Endstage renal disease owing to diabetic nephropathy in Mississippi: an examination of factors influencing renal survival in a population prone to late referral.

BACKGROUND: Diabetic nephropathy (DN) is the leading cause of endstage renal disease (ESRD) in the United States. We reviewed our experience with DN as a cause of ESRD in a predominantly poor, African American (AA) population. METHODS: Charts of patients who entered the ESRD program through the University of Mississippi Medical Center with a primary diagnosis of DN from 1993 through 1998 were reviewed for factors that may affect renal survival. Time from initial clinic visit to entry into the ESRD program, or time to ESRD (TTE), was the primary end point. RESULTS: Five hundred sixty-two patients entered the ESRD program (85% AA), and 210 of them had DN as their primary ESRD diagnosis. DN accounted for 50.5% of ESRD cases among AA females, but for less than 20% among AA males. In contrast, hypertension was the ESRD diagnosis in 48% of AA males. Patients observed in our nephrology clinic were analyzed further (n=171). At presentation, patients had advanced disease (serum creatinine [Cr]=5.92 mg/dL), were hypertensive, obese, and not likely to be on an angiotensin-converting enzyme (ACE) inhibitor. Determinants of TTE in univariate analysis were race (AA did better), initial blood urea nitrogen and plasma serum Cr levels, starting an ACE inhibitor at the University of Mississippi Medical Center, and the level of mean arterial pressure (MAP) during the course of follow-up. On multivariate analysis only initial Cr and race remained significant The 142 AA diabetics (111 female) were analyzed separately. The only significant sex difference was body mass index (female, 33.6 vs male, 28.4 kg/m2; P=0.0069), but females tended to have relatively shorter TTE and higher blood pressure (BP). Univariate and multivariate analyses revealed the same factors as above as determinants of TTE; however, among AAs, presenting on a calcium channel blocker was negatively correlated with TTE in univariate analysis. Among the entire cohort and the AAs, patients who had MAP between 100 and 110 mm Hg during the course of follow-up did better in terms of renal survival than those who fell outside of that range. CONCLUSIONS: We conclude that AA females in Mississippi are significantly more predisposed to DN as a cause of ESRD than are AA males. Patients with DN in our population had poor BP control, presented to nephrologists with advanced disease, and often were not on an ACE inhibitor. The optimal level of BP control and which BP agents are best for this population need to be determined.

Overexpression of glutamine:fructose-6-phosphate amidotransferase in rat-1 fibroblasts enhances glucose-mediated glycogen accumulation via suppression of glycogen phosphorylase activity.

The hexosamine biosynthesis pathway (HBP) mediates many of the adverse effects of excess glucose. We have shown previously that glucose down-regulates basal and insulin-stimulated glycogen synthase (GS) activity. Overexpression of the rate-limiting enzyme in the HBP, glutamine:fructose-6-phosphate amidotransferase (GFA), mimics these effects of high glucose and renders the cells more sensitive to glucose. Here we examine the role of the HBP in regulating cellular glycogen content. Glycogen content and glycogen phosphorylase (GP) activity were determined in Rat-1 fibroblasts that overexpress GFA. In both GFA and controls there was a dose-dependent increase in glycogen content (approximately 8-fold) in cells cultured in increasing glucose concentrations (1-20 mM). There was a shift to the left in the glucose dose-response curve for glycogen content in GFA cells (ED50 for glycogen content = 5.80+/-1.05 vs. 8.84+/-0.87 mM glucose, GFA vs. control). Inhibition of GFA reduced glycogen content by 28.4% in controls cultured in 20 mM glucose. In a dose-dependent manner, glucose resulted in a more than 35% decrease in GP activity in controls. GP activity in GFA cells was suppressed compared with that in controls, and there was no glucose-induced down-regulation of GP activity. Glucosamine and uridine mimicked the effects of glucose on glycogen content and GP activity. However, chronic overexpression of GFA is a unique model of hexosamine excess, as culturing control cells in low dose glucosamine (0.1-0.25 mM) did not suppress GP activity and did not eliminate the glucose-mediated down-regulation of GP activity. We conclude that increased flux through the HBP results in enhanced glycogen accumulation due to suppression of GP activity. These results demonstrate that the HBP is an important regulator of cellular glucose metabolism and supports its role as a cellular glucose/satiety sensor.

Focal segmental glomerulosclerosis in African Americans: effects of steroids and angiotensin converting enzyme inhibitors.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a common primary glomerulopathy in African Americans. In this report, we present data on 40 African American patients with FSGS from our medical center. METHODS: Patients were identified from a review of all charts seen in our conservative management renal clinic in 1996, a review of renal biopsy rolls (1994-1998), and a review of patients entering the end-stage renal disease (ESRD) program with a primary diagnosis of FSGS (1993- 1997). Charts were reviewed for demographic, biopsy, and treatment data. Patients who were observed for at least 4 months (range, 4-125 months) were included. ESRD was used as the primary endpoint (n = 12). Data were analyzed using univariate and multivariate Cox hazards and Kaplan-Meier survival analysis. Twenty-four patients were treated with angiotensin-converting enzyme (ACE) inhibitors. Similarly, 24 patients were treated with corticosteroids for a mean of 8.75 +/- 2.6 months and a total dose of 9.3 +/- 2.2 g. RESULTS: On univariate analysis, factors found to be significant determinants for reaching ESRD were the initial creatinine (P = 0.0001), interstitial fibrosis (P = 0.032), the percentage of globally sclerosed glomeruli (P = 0.0018), and the mean arterial blood pressure over the course of follow-up (P = 0.05). Neither the ACE inhibitors nor the corticosteroids had a significant impact on reaching ESRD. The patients reaching ESRD (n = 12) were analyzed separately. The mean time from biopsy to ESRD was 24.7 +/- 9.8 months. ACE inhibitors prolonged renal survival (P = 0.023), but steroids did not. Initial creatinine was the only factor found to be a significant determinant for ESRD. CONCLUSIONS: We conclude that FSGS is common in African Americans. Early diagnosis and blood pressure control are important, but the beneficial effects of steroids and ACE inhibitors in this population are still unclear.

Vaccination of dairy cattle against Q fever (Coxiella burneti): results of field trials.

A phase I formalin-inactivated Q fever vaccine, using the Nine Mile strain of the organism, was tested for its ability to prevent dairy cows from shedding Coxiella burnetti in their milk. More than 1,400 Holstein-Friesian dairy calves and heifers from 5 dairies were used in field trials lasting over a 3-year period. Vaccination of 476 calves resulted in a geometric mean antibody titer of 1:123.3 compared with 1:2.4 for 486 nonvaccinated calves. The milk samples from 163 vaccinated calves were tested by mouse inoculation after the cows commenced lactation and were placed in their respective milking herds. Of these vaccinated animals, only 2 cows (1%) from 1 herd were suspected shedders, but on subsequent testing gave negative results. Among 164 nonvaccinated (control) cows, 39 (24%) were shedding C burnetii in their milk; this figure corresponded to the prevalence (23%) of shedders in the general population of dairy cows in California. The results of the current field trials indicated that vaccination greatly reduced the shedding of the Q fever organism in the milk of dairy cows.

Q fever (Coxiella burnetii) investigations in dairy cattle: challenge of immunity after vaccination.

The immunity of Holstein-Friesian dairy cows vaccinated against Coxiella burnetii was challenged with 4 X 10(8) infective guinea pig doses of viable rickettsiae. Cows that were vaccinated had normal full-term calves, whereas 2 nonvaccinated cows aborted late in pregnancy. Intrauterine infection of the fetus was indicated by recovery of the organism from tissues of the fetus. Coxiella burnetii was recovered from milk, colostrum, and placenta of vaccinated and nonvaccinated cows after challenge inoculation, but the rickettsiae recovered were as many as 1,000 times more numerous in nonvacinated cows.

Bactericidal activity of bovine neonatal serums for selected coliform bacteria in relation to total protein and immunoglobulin G1 and immunoglobulin M concentrations.

Bactericidal activity for a serum-sensitive Aerobacter aerogenes strain was associated with antibodies present in immunoglobulin G1 (IgG1) and immunoglobulin M (IgM), with the greatest activity on a weight basis in IgM. Activity in immunoglobulin G2 was absent. A total of 118 serums were prepared from blood collected from neonatal calves on farms experiencing unusually high mortality from diarrhea. The serums were allotted to 4 groups on the basis of total serum protein concentrations as follows: group I=7.0 to 9.5 g/dl, group II=6.00 to 6.98 g/dl, group III=5.00 to 5.90 g/dl, and group IV=3.9 to 4.9 g/dl. Bactericidal activity for the serum-sensitive aerobacter strain was distributed approximately equally throughout the 4 groups. Activity for 3 strains of Escherichia coli was minimal to absent. Concentrations of IgG1 and IgM were determined in 82 of the serums. Concentrations of IgG1 ranged from 0 to 54.2 mg/ml, with overlapping among the 4 groups. Concentrations of IgM could not be determined in serums with concentrations greater than 1.6 mg/ml. However, bactericidal activity did not correlate with the immunoglobulin concentrations, since activity was present to the same degree in serums with small concentrations of immunoglobulins compared with serums with as much as threefold larger concentrations.