Renal injury of diet-induced hypercholesterolemia in rats

Abnormalities in lipid metabolism frequently accompany renal disease and may be important in the pathogenesis of progressive renal injury. In the present study, the effects of a high cholesterol diet on renal histology, cortical lipids, and glomerular hemodynamic function were examined in normal rats with and without reduced renal mass. Cholesterol feeding for 19 weeks increased serum cholesterol from 66 +/- 10 mg/dl to 256 +/- 93 mg/dl in two-kidney rats, and from 73 +/- 15 mg/dl to 407 +/- 274 mg/dl in nephrectomy rats (P less than 0.01). Both sham-operated and unilateral nephrectomy rats fed a high cholesterol diet had a greater amount of glomerulosclerosis and tubulointerstitial damage than rats fed standard chow. Cortical cholesteryl esters were increased by the cholesterol diet, and correlated with the amount of glomerulosclerosis (r = 0.90, P less than 0.01) and tubulointerstitial injury (r = 0.64, P less than 0.05). Cholesterol feeding and nephrectomy both caused alterations in tissue essential fatty acids, and a panel of specific monoclonal antibodies indicated that renal injury and cortical lipid alterations were associated with an increase in glomerular macrophages. Finally, micropuncture experiments carried out in a separate group of rats fed high cholesterol for 8 to 10 weeks demonstrated increases in glomerular capillary pressure. These results suggest that additional investigations may ultimately determine how cholesterol deposition, altered fatty acid metabolism, macrophages, and increased glomerular pressure might combine to cause chronic progressive renal injury.     

Absence of glomerular injury or nephron loss in a normotensive rat remnant kidney model

Severe reduction in renal mass (greater than 50%) in the rat uniformly results in progressive glomerular injury and loss of remnant nephrons postulated to be due to increases in glomerular function (hyperfiltration) and/or size (hypertrophy). Reduction in renal mass in the rat also leads to the development of systemic and/or glomerular hypertension. To examine the independent contributions of systemic hypertension and glomerular hyperfiltration and/or hypertrophy to progressive glomerular injury, a normotensive rat remnant kidney model was developed in the Wistar-Kyoto (WKY) strain. Of the 34 WKY rats that underwent 5/6 nephrectomy, 25 remained normotensive and without evidence of morphologic glomerular injury and/or nephron loss for up to 14 to 16 weeks, despite glomerular hyperfiltration and hypertrophy comparable to that previously observed in other rat strains. Micropuncture studies at approximately six weeks after reduction in renal mass demonstrated markedly increased SNGFR in remnant nephrons of normotensive rats as compared to controls (66 +/- 7 vs. 25 +/- 4 nl/min, P less than 0.01), but glomerular capillary pressures (PGC) estimated from stop flow pressures were only slightly increased (52.7 +/- 1 vs. 47.3 +/- 1 mm Hg, P less than 0.01). These data indicate that compensatory glomerular hyperfiltration and hypertrophy after 5/6 nephrectomy may not lead to progressive glomerular injury provided hypertension does not develop. These data further suggest that in the absence of systemic hypertension, increases in PGC required for adaptive hyperfiltration, may not be sufficient to initiate progressive glomerular injury and nephron loss.     

Excess parathyroid hormone adversely affects lipid metabolism in chronic renal failure

Hyperlipidemia is common in chronic renal failure (CRF), but the underlying mechanisms are not clearly defined. Certain data points toward a potential role for the state of secondary hyperparathyroidism of CRF in its pathogenesis. We examined the effects of parathyroid hormone (PTH) on lipid metabolism utilizing intravenous fat tolerance test (IVFTT) and post-heparin lipolytic activity in five normal dogs, in six animals with CRF and secondary hyperparathyroidism (NPX) and in six normocalcemic-thyroparathyroidectomized dogs (NPX-PTX) with comparable degree and duration of CRF. NPX dogs had fasting hypertriglyceridemia (82 + 6.0 mg/dl vs. 49 +/- 2.7 mg/dl in normal dogs, P less than 0.01), abnormal IVFTT, and reduced post-heparin plasma LPL activity (151 +/- 10 vs. 275 +/- 15 mumol fatty acids/ml/min in normal dogs, P less than 0.01). The NPX-PTX dogs had normal fasting levels of serum triglycerides (42 +/- 0.6 mg/dl), normal IVFTT, and normal post-heparin plasma LPL (317 +/- 19 mumol fatty acids/ml/min) despite CRF. Post-heparin HL activity in plasma was not different between NPX and NPX-TPX dogs. The results show that excess blood levels of PTH and not other consequences of CRF are mainly responsible for the abnormalities in lipid metabolism. The data are consistent with the notion that excess PTH reduces post-heparin LPL activity in plasma, which in turn results in impaired lipid removal from the circulation and consequently hyperlipidemia.     

Impact of dietary fatty acid supplementation on renal injury in obese Zucker rats

We previously reported that renal injury in hyperlipidemic, obese Zucker rats was associated with a relative deficiency of tissue polyunsaturated fatty acids (PUFA). In the present study 10-week-old obese Zucker rats were pair fed regular chow or chow containing either 20% sunflower oil rich in n-6 PUFA, fish oil rich in n-3 PUFA, coconut oil medium-chain saturated fatty acid, or beef tallow long-chain saturated fatty acid. At 34 weeks of age there were comparable reductions in albuminuria, mesangial matrix expansion, and glomerulosclerosis in the fish oil and sunflower oil groups. While both fish oil and sunflower oil reduced serum triglycerides, and improved the composition of triglyceride-enriched lipoproteins, only fish oil decreased serum cholesterol. The effect of the dietary fatty acid supplementation on fatty acid profiles were similar in isolated glomeruli and cortical tissue. In general, the amelioration in injury in the fish oil and sunflower oil fed rats was most closely linked to glomerular levels of PUFA, either n-6 or n-3. These data suggest that hyperlipidemia and abnormalities in tissue FA are closely linked, and that dietary supplementation with PUFA may ameliorate chronic, progressive renal injury.     

Evaluation of the nonneoplastic pathology in tumor nephrectomy specimens: predicting the risk of progressive renal failure

Pathologic changes in nonneoplastic renal parenchyma of nephrectomy specimens for renal tumors and the significance of these changes with regard to the outcome of contralateral kidney function have not been studied previously. We examined the nonneoplastic renal parenchymal changes in 110 consecutive tumor nephrectomy specimens, and we correlated our findings with patients' clinical information. The material was examined for the presence of any glomerular, tubulointerstitial, or vascular pathology. In our analysis, only about 10% of cases had unremarkable renal parenchyma and vasculature. A further 28% of cases had unremarkable parenchyma, but some degree of vascular sclerosis was noted. The remaining cases (>60%) had evident pathologic abnormalities, most commonly related to vascular disease or diabetes mellitus. Regardless of the type of renal cancer they have, the majority of our cases can be placed in one of three principal groups: 1) unremarkable kidney parenchyma, with or without vascular sclerosis (38%); 2) parenchymal scarring and marked vascular changes, including cases of atheroembolic disease, and chronic thrombotic microangiopathy (28%); and 3) changes related to diabetes mellitus, such as glomerular hypertrophy, mesangial expansion, and diffuse glomerulosclerosis (24%). Follow-up data on serum creatinine 6 months postoperatively were available in a third of our patients. Patients with severe histopathologic findings (parenchymal scarring with >20% global glomerulosclerosis and advanced diffuse diabetic glomerulosclerosis) showed a significant change in serum creatinine from the preoperative period to 6 months after radical nephrectomy (P=0.001), indicative of progressive worsening of renal function; this change is significantly greater than that seen in patients with unremarkable renal parenchyma (P=0.01). We conclude that adequate examination of nonneoplastic renal parenchyma is an important tool in recognizing patients at risk for progressive renal disease after nephrectomy and could be an essential step in providing early preventive and treatment measures and better medical care of patients undergoing nephrectomy for neoplastic processes.     

Effects of dietary fatty acids in an animal model of focal glomerulosclerosis

The obese Zucker rat develops hyperlipidemia, proteinuria and focal glomerulosclerosis without prior changes in renal hemodynamics. To study the effects of oral fatty acid intake on the development of renal injury in this model, rats were fed standard chow or chow supplemented with either 14% fish oil or 14% beef tallow after unilateral nephrectomy at the age of 10 weeks. At 32 weeks post-nephrectomy animals were sacrificed and renal tissue saved to assess histology and glomerular eicosanoid production. Fish-oil treated rats had lower mean plasma cholesterol levels and developed less proteinuria than control or tallow-fed animals although there was no difference in plasma creatinine or blood pressure. Histological analysis showed significantly fewer sclerosed glomeruli in the fish oil group (4.0 +/- 0.8% vs. control 19.4 +/- 4.1%, P less than 0.0005 and vs. beef tallow 10.8 +/- 1.9%, P less than 0.005). Glomeruli derived from rats on fish oil supplements produced smaller amounts of prostaglandin (PG)E2 and of the stable metabolites of PGI2 (6-oxo-PGF1 alpha), PGF2 (PGF2 alpha) and thromboxane (TX)A2 (TXB2) than those from tallow-fed animals. This study demonstrates that oral fatty acid intake may influence the development of glomerulosclerosis. The apparent beneficial effects of fish oil have not been fully defined, but may relate to favorable changes in plasma lipid concentration and renal eicosanoid production.     

Correlation between glomerular size and long-term renal function in patients with substantial loss of renal mass

PURPOSE: Focal segmental glomerulosclerosis and progressive renal failure have been reported in reduced renal mass models. However, these findings are not consistent across all species. Increased intracapillary pressure and chronic glomerular hyperfiltration have been shown to contribute to this progression. Studies also have shown that a strong correlation exists between higher glomerular size and the degree of glomerular sclerosis that develops following loss of functioning nephrons. MATERIALS AND METHODS: To evaluate the relationship between glomerular size and long-term renal function following massive renal mass removal we describe 9 patients with less than 50% renal mass. All patients had undergone initial nephrectomy followed by partial second nephrectomy, with 30% to 50% of the second kidney excised for localized tumor. RESULTS: In 3 patients moderate to severe renal failure developed. Mean planar glomerular area (MPA) was 29.45 +/- 2.2 mm3 for all patients. Multivariate linear regression analysis demonstrated a significant association between MPA 30 mm3 or greater and increased serum creatinine. For patients with MPA 30 mm3 or greater the predicted delta creatinine was 2.43 mg/dl higher than that in patients with MPA less than 30 mm3 (p = 0.0028). Age was the only other covariate significantly associated with outcome in multivariate analysis. CONCLUSIONS: Our data indicate an individual susceptibility toward developing renal failure after significant renal mass reduction. We suggest that patients with less than 50% renal mass and higher MPA are at greater risk for progressive renal failure. MPA may be used as a marker in high risk patients with substantial loss of renal mass to predict long-term renal function.     

Effect of free fatty acids on insulin receptor binding and tyrosine kinase activity in hepatocytes isolated from lean and obese rats.

We demonstrated previously that high physiological concentrations of free fatty acids (FFA) rapidly decrease insulin binding, degradation, and action in isolated rat hepatocytes. In this study, hepatocytes from lean and obese Sprague-Dawley rats (Alab, Stockholm) were preincubated with or without 0.4 mM oleic acid, and the effect on insulin binding and tyrosine kinase activity was measured. In the absence of exogenous FFA, insulin binding was reduced in hepatocytes from obese compared with lean rats (mean +/- SE reduction 44 +/- 7%, n = 8, P less than 0.01). Furthermore, the inhibitory effect of oleic acid added to hepatocytes from lean rats (n = 8; 40 +/- 9%, P less than 0.01) was not seen in cells from obese rats. Treating obese rats with Etomoxir, a carnitine palmitoyl transferase I inhibitor, increased insulin binding to isolated hepatocytes by 41 +/- 13% (n = 5, P less than 0.05). There was no difference in total binding to partially purified insulin receptors from solubilized hepatocytes from lean and obese rats, whether cells were or were not preincubated with oleic acid. Tyrosine kinase activity of partially purified receptors from basal or insulin-stimulated cells was not affected by either obesity, treatment with Etomoxir, or preincubating the cells with oleic acid. Thus, both obesity and elevated ambient FFA levels are associated with impaired insulin cell surface binding to isolated hepatocytes, possibly through an effect of lipid oxidation on the internalization/recycling of the insulin-receptor complex without any perturbation of the receptor tyrosine kinase activity. The data suggest that the reduced insulin binding to hepatocytes from obese rats is due to elevated ambient FFA levels.     

Renal injury: similarities and differences in male and female rats with the metabolic syndrome

The metabolic syndrome is complicated by nephropathy in humans and rats, and males are more affected than females. We hypothesized that female rats had reduced expression of glomerular oxidized low-density lipoprotein (oxLDL) receptor 1 (LOX-1), attendant glomerular oxidant injury, and renal inflammation. Three groups, obese males (OM), obese females (OF), and lean males (LM) of first-generation (F(1)) hybrid rats derived from the Zucker fatty diabetic (ZDF) strain and the spontaneous hypertensive heart failure rat (SHHF/Gmi-fa) were studied from 6 to 41 weeks of age. OM had severe renal oxidant injury and renal failure. Their glomeruli expressed the LOX-1, and exhibited heavier accumulation of the lipid peroxide 4-hydroxynonenal (4-HNE). OM had compromised mitochondrial enzyme function, more renal fibrosis, and vascular leakage. Younger LM, OM, and OF ZS (ZDF/SHHF F(1) hybrid rat) rats, studied from 6 to 16 weeks of age, showed that unutilized renal lipids were comparable in OM and OF, although young OM had worse nephropathy and inflammation. In conclusion, glomerular LOX-1 expression is coupled to deposits of 4-HNE and glomerulosclerosis in OM. We presume that LOX-1 enhances glomerular uptake of oxidized lipids and renal inflammation, causing greater oxidant stress and severe glomerulosclerosis. In OF, renal protection from lipid oxidants appears to be conferred by blunted glomerular LOX-1 expression and renal inflammation.     

Brief periods of hyperphagia cause renal injury in the obese Zucker rat

BACKGROUND: Female obese (fa/fa) Zucker rats are maximally hyperphagic from the beginning of access to solid food until 20 weeks of age and die primarily from renal failure. We documented that urinary albumin excretion (UAE) rises early in obese rats during this time of greatest hyperphagia. This study was conducted to examine if this early surge of hyperphagia is critical to the initiation of glomerular damage. METHODS: Three groups of six-week-old rats were used: (a) obese females fed ad libitum (AL-obese), (b) obese females pair fed to lean controls until 21 weeks and then allowed to eat ad libitum until 57 weeks (PF. AL-obese), (c) lean (Fa/Fa) Zucker rats fed ad libitum (AL-lean). Cohorts of AL-obese and PF.AL-obese rats were allowed to continue to death or 57 weeks of age, and the rest were terminated at 21 weeks for renal histology. RESULTS: At 21 weeks, neither PF.AL-obese nor AL-lean rats had elevated UAE or glomerular histopathology. In contrast, glomerular injury was severe in AL-obese rats. UAE increased by 10 and 29 weeks in AL- and PF.AL-obese rats, respectively. Plasma triglycerides increased prior to UAE in both PF. AL- and AL-obese rats. CONCLUSIONS: In obese rats fed ad libitum, hyperphagia is followed within a few weeks by hypertriglyceridemia and then by glomerular injury regardless of when ad libitum feeding is initiated. These events do not occur in lean rats or in obese rats pair fed to lean rats. Protective effects of pair feeding did not extend into the period of ad libitum feeding for PF.AL-obese rats. Hyperphagia quickly initiates glomerular injury in obese female Zucker rats.     

Cyclooxygenase-2 (COX-2) inhibition limits abnormal COX-2 expression and progressive injury in the remnant kidney

BACKGROUND: The pathogenesis of progressive nephropathies involves hemodynamic and inflammatory factors. In the 5/6 nephrectomy model, a selective increase of cyclooxygenase-2 (COX-2) expression was shown, whereas treatment with a nonsteroidal anti-inflammatory or a specific COX-2 inhibitor was renoprotective. We investigated in the 5/6 nephrectomy model (1) the renal distribution of COX-2; (2) the hemodynamic and cellular mechanisms by which chronic COX-2 inhibition prevents renal injury. METHODS: After 5/6 nephrectomy, adult male Munich-Wistar rats were subdivided in two groups: 5/6 nephrectomy (N=20), receiving vehicle, and 5/6 nephrectomy + celecoxib (N=19), treated orally with the COX-2 inhibitor, celecoxib, 10 mg/kg/day. Untreated and treated (celecoxib) sham-operated rats were also studied. Renal hemodynamics were examined at 4 weeks, whereas renal morphologic/immunohistochemical studies were carried at 8 weeks. RESULTS: At 4 weeks, 5/6 nephrectomy rats exhibited marked systemic and glomerular hypertension. Celecoxib attenuated both systemic and glomerular hypertension, without affecting glomerular filtration rate (GFR). At 8 weeks, glomerulosclerosis and interstitial expansion were evident in 5/6 nephrectomy rats, and markedly attenuated in 5/6 nephrectomy rats given celecoxib. In both sham-operated and 5/6 nephrectomy rats, COX-2 was expressed at the macula densa. The extent of COX-2 expression at the macula densa was nearly tripled by celecoxib, indicating the existence of a feedback mechanism. In 5/6 nephrectomy rats, COX-2 was also expressed in glomeruli, arterioles, and the cortical interstitium, mostly at inflamed or sclerosing areas. Celecoxib markedly attenuated renal injury, inflammation, and ectopic COX-2 expression in 5/6 nephrectomy rats. CONCLUSION: Chronic COX-2 inhibition attenuated progressive nephropathy by reducing glomerular hypertension, renal inflammation, and ectopic COX-2 expression, indicating a complex contribution of COX-2 to progressive renal injury in 5/6 nephrectomy rats.     

Beneficial effect of atrial natriuretic factor on ischemically injured kidneys in the rat. A new approach to improve early renal function

In a rat experimental study we investigated whether the atrial natriuretic peptide by itself is able to improve early renal function after an ischemic injury. Two groups of Wistar male rats underwent a right nephrectomy and a left renal artery occlusion for 30 min and were infused for 2 hr after ischemia with isotonic saline or rat atrial natriuretic peptides (alpha ANF: 28 amino acids (AP 28) and atriopeptin III (AP 24): 24 amino acids). ANF infusion increased the urinary flow (P less than 0.001), the urinary sodium concentration (P less than 0.001), the sodium excretion rate (P less than 0.0001), and improved the glomerular filtration rate (GFR) recovery (P less than 0.02) determined at the end of the 2-hr infusion period. AP 24 exhibited higher natriuretics activities than AP 28. The effect of both peptides upon GFR recovery was equivalent. These effects of ANF observed after acute ischemia suggest that this peptide may be beneficial on the resumption of renal function in the early phases following transplantation.     

Metabolic consequences of very-low-calorie diet therapy in obese non-insulin-dependent diabetic and nondiabetic subjects

To determine the effects of very-low-calorie diets on the metabolic abnormalities of diabetes and obesity, we have studied 10 obese, non-insulin-dependent diabetic (NIDDM) and 5 obese, nondiabetic subjects for 36 days on a metabolic ward during consumption of a liquid diet of 300 kcal/day with 30 g of protein. Rapid improvement occurred in the glycemic indices of the diabetic subjects, with mean (+/- SEM) fasting plasma glucose falling from 291 +/- 21 to 95 +/- 6 mg/dl (P less than 0.001) and total glycosylated hemoglobin from 13.1 +/- 0.7% to 8.8 +/- 0.3% (P less than 0.001) (normal reference range 5.5-8.5%). Lipid elevations were normalized with plasma triglycerides reduced to less than 100 mg/dl and total plasma cholesterol to less than 150 mg/dl in both groups. Hormonal and substrate responses were also comparable between groups with reductions in insulin and triiodothyronine and moderate elevations in blood and urinary ketoacid levels without a corresponding rise in free fatty acids. Electrolyte balance for sodium, potassium, calcium, and phosphorus was initially negative but approached equilibrium by completion of the study. Magnesium, in contrast, remained in positive balance in both groups throughout. Total nitrogen loss varied widely among all subjects, ranging from 70 to 367 g, and showed a strong positive correlation with initial lean body mass (N = 0.83, P less than 0.001) and total weight loss (N = 0.87, P less than 0.001). The nondiabetic group, which had a significantly greater initial body weight and lean body mass than the diabetic group, also had a significantly greater weight loss of 450 +/- 31 g/day compared with 308 +/- 19 g/day (P less than 0.01) in the diabetic subjects. The composition of the weight lost at completion was similar in both groups and ranged from 21.6% to 31.3% water, 3.9% to 7.8% protein, and 60.9% to 74.5% fat. The contribution of both water and protein progressively decreased and fat increased, resulting in unchanged caloric requirements during the diet. This study demonstrates that short-term treatment with a very-low-calorie diet in both obese diabetic and nondiabetic subjects results in: safe and effective weight loss associated with the normalization of elevated glucose and lipid levels, a large individual variability in total nitrogen loss determined principally by the initial lean body mass, and progressive increments in the contribution of fat to weight loss with stable caloric requirements and no evidence of a hypometabolic response.     

Cyclosporine-induced renal dysfunction in human renal allograft recipients

Cyclosporine-treated renal allograft recipients frequently suffer CsA-related nephrotoxicity and hypertension. This study demonstrates that glomerular filtration rate is reduced acutely by 13% (P less than 0.02) and renal vascular resistance increased by 30% (P less than 0.05), immediately after patients take their CsA dose. The reduction in GFR is directly related to their trough CsA level (r = 0.82; P less than 0.01). The lower the trough CsA level the greater the fall in GFR after the CsA dose. Plasma renin activity does not increase after the CsA dose (pre-CsA 0.6 +/- 0.2 ng/L/sec vs. post-CsA 0.4 +/- 0.1 ng/L/sec; P = NS), and therefore cannot be responsible for the reduction in renal function. Short-term nifedipine treatment is effective in preventing the acute reduction in GFR (P less than 0.05). This occurred despite no apparent effect of nifedipine in altering trough or post-dose CsA levels. Furthermore nifedipine was effective in lowering both the mean arterial blood pressure (109 mmHg to 94 mmHg; P less than 0.01) and the elevated renal vascular resistance (25% reduction; P less than 0.02) observed in these patients. These results suggest that nifedipine may be a suitable agent for limiting acute CsA nephrotoxicity and for treating CsA-associated hypertension in renal allograft recipients.     

Effect of carbohydrate intake on kidney function and structure in SHR/N-cp rats. A new model of NIDDM

The SHR/N corpulent (cp) rat is a genetically obese rat that develops hyperglycemia, hyperinsulinemia, and proteinuria. This study was designed to evaluate the effects of high carbohydrate (CHO) intake on renal function and structure in this animal model and to determine whether the renal effects are related to the type of CHO ingested. Two groups of 5-wk-old obese male SHR/N-cp rats and lean male littermates were fed diets containing 54% CHO in the form of sucrose or starch. After 12 wk, renal function parameters, including creatinine clearance, urinary glucose excretion, and urinary protein excretion, were measured. Renal morphology was evaluated by semiquantitative light and electron microscopy. On either diet, obese rats had significantly higher urinary glucose and protein excretions than their lean littermates. Mean creatinine clearance (ml/min) in obese rats did not differ significantly from values observed in lean rats. When corrected for body weight, creatinine clearance (ml.min-1.kg-1) tended to be lower in obese than in lean rats, but the difference was significant (P less than .02) only for obese and lean sucrose-fed animals. Obese rats fed sucrose compared with their obese counterparts fed starch had higher body weight (+8%, P less than .05), glucose excretion (+63%, P less than .02), and protein excretion (+242%, P less than .005). In obese rats, protein excretion correlated with glucose excretion (r = .71, P less than .01). Glomerular lesions consisting of mesangial expansion and intercapillary nodules were found in obese but not in lean rats. Moreover, obese rats fed sucrose had a significantly greater number of involved glomeruli than obese rats fed starch.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal injury in the extremely obese patients with normal renal function

We studied the glomerular architecture in renal biopsies of 95 patients undergoing bariatric surgery for extreme obesity but whose renal function was normal. The comparison group was 40 control patients having protocol biopsies. These latter patients had normal weight and renal function, were non-diabetic, non-hypertensive, and were undergoing nephrectomy or donating a kidney. Logistic regression models determined associations between the clinical and biochemical variables and glomerular lesions. Arterial hypertension, sleep apnea syndrome (SAS), and microalbuminuria were prevalent in the obese patients, as was hyperglycemia to a lesser extent. Focal and segmental glomerulosclerosis was present in only five extremely obese (EO) patients but absent in controls. Increased mesangial matrix, podocyte hypertrophy, mesangial cell proliferation, and glomerulomegaly were more frequent in the obese cohort than in the control group. Body mass index was a significant independent risk factor associated with glomerular lesions in all 135 patients and in the 95 EO patients, whereas SAS was associated with glomerulomegaly only in the EO. Our study shows that EO patients who lack overt clinical renal symptoms have a variety of glomerular abnormalities that correlate with body mass.     

Role of altered renal lipid metabolism in the development of renal injury induced by a high-fat diet

Metabolic syndrome is associated with increased risk of chronic kidney disease, and the renal injury in patients with metabolic syndrome may be a result of altered renal lipid metabolism. We fed wild-type or insulin-sensitive heterozygous peroxisome proliferator-activated receptor gamma-deficient (PPARgamma(+/-)) mice a high-fat diet for 16 weeks. In wild-type mice, this diet induced core features of metabolic syndrome, subsequent renal lipid accumulation, and renal injury including glomerulosclerosis, interstitial fibrosis, and albuminuria. Renal lipogenesis accelerated, determined by increased renal mRNA expression of the lipogenic enzymes fatty acid synthase and acetyl-CoA carboxylase (ACC) and by increased ACC activity. In addition, renal lipolysis was suppressed, determined by reduced mRNA expression of the lipolytic enzyme carnitine palmitoyl acyl-CoA transferase 1 and by reduced activity of AMP-activated protein kinase. In PPARgamma(+/-) mice, renal injury, systemic metabolic abnormalities, renal accumulation of lipids, and the changes in renal lipid metabolism were attenuated. Thus, a high-fat diet leads to an altered balance between renal lipogenesis and lipolysis, subsequent renal accumulation of lipid, and renal injury. We suggest that renal lipid metabolism could serve as a new therapeutic target to prevent chronic kidney disease in patients with metabolic syndrome.     

Interaction of eicosanoids and nitric oxide in renal reperfusion injury.

BACKGROUND: Both the eicosanoids and nitric oxide are known to play an important role in the pathogenesis of postischemic injury. Recent evidence has suggested that the generation of each may affect the other via a feedback loop. This was investigated in an experimental model of renal warm ischemia reperfusion injury. METHODS: Rats underwent bilateral renal warm ischemia (15-60 min) then reperfusion (20 or 80 min) followed by a unilateral nephrectomy to measure renal nitric oxide (as nitroxides) and eicosanoids. Renal function was measured on days 2 and 7 prior to terminal nephrectomy for tissue analysis. RESULTS: Vasodilator eicosanoids (6-KPGF1alpha and PGE2) fell on reperfusion in line with the duration of warm ischemia with a concomitant rise in the vasoconstrictor TxA2. The ratio of vasodilator to vasoconstrictor eicosanoids fell from 8.22 (2.3) in the control to 0.82 (0.1) in the 60-min warm ischemia group (P<0.01). Renal levels of nitroxides rose on reperfusion demonstrating an inverse correlation with the eicosanoid ratio (r2=0.86). Renal function was impaired at both day 2 and day 7 and showed a positive correlation with the eicosanoid ratio (r2=0.67 and 0.62, respectively). CONCLUSIONS: Renal warm ischemic injury is associated with a progressive fall in the ratio of vasodilator-to-vasoconstrictor eicosanoids from early in reperfusion through to day seven although nitric oxide was elevated throughout the same period. There was no evidence of coinduction of nitric oxide synthase and cyclooxygenase in this model.     

Glomerular volume and renal histology in obese and non-obese living kidney donors

The link between obesity and renal disease is unclear, and there is no consensus as to whether obese individuals are at increased risk for kidney disease after living kidney donation if they otherwise meet acceptance criteria. We retrospectively studied time-zero (implantation) biopsies in 49 obese (body mass index (BMI) > or = 30 kg/m2) and 41 non-obese (BMI < 30 kg/m2) renal donors that met acceptance criteria. We found that our obese donor population had higher systolic blood pressure (P < 0.001 vs non-obese) and higher absolute iothalamate clearance (P = 0.001 vs non-obese) before donation. The obese donors had larger glomerular planar surface area compared to non-obese controls (P = 0.017), and this parameter correlated with patient weight and urinary microalbumin excretion. Detailed examination of the biopsies revealed that although most histologic findings were similar between groups, the obese donors had more tubular dilation (P = 0.01), but less tubular vacuolization (P = 0.02) than the non-obese controls. There was also a trend toward more arterial hyalinosis in the obese patients than controls (P = 0.08). From these data, our studies detected subtle differences in donor organs obtained from obese compared to non-obese individuals. Further studies should be carried out to quantify the long-term impact of these findings.