D-lactic acidosis 23 years after jejuno-ileal bypass.

Accumulation of D-lactate after gastrointestinal surgery, particularly jejuno-ileal bypass, is an uncommon and often misdiagnosed clinical disturbance. The syndrome may be complicated by dizziness, ataxia, confusion, headache, memory loss, and aggressive behavior. Serum chemistries are often deceptive because the anion gap is frequently normal in spite of severe metabolic acidosis. Moreover, the urine anion gap may be positive, incorrectly suggesting a defect in renal net acid excretion. Indeed, the combination of a normal anion gap metabolic acidosis and positive urine anion gap may erroneously suggest a diagnosis of renal tubular acidosis. Importantly, all reported cases of D-lactic acidosis secondary to bypass surgery have been encountered within 5 to 10 years following the surgery. Here we present an unusual case of D-lactic acidosis (complicated by encephalopathy) presenting 23 years after a jejuno-ileal bypass procedure. The patient was initially diagnosed with a drug intoxication secondary to benzodiazepines. Ultimately, the diagnosis of D-lactate encephalopathy was established after challenging the patient with a carbohydrate load. Thus, administration of 40 kcal/kg over 16 hours reproduced the clinical syndrome and was accompanied by a marked increment in serum and urine D-lactate concentration. The patient had sustained resolution of her symptoms after treatment with oral vancomycin.

Progressive renal insufficiency. Office strategies to prevent or slow progression of kidney disease.

Prevention of chronic renal failure should be a primary healthcare goal in the new millennium. Better control of blood pressure, blood glucose, and lipid levels shows promise for slowing and perhaps even preventing renal dysfunction. Protein-sparing diets also may prove to be important. While it is not yet known whether combining interventions to treat each of these factors will have additive or synergistic effects, it seems prudent to approach these problems aggressively.

Eicosapentaenoic acid suppresses PDGF-induced DNA synthesis in rat mesangial cells: involvement of thromboxane A2.

BACKGROUND: The administration of eicosapentaenoic acid (EPA) derived from marine oils has been shown to suppress vascular myocyte, lymphocyte, keratinocyte, and mesangial cell proliferation in vitro, although the effects are variable and most reports provide fragmented insight into the mechanism(s) responsible for altering cell growth, particularly the relationship of membrane lipid remodeling to changes in cell proliferation. Thus, these studies were designed to elucidate the effects of mesangial cell membrane fatty acid remodeling (induced by EPA) on cell growth, and to define the relevance of changes in the synthesis of growth-modulating eicosanoids. METHODS: Mesangial cells were grown in RPMI and 17% fetal calf serum, and were subcultured and grown for 48 hours in 17% delipidated serum or delipidated serum supplemented with 0 to 50 micrograms/mL of EPA. Quiescent EPA-loaded and control mesangial cells were subjected to stimulation with 20 ng/mL of platelet-derived growth factor (PDGF) followed by measurement of 3H-thymidine incorporation and cell number. RESULTS: Mesangial cells remodeled with EPA exhibited a significant decrease in PDGF-stimulated 3H-thymidine incorporation and cell number associated with a reduction in thromboxane A2 (TXA2) in the media. Importantly, the phospholipid fatty acid composition of mesangial cells grown in media enriched with EPA revealed an increase in EPA (0.5 +/- 0.02% to 17.02 +/- 0.52%) coupled with a reciprocal decrease in the precursor for TXA2, arachidonic acid (18.9 +/- 3.17% to 3.55 +/- 0.30%). Blockade of TXA2 synthesis in mesangial cells treated with indomethacin (0.1 to 100 mumol/L) or the specific TXA2 synthase inhibitor, U-63557A (0.1 to 100 mumol/L), evoked a similar reduction in PDGF-stimulated proliferation and TXA2 synthesis. Coincubation of PDGF with the TXA2 mimetic, U-46619 (1 mumol/L), reversed the growth suppression induced by cell membrane remodeling. CONCLUSIONS: These studies suggest that changes in membrane fatty acid composition induced by EPA modulates PDGF-stimulated proliferation by engendering a change in PDGF-stimulated TXA2 synthesis. Furthermore, we conclude that TXA2 functions as a comitogen for PDGF-stimulated mesangial cell growth.

Percutaneous renal biopsy in the 1990s: safety, value, and implications for early hospital discharge.

To determine the parameters associated with significant bleeding and to examine the value of performing a renal biopsy, we studied 83 consecutive patients, including 24 renal allograft recipients, who had undergone percutaneous renal biopsy. The patients were stratified into four groups according to the percentage of decline in their hematocrit (Hct) at 24 hours postbiopsy, as follows: 10% or greater (n = 21; 25%) and less than 10% decline (n = 62; 75%). The latter group was further subgrouped into 5% to 10% (n = 22) and less than 5% decline (n = 40). There was a significant decline in Hct postbiopsy, with a linear correlation between the decrease in Hct at 6 and 24 hours (R2 = 0.47; P < 0.0001), suggesting that the former was a predictor of the latter. There was a linear correlation between the number of passes and number of cores obtained for the first four passes, but an inverse correlation when five passes or greater were required. Interestingly, there was no correlation between bleeding (>10% decline in Hct) and the number of passes or cores obtained. Gross hematuria and blood transfusion requirement were each encountered in three patients (3.6%). Importantly, the prebiopsy clinical diagnosis was altered in 18 of 59 native kidney biopsies (33%) and 10 of 24 transplant biopsies (41%). We conclude that percutaneous renal biopsy using an automated spring-loaded gun device coupled with ultrasound guidance is a safe technique and provides essential clinical information. Importantly, patients with a stable Hct at 6 hours were at low risk for bleeding at 24 hours while hospitalized. It remains to be determined if these findings could be extrapolated to early discharge from hospital.

Chronic administration of furosemide augments renal weight and glomerular capillary pressure in normal rats.

Angiotensin II (ANG II) is believed to promote progressive renal injury via augmented glomerular capillary hydraulic pressure (PGC). Acute volume reduction secondary to diuretic administration increases circulating ANG II and augments PGC, yet the hemodynamic effects of sustained diuretic administration are unknown. Therefore, glomerular micropuncture studies were performed in male Munich-Wistar rats after 6-8 wk of treatment with daily furosemide (F, 40 mg/day), furosemide plus the AT1 receptor antagonist, losartan (F + L, 5 mg/day), or no therapy (C, control). Renal weight was increased in F rats (1.23 +/- 0.7 g) vs. C (1.00 +/- 0.06 g) or F + L (0.97 +/- 0.01 g). In addition, PGC was elevated in F animals (52.1 +/- 1.5 mmHg) vs. C (43.7 +/- 1.5) or F + L-treated rats (41.3 +/- 1.7). F-treated rats were also characterized by a relative increase in efferent arteriolar resistance and filtration fraction. The latter was markedly attenuated in F + L-treated animals. Collectively, these findings are consistent with an ANG II-mediated alteration in intrarenal hemodynamics. In contrast to acute volume manipulations, however, chronic furosemide augmented renal growth, whereas losartan administration completely arrested this phenomenon. Further studies are warranted to determine whether the hemodynamic and growth adaptations elicited by chronic F administration induce or accelerate renal injury.

Acute and chronic kidney disease.

The presentation of many renal diseases in older adults is remarkably similar to that in younger patients, although the symptoms and clinical findings are frequently attributed to diseases of aging. Since older patients often respond to treatment as well as younger patients do, they deserve a thorough investigation, including renal biopsy when indicated. It is important to base decisions regarding access to evaluation and treatment, quality of life, and initiation of termination of dialysis on strong moral and ethical grounds.

Paracetamol-induced pancreatitis and fulminant hepatitis in a hemodialysis patient.

The occurrence of hepatotoxicity and acute renal dysfunction following an acute paracetamol overdose has been well documented. Acute pancreatitis, however, has been rarely described. We would like to report a hemodialysis patient who developed acute pancreatitis and hepatic failure from acute paracetamol toxicity. To our knowledge, this represents the first description in a dialysis patient of paracetamol induced pancreatitis. Given the frequency of paracetamol usage in these patients, we believe that it is important to consider this diagnosis in patients with unexplained acute pancreatitis, particularly if there is associated hepatic dysfunction.

Serum bicarbonate is an independent determinant of protein catabolic rate in chronic hemodialysis.

Serum bicarbonate is an independent determinant of protein catabolic rate in chronic hemodialysis. Recent biochemical studies suggest that metabolic acidosis induces an increase in protein catabolic rate. Therefore, we retrospectively examined the relationship between serum total CO2, normalized protein catabolic rate (NPCR), midweek BUN, KT/V, and serum albumin in 70 chronic hemodialysis patients over a period of 4-6 months (total of 270 determinations). Multiple regression analysis indicated an independent and inverse association of tCO2 with NPCR (p < 0.0001). Subsequent analysis of the data indicated a nonlinear relationship between serum CO2 and NPCR. Indeed, the slope of the regression abruptly increased from -0.015 +/- 0.005 to -0.108 +/- 0.032 when analyzed for serum CO2 < or = 15 mEq/l. We conclude that metabolic acidosis may modulate protein kinetics in patients receiving maintenance hemodialysis. Moreover, this relationship appears to be exaggerated at moderate to severe reductions in tCO2. Thus, this analysis suggests that decreases in tCO2 have a detrimental effect on protein catabolism in stable patients maintained on chronic hemodialysis.

Omega-3 fatty acids attenuate glomerular capillary hydraulic pressure in rats with renal ablation.

To clarify the emerging role of omega-3 fatty acids (FAs) in the regulation of the renal microcirculation, we recently performed micropuncture studies in normal rats maintained on diets enriched with omega-3 FAs. Although those studies suggested that omega-3 FAs alter the renal microcirculation in normal rats, it was not apparent whether this dietary maneuver could modulate intrarenal hemodynamics in the setting of renal disease. Therefore, the present renal micropuncture studies were performed in nephrectomized rats maintained on control diets or diets enriched with omega-3 FAs. Omega-3 FAs abrogated glomerular capillary (56.2 +/- 0.8 vs. 63.9 +/- 2.0 mm Hg) and transcapillary hydraulic pressure (40.9 +/- 1.4 vs. 50.6 +/- 1.3 mm Hg) compared to untreated rats. This effect was attributable to (1) a reduction in mean arterial pressure (138 +/- 3 vs. 163 +/- 2 mm Hg) and (2) a decrease in efferent arteriolar resistance (0.43 +/- 0.06 vs 0.98 +/- 0.19 dyn x seconds x cm-5 x 10(10)). Sclerosis index and albuminuria were also lessened by this dietary maneuver. To further characterize the mechanism of altered renal arteriolar resistance, we then explored the effects of omega-3 FAs on renal prostaglandin synthesis and angiotensin II-stimulated phospholipid turnover. A significant decrease in the urinary excretion of the renal vasoconstrictor, TXA2 (12.8 +/- 2.3 vs. 35.1 +/- 14.0 ng/24 hr), was induced by treatment with omega-3 FAs. Moreover, angiotensin II-stimulated phospholipid turnover was attenuated in intact glomeruli pretreated with omega-3 FAs. We conclude that omega-3 FAs exert favorable effects on experimental renal injury by eliciting a salutary effect on the renal microcirculation of rats subjected to subtotal renal ablation. Moreover, the similarities between these findings and those obtained with sustained inhibition of angiotensin II converting-enzyme suggest that these compounds act through parallel pathways of inhibition.

Absence of vacuolar H(+)-ATPase pump in the collecting duct of a patient with hypokalemic distal renal tubular acidosis and Sjögren's syndrome.

Distal renal tubular acidosis (dRTA) is a common complication of autoimmune connective tissue diseases. The underlying pathophysiology of renal tubular acidosis in these syndromes is frequently characterized by impaired hydrogen ion secretion, i.e., secretory defect dRTA. However, the precise molecular events leading to this disturbance remain poorly understood. An opportunity was recently afforded to examine the ultrastructural features of the collecting duct in a patient with Sjögren's syndrome and secretory defect dRTA. Immunocytochemical analysis of a renal biopsy obtained 12 months after the patient's initial presentation demonstrated a complete absence of vacuolar H(+)-ATPase in the collecting duct. Antibodies to the 31- and 56-kd kidney-specific subunits of the H(+)-ATPase pump were used to characterize pump distribution. Interestingly, although antiserum to the CI-:HCO3- anion exchanger (band-3 protein) reacted strongly with normal human kidney and the patient's red blood cells, no immunoreactivity was observed in the patient's collecting duct epithelium. Importantly, electron microscopy of the patient's renal biopsy specimen disclosed cells that ultrastructurally were indistinguishable from intercalated cells. These results suggest that the functional basis of impaired hydrogen ion secretion in this patient was secondary to the absence of intact H(+)-ATPase pumps rather than defective pump function or distribution. The presence of intercalated cells ultrastructurally, but the absence of discernible staining for band-3 protein and H(+)-ATPase, also suggests that the defect in proton secretion may represent a defect involving the assembly of at least two of the ion transport pumps essential for the normal maintenance of acid-base homeostasis by the intercalated cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired essential fatty acid depletion in the remnant kidney: amelioration with U-63557A.

Previous studies have demonstrated an association between renal cortical fatty acid composition and experimental models of renal injury. The present study was designed to extend these observations to the remnant kidney and to investigate the hypothesis that increased endogenous turnover of arachidonic acid metabolites results in the depletion of progenitor fatty acids. Remnant kidney cortex demonstrated a relative reduction of the essential fatty acids, linoleate and arachidonate (20 +/- 7.2% and 11 +/- 0.3%, respectively), nine weeks after subtotal nephrectomy. In addition, the monounsaturated fatty acid, oleate, was increased (48 +/- 10.6%) while its saturated progenitor, stearate, was decreased (13 +/- 4.3%). Serial evaluation of dienoic prostanoids revealed a significant increase in the renal excretion of TXB2 in rats with remnant kidneys (27 +/- 3.0, 29 +/- 1.1, and 34 +/- 3.3 ng/day vs. 21 +/- 0.8, 20 +/- 1.5, and 22 +/- 3.3 ng/day in control rats, at 3, 6, and 9 weeks, respectively). Moreover, TXB2 excretion inversely correlated with dienoic progenitor fatty acids [18:2(n-6), r2 = 0.76; 20:4(n-6), r2 = 0.79], suggesting that these events are biochemically coupled. Endogenous turnover of precursor fatty acids, confirmed by an increase in renal TXB2 excretion, preceded overt depletion of essential fatty acids by several weeks. Importantly, blockade of endogenous synthesis of TXA2 with the specific TXA2 synthase antagonist, U-63557A, restored the essential fatty acid composition to normal and ameliorated progressive glomerular destruction. Moreover, the ancillary fatty acid disturbances were attenuated by administration of U-63557A.(ABSTRACT TRUNCATED AT 250 WORDS)

Lovastatin retards the progression of established glomerular disease in obese Zucker rats.

Considerable experimental evidence indicates that hyperlipidemia can induce glomerular injury. The importance of lipids in the progression of established glomerular disease has not been established and is of clinical relevance because of the frequent association of lipid abnormalities with human renal disease. In the present study, 26-week-old hyperlipidemic obese Zucker rats (OZRs) with established nephropathy were treated for a period of 18 weeks with daily injections of the cholesterol synthesis inhibitor lovastatin (4 mg/kg). Compared with control OZRs treated with vehicle, lovastatin-treated OZRs had significantly (P < 0.05) lower serum cholesterol and triglyceride levels throughout the treatment period. Blood pressure and urine albumin excretion in lovastatin-treated OZRs were reduced over the first 12 weeks of therapy, but increased toward the levels in the control OZRs at the end of the protocol. After 18 weeks of therapy, the incidence of glomerulosclerosis in lovastatin-treated OZRs (23.2% +/- 5.8%) was approximately half of that in vehicle-treated OZRs (44.6% +/- 7.7%) (P < 0.05). The reduction in glomerular injury in lovastatin-treated OZRs was not associated with changes in either glomerular area or glomerular macrophage content. In separate experiments, mesangial cells were cultured from glomeruli isolated from 26-week-old proteinuric OZRs. Lovastatin (5 to 40 mumol/L) caused a significant dose-dependent inhibition of serum-stimulated mesangial cell DNA synthesis. The inhibitory effects of lovastatin were completely prevented in the presence of exogenous mevalonate (100 mumol/L). Thus, lovastatin retarded the progression of established glomerular disease in OZRs.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of epidermal growth factor in the rat 5/6 renal ablation model.

Acute administration of epidermal growth factor (EGF) has been shown to promote recovery from ischemic and nephrotoxic acute renal failure in vivo. The question of whether chronic subcutaneous administration of EGF (19.1 micrograms/day for 3 or 6 wk) could alter the course of chronic renal failure in rats subjected to 5/6 nephrectomy was studied. By week 6, there was no difference in renal function, as assessed by animal survival, BUN, urea and inulin clearances, proteinuria, renal morphometry, or renal size, between EGF- and vehicle-treated rats. This suggests that chronic renal insufficiency differs from acute tubular injury in its sensitivity to exogenous EGF. Unexpectedly, EGF significantly attenuated the rise in systolic blood pressure that occurred by the fourth week after 5/6 nephrectomy. The antihypertensive effect of EGF was still evident at week 5. Urinary flow rate, free water clearance, and excretion of total solutes, Na+, and K+, however, were not significantly altered by EGF at weeks 2, 4, 5, or 6, suggesting a mechanism other than increased natriuresis or diuresis for this antihypertensive effect.

Lovastatin but not enalapril reduces glomerular injury in Dahl salt-sensitive rats.

Dahl salt-sensitive (S) rats fed a high salt diet develop hypertension, hyperlipidemia, and progressive renal disease. Previous studies have suggested that lipids may be important in the pathogenesis of glomerulosclerosis in Dahl S rats. To investigate this possibility, Dahl S rats fed 4% NaCl chow were treated chronically with the cholesterol synthesis inhibitor lovastatin. After 22 weeks, lovastatin-treated rats had a 38% reduction in serum cholesterol, a 76% reduction in urine albumin excretion, and one-sixth the incidence of focal glomerulosclerosis compared with vehicle-treated control rats. Blood pressure in lovastatin-treated rats was significantly (p < 0.05) lower than that in vehicle-treated rats both early in the study (4 weeks of treatment) and at the end of the protocol. Lovastatin had no effect on glomerular filtration rate or glomerular ultrafiltration dynamics. The efficacy of angiotensin converting enzyme inhibitors in attenuating proteinuria and experimental glomerular disease may be dependent on sodium intake. Thus, we also investigated the effects of long-term enalapril treatment on glomerular injury in Dahl S rats fed high salt chow. Enalapril treatment (50 or 200 mg/l drinking water) significantly lowered blood pressure in Dahl S rats, but did not significantly affect albuminuria or glomerulosclerosis. Enalapril also had no effect on glomerular hemodynamics. These results suggest that lipids may be important in the development of both glomerular disease and hypertension in Dahl S rats and that angiotensin converting enzyme inhibition may not affect the course of renal disease in a setting of high salt intake.

Renal injury in obese Zucker rats: glomerular hemodynamic alterations and effects of enalapril.

Angiotensin-converting enzyme inhibitors may ameliorate experimental glomerular injury by either hemodynamic or nonhemodynamic mechanisms. In a long-term study, we examined the effects of 30 wk of enalapril treatment on the development of glomerular disease in obese Zucker rats (OZR). Enalapril significantly (P less than 0.05) lowered blood pressure, fasting serum cholesterol, and urine albumin excretion in OZR throughout the experimental period. At 38 wk of age, enalapril-treated OZR had a sixfold reduction in the percent glomeruli exhibiting focal glomerulosclerosis and a 20-30% reduction in kidney weight and glomerular area. A separate micropuncture study in 22- to 26-wk-old rats revealed that untreated OZR with albuminuria and increased blood pressure had elevated glomerular capillary pressure (Pgc). Enalapril-treated OZR had less albuminuria and lower blood pressure, but Pgc was not reduced. The value of the transcapillary hydraulic pressure difference (delta P) in enalapril-treated OZR was intermediate between values in untreated OZR and lean Zucker rats. Thus enalapril markedly attenuated the development of glomerular injury in OZR. The salutary effects of enalapril may have involved a reduction in delta P coupled to a nonhemodynamic action, possibly restriction of glomerular growth or lowering of serum cholesterol.

Fever, hyperdynamic shock, and multiple-system organ failure. A pseudo-sepsis syndrome associated with chronic salicylate intoxication.

OBJECTIVE: To describe a sepsis-like syndrome associated with chronic salicylate intoxication. DESIGN: Retrospective clinical study. SETTING: University-affiliated county hospital. PATIENTS: Five patients who became accidentally intoxicated while ingesting salicylates on a long-term daily basis. RESULTS OF DATA ANALYSIS: All five salicylate-intoxicated patients had clinical and laboratory features that were highly suggestive of sepsis, but no bacteriologic or pathologic evidence of infection could be documented. Features included fever, leukocytosis with increased band forms, hypotension with a reduced SVR and multiple system organ failure (ARDS, encephalopathy, renal failure, and DIC). A diagnosis of salicylate intoxication was made at the time of admission to the hospital in only one case. In the other four cases, the presumptive diagnosis was sepsis; a correct diagnosis of salicylate intoxication was not established until between 16 h and 10 days after admission in these four cases. Two patients died, one patient required permanent hemodialysis, and two patients recovered fully only after prolonged and complicated hospitalizations. The pathogenesis of this syndrome is uncertain. In two cases, serum levels of TNF-alpha, IL-1 beta and IL-6 were measured by ELISA. In both cases serum IL-6 was markedly increased, and in one case serum TNF-alpha was also elevated. CONCLUSION: Occult salicylate intoxication should be considered when apparent sepsis syndrome occurs without a readily easily identifiable source of infection.

Glomerular hemodynamic effects of dietary polyunsaturated fatty acid supplementation.

Dietary supplementation with polyunsaturated fatty acids (PUFAs) has been shown to alter the course of experimental renal disease. Although hemodynamic factors such as glomerular hypertension are felt to be important in the progression of renal disease, the effects of dietary PUFA supplementation on glomerular hemodynamics are unknown. The present investigation, therefore, was designed to evaluate the glomerular hemodynamic effects of dietary PUFA supplementation in normal rats. Male Sprague-Dawley rats were fed standard chow supplemented with either 20% (wt/wt) fish oil (FO) as a source of omega-3 PUFAs, 20% sunflower oil (SO) as a source of omega-6 PUFAs, or 20% coconut oil (CO) as a control diet. Micropuncture studies were performed after 4 to 6 weeks of dietary supplementation. Compared with CO rats, SO rats did not demonstrate any changes in glomerular hemodynamics. However, rats supplemented with FO demonstrated significant (p less than 0.05) increases in both single nephron glomerular filtration rate and single nephron plasma flow. These hemodynamic changes were not associated with alterations in glomerular capillary hydraulic pressure or the glomerular ultrafiltration coefficient. The increase in SNPF was primarily the consequence of a 37% reduction (p less than 0.05) in efferent arteriolar resistance. Thus dietary FO supplementation resulted in glomerular hyperfiltration and hyperperfusion. These hemodynamic actions may have important consequences in determining the effect of omega-3 PUFAs on the course of experimental and clinical renal disease.

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.

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.

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.