Hypertension and anemia may be causes of left ventricular hypertrophy (LVH) in uremia but the molecular mechanism is not known. Uremia was induced in male Spraugue Dawley rats by 5/6 nephrectomy. The following groups of rats were studied for 6 weeks; uremic rats (U) fed ad. lib., control rats (C) pair-fed with U, U rats given hydralazine (100 mg/kg/day) (UH), U rats given erythropoietin (48U/kg/week, i.p.) (UE). Both diastolic and mean arterial pressures are higher (P<0.01) in U and UE compared with C whereas both pressures in UH were normalized. Hemoglobin in U was lower than in C, and was normalized in UE. U, UH and UE had higher heart weight/body weight ratios (HW/BW) as well as left ventricular weight/body weight ratios (LV/BW) compared with C (P<0.01). Compared with U, UH has lower HW/BW and LV/BW (P <0.05) and UE has normal HW/BW but lower LV/BW than U (P<0.05). To see if the gene expression in uremic LVH is similar to that described in pressure overload LVH in which mRNA levels of angiotensin converting enzyme (ACE), transforming growth factor-beta1 (TGF-beta1), atrial natriuretic factors (ANF) and skeletal alpha-actin were increased, we measured these mRNA levels by Northern analysis. TGF-beta, ACE and alpha-actin mRNA levels were not changed in all 4 groups. ANF mRNA in U and UE was increased 3 fold over C, and normalized in UH. Treatment of anemia with erythropoietin improved uremic LVH but did not change ANF mRNA; whereas treatment of hypertension with hydralazine normalized ANF mRNA but did not completely correct uremic LVH. Thus, gene expression in uremic LVH is distinct from that in pressure- overload LVH, suggesting that other unidentified factor(s) might be involved in uremic LVH.
Actins/genetics/metabolism ; Anemia/*complications/drug therapy/metabolism ; Animals ; Atrial Natriuretic Factor/genetics/metabolism ; Erythropoietin/pharmacology/therapeutic use ; *Gene Expression ; Heart Ventricles/chemistry/drug effects/pathology ; Hydralazine/pharmacology/therapeutic use ; Hypertension/*complications/drug therapy/metabolism ; Hypertrophy, Left Ventricular/etiology/*genetics/metabolism ; Male ; Peptidyl-Dipeptidase A/genetics/metabolism ; RNA, Messenger/analysis/metabolism ; Rats ; Rats, Sprague-Dawley ; Transforming Growth Factor beta/genetics/metabolism ; Uremia/etiology/*genetics/metabolism

Insulin-like growth factor (IGF)/IGF binding protein (IGFBP) abnormalities may be important in the pathogenesis of growth failure in chronic renal failure (CRF). We induced experimental CRF by 5/6 nephrectomy in Sprague Dawley rats (100 g) and observed for 2 weeks comparing with sham-operated pair-fed control rats (Sham- C). CRF rats gained 30% less height than Sham- C rats (P<0.01). Serum IGFBP profiles by Western ligand blot revealed that IGFBP4 was elevated two fold in CRF rats (P<0.01 vs. Sham-C). However, IGFBP4 mRNA levels in liver or skeletal muscle were not different in two groups. To determine if the increase of serum IGFBP4 in CRF retarded the growth of cartilage, epiphyseal chondrocytes were isolated from CRF or control rats and cultured in the presence of control or CRF rat sera. Incubation with 10% CRF serum reduced proliferations of normal chondrocytes and L6 rat skeletal muscle cells. In contrast, 10% CRF serum did not inhibit the growth of CRF chondrocytes. Rat sera from two groups were separated into two different fractions, high (>10 kDa, containing IGFBPs) and low (<10 kDa, containing free IGF) molecular weight fractions using a gel filtration column. Both fractions obtained from CRF sera decreased the growth of control chondrocytes up to 40% compared with those from control sera. We suggest that the pathogenesis of growth failure in CRF may be involved in the increase of circulating IGFBP4 as well as the unidentified small molecular weight uremic serum factors which block the growth of chondrocytes in growth plate.
Animals ; Cell Proliferation ; Cells, Cultured ; Chondrocytes/*cytology/metabolism ; Insulin-Like Growth Factor Binding Protein 4/analysis/*blood/genetics ; Kidney Failure, Chronic/*blood/metabolism/physiopathology ; Liver/chemistry ; Male ; Muscle, Skeletal/chemistry ; RNA, Messenger/analysis/metabolism ; Rats ; Rats, Sprague-Dawley ; Somatomedins/analysis/metabolism

Primary non-function (PNF) after liver transplantation has been found to be the most common cause of early graft loss, which accounts for up to 36% of such failures. The cause of PNF is not known. The purpose of this study was to identify factors associated with and independently predictive of PNF after liver transplantation. Four hundreds twenty-four liver transplants performed at the Charles O. Strickler Transplant Center, University of Virginia were retrospectively reviewed. PNF was defined as the failure of an allograft after revascularization with no discernable cause, leading either to retransplantation or to patient death. Risk factors were analyzed using the Pearson chi-square test for univariate analysis and logistic regression for multivariate analysis. Factors found to be associated with PNF included: female recipient (6.4% vs. 2.6%, p=0.045), African-American donor (9.5% vs. 3.2%, p=0.043), inter-racial donor to recipient transplantation (9.5% vs. 2.8%, p=0.008), severe encephalopathy pretransplant (11.1% vs. 3.1%, p=0.034), pretransplant recipient PTT > 50 seconds (10.9% vs. 2.8%, p=0.004), portal vein reconstruction with conduit (15.0% vs. 3.5%, p=0.011), and downsizing of graft (22.9% vs. 3.8%, p=0.007). Logistic regression identified the use of donor iliac vein conduit for the portal vein reconstruction (p=0.003, odds ratio=3.15, 95% confidence interval: 1.49-6.64) and the racial difference between donor and recipient (p=0.012, odds ratio=2.31, 95% confidence interval: 1.20- 4.45) to be independent predictors of PNF. The exact cause of these findings, whether physiologic or immunologic, remains unknown. If confirmed in larger data sets, the attention to these factors may minimize the possibility of PNF in non- emergency situations.
Anastomosis, Surgical/adverse effects ; Continental Population Groups ; Female ; Humans ; Iliac Vein/surgery ; Liver/*physiopathology ; *Liver Transplantation/mortality ; Male ; Portal Vein/surgery ; Postoperative Period ; Prognosis ; Reoperation ; Retrospective Studies ; Treatment Failure