The role of altered lipid metabolism in the progression of renal disease: experimental evidence.
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Animals↗
Biomedical subjects
W F Keane
Publications and source records attributed to W F Keane.
Hyperlipidemia and progressive renal disease.
Experimental studies have suggested an important role for abnormal lipid metabolism as an integral factor in modulating progressive renal damage. Dietary induced hypercholesterolemia induced relatively modest glomerular injury. However, in the presence of reduced nephron population or in the presence of underlying renal diseases, such as diabetes, nephrotic syndrome, and hypertension, nephron injury can be markedly exaggerated. These experimental results suggest that an important interaction may occur between renal disease and the occurrence of abnormalities of lipid metabolism. Additional support for the role of lipids in progressive renal injury can be obtained from studies in which pharmacological interventions reduced circulating lipids and this led to decreased glomerular damage. The mechanisms whereby lipids may amplify glomerular injury are not completely understood but may include an interaction with macrophages, alteration in vascular and mesangial functions, changes in production of mediator substances or alterations in membrane fluidity. Local glomerular modification of lipoproteins could also occur and contribute to the development of glomerular pathologic changes. Clinically, few data are available that provide insights into the potential role of renal-related lipid abnormalities in the progression of human renal disease.
Animals↗
The role of lipid abnormalities in the pathogenesis of chronic, progressive renal disease.
Altogether, a growing amount of clinical and experimental data suggests that lipids may be important in the development and progression of chronic renal injury. Abundant clinical data have demonstrated that hyperlipidemia is associated with diabetes, decreased renal function, and the nephrotic syndrome. Although clinical correlations between plasma lipid levels and renal dysfunction do not prove a cause-and-effect relationship, potentially injurious lipid abnormalities are invariably present in those patients most likely to progress to end-stage renal disease. In several animal models, pharmacologic treatment of lipid abnormalities has been shown to ameliorate renal disease. Moreover, experimental data suggest that lipid-induced alterations in a number of immune and nonimmune mechanisms could explain the association between lipids and renal injury. A better understanding of these alterations and mechanisms may ultimately lead to more effective treatment of patients with chronic progressive renal disease.
Animals↗
Hyperlipidemia in the nephrotic syndrome.
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Humans↗
Renal protective effects of angiotensin-converting enzyme inhibition.
Nephron loss is a common progression of a diverse range of kidney diseases. Recent experimental models of chronic renal disease have suggested that hemodynamic and nonhemodynamic mechanisms play key roles in progressive renal injury. Extensive renal ablation in the rat was followed by development of altered glomerular hemodynamics. Albuminuria and histologic damage leading to focal glomerulosclerosis were preceded by the development of increased glomerular pressures and were prevented by interventions such as severe dietary protein restriction and angiotensin-converting enzyme (ACE) inhibitor therapy. Both experimental interventions ameliorated glomerular hypertension. It was therefore concluded that these interventions ameliorated injury by glomerular hemodynamic effect. Similar findings were obtained in a rat model of type I diabetes mellitus induced by streptozotocin in which glomerular hemodynamic factors appeared important to the development of progressive renal disease. Recent studies have suggested that nonhemodynamic factors have important roles in the progression of glomerular injury. For example, although the predominant effects of ACE inhibitor therapy appear to be hemodynamically mediated, data are emerging which suggest that these agents may also influence growth/proliferation of glomerular cells. Because hyperplasia/hypertrophy may influence glomerular susceptibility to injury, this may also be a potential mechanism whereby ACE inhibitor therapy influences glomerular damage. In addition, a variety of studies have suggested that hyperlipidemia, which is frequent accompaniment of glomerular disease, is an important modulator of glomerular injury independent of glomerular hemodynamic effects. Coagulation factors, calcium phosphorus balance, as well as the genetic susceptibility of the glomerulus to injury, all appear to contribute to progressive nephron destruction.
Angiotensin-Converting Enzyme Inhibitors↗
Renal effects of angiotensin converting enzyme inhibitors: nondiabetic chronic renal disease.
Based on studies in the rat remnant kidney model, it has been proposed that glomerular hypertension is responsible for the progressive nature of chronic renal disease. In that model, therapy with angiotensin converting enzyme (ACE) inhibitors reduced glomerular pressures. As a result, glomerular injury was reduced and the rate of progression of renal disease was slowed. Thus, alterations in hemodynamics may play an important role in glomerular injury. However, it is now evident that a variety of metabolic and other factors affect the progression of renal disease. Moreover, recent studies suggest that ACE inhibitors may also have beneficial effects that are independent of alterations in glomerular pressure. In humans, the glomerular hemodynamic response to renal disease cannot be measured, and it is not known whether or under which conditions glomerular capillary pressure might be elevated. Treatment with ACE inhibitors safely lowers blood pressure without adversely affecting renal function in most patients with nondiabetic chronic renal failure. Although proteinuria and the rate of progression of renal disease may decrease in some patients, these effects are inconsistently seen. Identification of the factors that modulate this variability in response to ACE inhibition may provide new insight into the pathogenesis and treatment of progressive renal disease in humans.
Angiotensin-Converting Enzyme Inhibitors↗
The effects of lovastatin in hyperlipidemic patients with the nephrotic syndrome.
Hypercholesterolemia may pose a substantial risk for cardiovascular disease. The present investigation was designed to evaluate the safety and efficacy of the cholesterol synthesis inhibitor, lovastatin, in 13 nephrotic patients with 5.6 +/- 0.7 g/24 h of albuminuria. All patients were maintained on a low cholesterol diet throughout the study. After a 4-week placebo period, lovastatin was administered, 20 mg twice daily for 6 weeks. Lovastatin reduced total cholesterol by 27% from 8.6 +/- 0.6 mmol/L (331 +/- 24 mg/dL) to 6.3 +/- 0.4 mmol/L (242 +/- 17 mg/dL) (P less than 0.01), low-density lipoprotein cholesterol by 27%, from 5.8 +/- 0.5 mmol/L (223 +/- 20 mg/dL) to 4.2 +/- 0.6 mmol/L (163 +/- 22 mg/dL) (P less than 0.01), and apolipoprotein B by 29%, from 153 +/- 12 mg/dL to 109 +/- 8 mg/dL to 109 +/- 8 mg/dL P less than 0.01). Triglycerides and very-low-density lipoprotein (VLDL) cholesterol levels were also reduced by 30% and 37%, respectively (P less than 0.01). High-density lipoprotein (HDL) cholesterol, and apolipoproteins A-1 and A-2 were not significantly altered. Renal function and urine protein excretion were not affected by lovastatin. Although one patient developed diarrhea and discontinued treatment before completing 6 weeks of lovastatin, the other 12 patients had no adverse effects. In this short-term study, lovastatin therapy had few side effects and had favorable effects on the lipoprotein profile of nephrotic syndrome patients.
Adult↗
High protein intake accelerates glomerulosclerosis independent of effects on glomerular hemodynamics.
It is unclear whether glomerular hemodynamic changes always accompany alterations in dietary protein, and whether nonhemodynamic factors associated with a high protein intake can influence glomerular injury. In the present study, uninephrectomized (UNx) male rats were fed either standard (20%) or high (40%) protein diets. Body growth was comparable in the two diet groups. At 30 weeks of age, UNx rats fed high protein had increased albuminuria (36.7 +/- 12.6 mg/24 hr), compared to UNx rats fed standard protein (10.2 +/- 6.2 mg/24 hr; P less than 0.05). The incidence of focal glomerulosclerosis (FGS) at 36 weeks was markedly increased in the high protein rats (19.0 +/- 7.7%), compared to the standard protein rats (3.2 +/- 2.0%; P less than 0.05). Moreover, FGS in the high protein rats correlated with the serum cholesterol level measured at 18, 24, and 30 weeks of age. Glomerular hemodynamics were assessed before glomerular injury developed in separate groups of UNx rats fed either standard or high protein. Single nephron GFR (SNGFR) and single nephron plasma flow (SNPF) were increased in UNx rats, compared to two-kidney rats fed standard protein. SNGFR and SNPF, however, were not different between UNx rats fed standard or high protein. Glomerular capillary pressure (PGC) was not different between UNx rats fed standard protein (51.7 +/- 1.3 mm Hg) and two-kidney controls (53.1 +/- 1.5 mm Hg). Moreover, PGC was not altered in UNx rats fed high protein (51.8 +/- 1.6 mm Hg). We conclude that high dietary protein can accelerate the development of glomerular injury independent of effects on glomerular hemodynamics.
Animals↗
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.
Animals↗
Angiotensin-converting enzyme inhibitors in chronic renal failure.
In contrast to some other antihypertensive drugs, angiotensin-converting enzyme (ACE) inhibitors lower glomerular capillary pressure, decrease proteinuria, and may halt progressive glomerular injury and loss of renal function in experimental chronic renal failure (CRF). Although these favourable effects of ACE inhibition may result from alterations in glomerular haemodynamics, there is some evidence to show that ACE inhibitors may reduce glomerular injury through other mechanisms. CRF in man may result from a variety of insults to the kidney. However, it is not known whether, or under which conditions, glomerular capillary pressure is elevated in this heterogeneous population. Limited data suggest that renal haemodynamics (and perhaps glomerular capillary pressure) may depend in part on the level of systemic blood pressure. In addition, several studies have demonstrated a positive correlation between systemic blood pressure and the rate of progression of CRF. ACE inhibitor therapy generally lowers systemic blood pressure, does not alter renal function and decreases proteinuria in patients with CRF. The reduction in proteinuria appears to be variable and may depend on pretreatment glomerular haemodynamics and/or the activity of the renin-angiotensin-aldosterone system. Preliminary evidence also suggests that ACE inhibitors may slow the progression of renal disease in humans with CRF. However, this effect, like the reduction in proteinuria, has not been observed consistently in all patients. In addition, it is not clear whether these effects on proteinuria and progression of disease are unique to ACE inhibitor therapy, since the lowering of systemic blood pressure with other drugs may have similar effects. The heterogeneity of the response to ACE inhibition suggests that there may be interpatient differences in glomerular haemodynamics in CRF, perhaps related to systemic blood pressure or the underlying disease process. Studies to date indicate that ACE inhibitors exert their beneficial effect by lowering glomerular capillary pressure and that not all patients will benefit from therapy with regard to proteinuria or amelioration of disease progression. However, further investigation of the haemodynamic and non-haemodynamic effects of ACE inhibitors, as well as the variability of response, may ultimately allow the selection of those patients who would benefit from such therapy.
Angiotensin-Converting Enzyme Inhibitors↗
Lipids and the progression of renal disease.
The mechanisms involved in progressive renal injury have been the subject of intense investigation during the past decade. Hemodynamic and nonhemodynamic factors have been implicated in progressive renal damage, including abnormalities of lipid metabolism. The idea that abnormal lipid metabolism may be important in the development and progression of renal injury has intrigued investigators for over 100 years. Studies in models of progressive renal insufficiency have demonstrated that abnormalities in lipid metabolism may participate in the development of glomerular and tubular alterations leading to nephron destruction. This concept has been supported by the demonstration that pharmacologic intervention with different classes of lipid-lowering agents is associated with a reduction in the extent and severity of glomerular and tubular injury. The mechanism whereby hyperlipidemia contributes to renal injury are at present unknown. Morphologically, marked expansion of the mesangial matrix, prior to the development of glomerulosclerosis, suggests the possibility that altered production of mesangial matrix proteins may contribute to glomerular injury. Increased numbers of glomerular monocyte-derived macrophages and foam cells in hyperlipidemic rats have been described. The role that these cells may play in the development of proteinuria and glomerular damage has not been clarified. Biochemically, increased renal tissue content of cholesterol esters and reduced concentrations of essential fatty acids have been described. Whether these changes in tissue lipids contribute to renal injury is also unknown. In addition, persistent hyperlipidemia, particularly hypercholesterolemia, may also lead to glomerular hypertension, possibly through alterations in eicosanoid metabolism. Finally, preliminary data have suggested that oxidized lipoproteins may contribute to the hemodynamic and structural changes described in lipid-induced renal injury. The roles of altered platelet function and other lipid-derived inflammatory mediators are yet to be explored. In conclusion, experimental studies have indicated that hyperlipidemia is an important modulator of nephron damage and may contribute to the progression of renal disease. Whether alterations in lipid metabolism participate in progressive renal insufficiency in humans remains to be determined.
Animals↗
Mild hypothermia gives better functional preservation than cold or normothermic perfusion of rat kidneys.
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Animals↗
Angiotensin converting enzyme inhibitors and progressive renal insufficiency. Current experience and future directions.
STUDY OBJECTIVE: To review the rationale for using angiotensin converting enzyme (ACE) inhibitors in progressive renal disease, and to evaluate the experience with these agents in patients with hypertension and renal insufficiency. DATA IDENTIFICATION: Experimental and clinical studies published from January 1977 to November 1988 were identified by searching the literature and by extensive hand searching of bibliographies of identified articles. STUDY SELECTION: Experimental studies of glomerular function during therapy with ACE inhibitors or other antihypertensive regimens were reviewed. Series using ACE inhibitors for treating hypertensive patients with renal disease were evaluated and reports of adverse events were studied. RESULTS OF DATA SYNTHESIS: Experimentally, ACE inhibitors seem to decrease glomerular injury by reducing both systemic and glomerular hypertension. Clinically, ACE inhibitors reduce systemic blood pressure in hypertensive patients with diabetic and nondiabetic renal disease without causing dramatic changes in glomerular filtration rate or renal blood flow. Most studies of nondiabetic renal insufficiency suggest that proteinuria is reduced in most patients. However, no long-term controlled study on the effect of ACE inhibitors on the progression rate of nondiabetic renal disease has been completed. ACE inhibitors have not yet been approved by the Food and Drug Administration (FDA) for treating or preventing progressive renal disease. Such use would therefore be considered "innovative" therapy. CONCLUSIONS: ACE inhibitors are tolerated by azotemic patients, although transient reductions in renal function can occur. Patients with bilateral renal insufficiency or low cardiac output are at increased risk for developing reversible acute renal insufficiency. Hyperkalemia may occur, particularly in patients with diabetes or severe renal insufficiency. In many patients with renal disease, ACE inhibitors dramatically reduce proteinuria, but whether they also reduce the rate of progression of renal disease remains unproved.
Angiotensin-Converting Enzyme Inhibitors↗
Association between active Wegener's granulomatosis and anticytoplasmic antibodies.
Autoantibodies reacting with the cytoplasm of granulocytes and monocytes (anticytoplasmic antibodies [ACPAs]) were found in 42 of 45 patients with active Wegener's granulomatosis (WG) (sensitivity, 93%). Specificity was tested in selected groups of patients with closely related diseases. Of 58 patients without a diagnosis of WG, 2 had ACPAs (specificity, 97%). The significance of ACPA titration for assessing or predicting disease activity was evaluated in a 16-month prospective study of 35 patients with WG. Seventeen relapses were observed and all were preceded by a significant rise of the ACPA titer. Anticytoplasmic antibodies are a specific and sensitive marker for active WG; a rising titer is a sensitive marker for the development of a relapse.
Adult↗
Effects of reduced renal mass on tissue lipids and renal injury in hyperlipidemic rats.
Increasing evidence from experimental models of chronic renal failure suggests that abnormalities in lipid metabolism may contribute to progressive renal injury. In the present study, hyperlipidemic obese, and normolipemic lean Zucker rats were subjected to unilateral nephrectomy or sham surgery at eight weeks of age. After 32 weeks, renal injury was greater in obese than in lean rats, and injury was made worse by nephrectomy. Among the major lipid classes, increased renal cortical cholesteryl esters were positively correlated with the degree of renal injury, suggesting that mechanisms analogous to those thought to be important in the pathogenesis of atherosclerosis may cause renal injury. Among phospholipid fatty acids, the ratio of oleic to linoleic acids (18:1/18:2) was strongly linked to both glomerular (r = 0.83, P less than 0.01) and tubulo-interstitial (rr = 0.80, P less than 0.01) injury, suggesting a possible role for a relative essential fatty acid deficiency in renal injury. There were also strong, negative associations between eicosapentaenoic acid levels and glomerular (r = -0.63, P less than 0.01) and tubulointerstitial (r = -0.71, P less than .01) injury. Altogether, these results suggest that specific abnormalities in renal lipid metabolism may be important in the pathogenesis of chronic, progressive renal injury.
Animals↗
Risk factors for glomerular injury in rats with genetic hypertension.
Systemic and glomerular hypertension, hyperlipidemia, and massive proteinuria have been described as risk factors for the development of focal glomerulosclerosis (FGS). Previous studies have shown that Dahl salt-sensitive (S) rats with severe hypertension have elevated glomerular pressures and develop extensive FGS. In the present study, we determined whether Dahl S rats exhibit other risk factors for FGS. Dahl S rats were found to have elevated serum triglycerides at six weeks of age, compared to Dahl salt-resistant (R) rats. Between six and 24 weeks, systemic hypertension and progressive increases in both serum lipids and albuminuria occurred in Dahl S rats fed high salt (4% NaCl) chow. No changes in blood pressure or serum lipids occurred in Dahl R rats fed high salt. At 30 weeks, the incidence of FGS was 20 times greater in hypertensive Dahl S than in Dahl R. In a separate study, we compared risk factors for FGS in Dahl S rats and spontaneously hypertensive rats (SHR). The magnitude of glomerular capillary pressure, serum lipid levels, and urine albumin excretion were measured in male Dahl S rats and male SHR between 12 and 20 weeks of age. Normal values for the various parameters were established in a group of normotensive male Sprague-Dawley rats. For this study, all rats were fed standard chow containing 0.6% NaCl. Blood pressure was elevated (P less than .01) in Dahl S (142 +/- 2 mm Hg) and in SHR (173 +/- 3 mm Hg) compared to the Sprague-Dawley rats (117 +/- 3 mm Hg). Glomerular capillary pressure, however, was similar in all three groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Albuminuria↗
Teicoplanin pharmacokinetics in patients undergoing continuous ambulatory peritoneal dialysis after intravenous and intraperitoneal dosing.
The pharmacokinetics of teicoplanin after single 6-mg/kg intravenous and intraperitoneal doses were studied in five noninfected patients undergoing continuous ambulatory peritoneal dialysis. Biological samples were assayed for teicoplanin content by a microbiological assay technique. Terminal disposition half-life (266.4 +/- 51.9 h [mean +/- standard error of the mean]) was prolonged and total body clearance (0.040 +/- 0.004 ml/min per kg) was reduced compared with values previously reported in subjects with normal renal function. The volume of distribution at steady state (1.15 +/- 0.19 liters/kg) was higher than values previously reported in subjects with normal renal function (0.56 to 0.72 liter/kg). Peritoneal dialysis clearance (0.007 +/- 0.001 ml/min per kg) accounted for only 16.1% of total body clearance. The absolute systemic bioavailability of teicoplanin after intraperitoneal administration was 81.5 +/- 10.7%.
Glycopeptides↗