of black, Hispanic, and older patients with chronic renal failure.

Delayed referral (defined as a serum creatinine concentration > 4 mg/dL at referral) of patients with chronic renal failure to the nephrologist is common in the United States. We retrospectively examined the records of 220 consecutive patients referred to an urban teaching hospital nephrology division for evaluation of chronic renal failure from January 1987 to December 1994 to detect any relationship between race, renal diagnosis, or age and the timing of referral of medically-insured patients with chronic renal failure. We documented serum creatinine concentration and hematocrit at referral, length of time under the care of a nephrologist (interval from referral to initiation of dialysis), and total number of clinic visits. The 220 study subjects (120 women, 100 men) included 139 blacks (63%), 61 whites (28%), 16 Hispanics (7%), and 4 Asians (2%) aged 51.7 +/- 1.06 years (mean +/- standard error of the mean) at referral. At referral, nonwhites (black and Hispanic patients) had a greater mean serum creatinine concentration than whites (4.3 +/- 0.38 v 3 +/- 0.24 mg/dL; P = 0.001), as well as a lower mean hematocrit (31.7% +/- 1.3% v 34.7% +/- 0.9%; P = 0.001). Mean length of time under the care of a nephrologist was shorter in nonwhites (13 +/- 0.8 months) than whites (43.5 +/- 4.8 months; P = 0.001). Delayed referral was almost six times more likely in nonwhites than whites (odds ratio, 5.6; 95% confidence interval [CI], 1.52 to 20; P = 0.008) and five times more likely in those aged older than 55 years than in those 55 years or younger (odds ratio, 4. 7; 95% CI, 1.37 to 16; P = 0.01). The greater the serum creatinine concentration at referral, the greater the odds of receiving less than 12 months of nephrologic care before initiation of dialysis (odds ratio, 1.8; 95% CI, 1.04 to 3.13; P = 0.03). We conclude that even among those patients with health insurance, delayed referral to the nephrologist is more likely in black, Hispanic, and older patients with chronic renal failure than in their white or younger counterparts.

Black or African American↗
PubMed1999

Advanced glycation end-products in diabetic nephropathy.

Throughout the industrialized (well-fed) world, diabetes mellitus is the most prevalent cause of end-stage renal disease (ESRD). Diabetic nephropathy is as likely to develop in long-duration non-insulin-dependent diabetes (type 2) as in insulin-dependent diabetes mellitus (type 1). Nephropathy in diabetes follows a well outlined course, starting with microalbuminuria through proteinuria, azotaemia and culminating in ESRD. Renal functional decline in diabetic nephropathy is slowed by establishment of euglycaemia and normalization of hypertensive blood pressure. Diabetic ESRD patients, compared with other causes of ESRD, sustain greater mortality and morbidity due to concomitant systemic disorders, especially coronary artery and cerebrovascular disease. A central role for glucose toxicity, especially the adverse impact of accumulated advanced glycosylated end-products (AGEs), appears likely from experimental data generated both in induced diabetic rodents and diabetic individuals. Treatment with aminoguanidine raises the possibility of blocking end-organ damage in diabetes without the necessity for correcting hyperglycaemia.

Animals↗
PubMed1999

Advanced glycosylated end products and hyperglycemia in the pathogenesis of diabetic complications.

Protein alteration resulting from a nonenzymatic reaction between ambient glucose and primary amino groups on proteins to form glycated residues called Amadori products is termed the Maillard reaction. By dehydration and fragmentation reactions, Amadori products are transformed to stable covalent adducts called advanced glycosylation end products (AGEs). In diabetes, accelerated synthesis and tissue deposition of AGEs is proposed as a contributing mechanism in the pathogenesis of clinical complications. Uremia in diabetes is associated with both a high serum level of AGEs and accelerated macro- and microvasculopathy. Diabetic uremic patients accumulate advanced glycosylated end products in "toxic" amounts that are not decreased to normal by hemodialysis or peritoneal dialysis but fall sharply to within the normal range within 8 h of restoration of half-normal glomerular filtration by renal transplantation. It follows that the higher mortality of hemodialysis-treated diabetic patients compared with those given a renal transplant may relate, in part, to persistent AGE toxicity. Pharmacologic prevention of AGE formation is an attractive means of preempting diabetic microvascular complications because it bypasses the necessity of having to attain euglycemia, an often unattainable goal. Pimagidine (aminoguanidine) interferes with nonenzymatic glycosylation and reduces measured AGE levels leading to its investigation as a potential treatment. The mechanism by which pimagidine prevents renal, eye, nerve, and other microvascular complications in animal models of diabetes is under investigation. Separate multicenter clinical trials of pimagidine in type 1 and type 2 diabetes, where proteinuria is attributable to diabetic nephropathy, are in progress. The effect of treatment on the amount of proteinuria, progression of renal insufficiency, and the course of retinopathy will be monitored.

Aldehyde Reductase↗
PubMed1998

Standardized hemodialysis prescriptions promote inadequate treatment in patients with large body mass.

BACKGROUND: Although a relation between the adequacy of hemodialysis and mortality has been established, hemodialysis prescription is rarely individualized precisely in adults with end-stage renal disease in the United States. OBJECTIVE: To test whether persons who receive standardized hemodialysis prescriptions have an increased risk for inadequate hemodialysis with increasing body mass. DESIGN: Cross-sectional study. SETTING: Four ambulatory hemodialysis facilities in Brooklyn, New York. PATIENTS: 214 patients receiving hemodialysis. Patients were sorted by body weight into quartiles (groups 1 through 4, in ascending order). MEASUREMENTS: Urea reduction ratio (percentage reduction in blood urea nitrogen concentration after a hemodialysis session), prescribed length of hemodialysis, and body weight quartile at the start of the study. Urea reduction ratio was measured at the start of the study and at weeks 4, 8, and 12, and a mean value was calculated for each patient. Inadequate hemodialysis was defined by a urea reduction ratio of 65% or less. RESULTS: Women had a higher mean urea reduction ratio (72% +/- 6%) than men (67.6% +/- 7%) (P < 0.001). The urea reduction ratio was inversely related to body weight (r = -0.47; P = 0.001). It was greater in group 1 (74% +/- 5.2%) than in group 2 (70% +/- 5.7%), group 3 (68% +/- 5.8%), or group 4 (66% +/- 8.4%) (P < 0.05). Logistic regression done with a urea reduction ratio of 65% or less as the outcome variable showed that the odds of receiving inadequate hemodialysis were increased 3.5-fold in men (95% CI, 1.53-fold to 8-fold; P = 0.003), 10-fold in group 3 (CI, 2.1-fold to 50.3-fold; P = 0.003), and 13-fold in group 4 (CI, 2.6-fold to 61.6-fold; P = 0.001). CONCLUSIONS: Standardized hemodialysis prescriptions result in inadequate hemodialysis in many patients who weigh more than 68.2 kg.

Adult↗
PubMed1998

Diabetes mellitus after renal transplantation: as deleterious as non-transplant-associated diabetes?

BACKGROUND: Despite use of lower doses of corticosteroid hormones after renal allotransplantation in the era of cyclosporine and tacrolimus, posttransplant diabetes mellitus remains a common clinical problem. METHODS: We prospectively investigated the effect of posttransplant diabetes on long-term (mean follow-up, 9.3+/-1.5 years) graft and patient survival in the 11.8% of our renal transplant population (n = 40) who developed diabetes after kidney transplantation, and we compared outcome in 38 randomly chosen nondiabetic control patients who had received transplants concurrently. RESULTS: Twelve-year graft survival in diabetic patients was 48%, compared with 70% in control patients (P = 0.04), and Cox's regression analysis revealed diabetes to be a significant predictor of graft loss (P = 0.04, relative risk = 3.72) independent of age, sex, and race. Renal function at 5 years as assessed by serum creatinine level was inferior in diabetic patients compared to control patients (2.9+/-2.6 vs. 2.0+/-0.07 mg/dl, P = 0.05). Two diabetic patient who experienced graft loss had a clinical course and histological features consistent with diabetic nephropathy; other diabetes-related morbidity in patients with posttransplant diabetes included ketoacidosis, hyperosmolar coma or precoma, and sensorimotor peripheral neuropathy. Patient survival at 12 years was similar in diabetic and control patients (71% vs. 74%). CONCLUSIONS: Posttransplant diabetes mellitus is associated with impaired long-term renal allograft survival and function, complications similar to those in non-transplant-associated diabetes may occur in posttransplant diabetes, and, hence, as in non-transplant-associated diabetes, tight glycemic control may also be warranted in patients with posttransplant diabetes.

Acute Disease↗
PubMed1998

Short-chain fatty acids induce cell cycle inhibitors in colonocytes.

BACKGROUND & AIMS: We tested the hypothesis that short-chain organic acids in the colon derived from dietary pectin, wheat bran, and oat bran are protective against the development of colon cancer because they induce transforming growth factor (TGF)-beta1, which in turn inhibits cell growth by inducing cyclin-directed kinase (cdk) inhibitors. METHODS: U4 human colon carcinoma cells differentiate into water- and salt-transporting columnar enterocytes and therefore model normal colonocytes. The composition and kinase activity of cdk/cyclin complexes were determined by immunoprecipitation and Western blotting studies in U4 cells treated in vitro with short-chain fatty acid (SCFA) mixtures that mimic the digestion products of wheat bran, oat bran, pectin, and cellulose (as control), which is largely unfermentable. RESULTS: Induction of the cdk inhibitors p21cip1 and p27kip1 by fiber-mimicking SCFA mixtures occurs much more rapidly and is many-fold greater than their induction by TGF-beta1. The SCFA mixtures most effective in causing growth inhibition and cdk inhibitor production mimicked those from wheat bran > oat bran > pectin. CONCLUSIONS: cdk inhibitor induction by SCFA mixtures is not mediated by TGF-beta1. The SCFA mixture mimicking digested wheat bran fiber was the most effective of all mixtures tested in inhibiting cell growth through induction of cdk inhibitors.

Cell Cycle↗
PubMed1998

Haemodialysis dose is independent of type of surgically-created vascular access.

BACKGROUND: In the United States, the use of polytertraflouroethylene (PTFE) graft compared with native arteriovenous fistula (AVF) for haemodialysis vascular access has been increasing despite a greater than twofold higher incidence of thrombosis and infection associated with PTFE grafts. METHODS: We studied 214 haemodialysis patients with not more than two revisions of their vascular access, to determine whether any relationship exists between the type of haemodialysis vascular access and dialysis dose assessed primarily by urea reduction ratio (per cent reduction in blood urea nitrogen concentration after a dialysis session). Serum albumin concentration was used as a secondary outcome measure of dialysis adequacy. Urea reduction ratio and predialysis serum albumin concentration were measured at onset of study and at 4-week intervals and mean values were calculated for each subject. RESULTS: The 214 patients (118 males, 96 females) included 173 Blacks (81%), 26 Whites (15%), and 15 Hispanics (7%), of mean (+/-SD) age 55.6+/-15.5 years. Of these 214 subjects, 111 (52%) had a native AVF, while 103 (48%) had a PTFE graft. Both mean urea reduction ratio (native AVF=69 +/-6.7% vs PTFE graft=70+/-7.3%; P=0.31), and mean serum albumin concentration (native AVF=4.02+/-0.39 g/dl vs PTFE graft=4+/-0.33 g/dl; P= 0.59) were equivalent in both groups. Separate multiple logistic regression analyses with type of vascular access as one of the independent variables, found no significant relationship between type of vascular access and either a urea reduction ratio > 65% (P= 0.67), or a serum albumin concentration >4g/dl (P=0.89), after adjustment for age of vascular access, access revision, location of access, dialyser urea clearance, length of dialysis treatment, body weight, and age. CONCLUSION: We conclude that PTFE grafts do not permit delivery of better dialysis than native AVF. The increasing use of PTFE grafts in the United States does not have any clinical justification.

Adult↗