RNA metabolism in uremic patients: accumulation of modified ribonucleosides in uremic serum. Technical note

To determine the metabolism of ribonucleic acid (RNA) in uremia, serum and urine levels of ribonucleosides in uremic patients were analyzed using reversed-phase high-performance liquid chromatography. The serum levels of xanthosine and all modified ribonucleosides were increased in undialyzed patients with chronic renal failure (CRF), and patients undergoing hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD). The serum level of pseudouridine was markedly increased in all the uremic patients especially CAPD patients (32 times higher than normal). By contrast, the serum level of adenosine did not show any significant change in the uremic patients. Interestingly, the serum and urine levels of inosine were significantly decreased in all the uremic patients, suggesting that the production of inosine is decreased in uremic patients. The serum level of uridine was significantly elevated only in the HD patients. The serum levels of all ribonucleosides except inosine and uridine decreased significantly after HD. The urinary excretion of inosine, 1-methyladenosine, 1-methylguanosine, N2,N2-dimethylguanosine and N4-acetylcytidine was significantly decreased in the CRF patients, leading to the accumulation of these modified ribonucleosides in the uremic serum. CAPD patients showed markedly increased serum levels of modified ribonucleosides such as pseudouridine, 1-methylinosine, and N2,N2-dimethylguanosine and N4-acetylcytidine as compared with the HD patients. These results demonstrate that there was an altered metabolism of RNA in uremic patients with marked accumulation of modified ribonucleosides.     

Effect of oral diazepam on the sensitivity of upper airway reflexes

Chronic renal failure was induced in 3-month-old male rats by 5/6 nephrectomy. Potency and fertility studies were performed after 3 months of chronic uremia. The mean serum testosterone at the end of the experiments was significantly lower: 0.96 +/- 0.14 ng/mL compared to a control group of sham-operated male rats, 2.86 +/- 0.59 ng/mL, p < .001. All the uremic male rats had normal accessory gland weights at the end of the study. Fertility and, in most animals, sexual behavior and mating were not different from the normal control group. It is concluded that in 5/6-nephrectomized uremic male rats, in spite of low testosterone level, fertility and reproductive system are maintained similar to normal control male rats.     

Low nitrogen diets preserve nutritional status but not residual renal function in rats with severe renal failure

The effects of low nitrogen diets (oral and parenteral) on nutritional status and residual renal function were evaluated in rats with experimentally induced severe renal failure (partial nephrectomy) and compared with the effects of a normal protein diet. Non-uremic rats were used as controls. Muscle protein synthesis was significantly lower in uremic rats fed a normal protein diet than in those fed low protein diets. Values for serum insulin-like growth factor 1 (IGF-1) were significantly lower than for controls in all uremic groups as were the wet and dry weights of skeletal muscle. The glomerular filtration rate was studied after 3 wk of nutritional intervention. Serum creatinine concentration was lower and creatinine clearance greater in uremic rats given the low nitrogen dietary treatments (both oral and parenteral) compared with those fed the normal protein diet. However, the glomerular filtration rate determined with 51Cr-EDTA clearance did not differ between uremic rats with normal and low protein intake. Thus, a low nitrogen diet had positive effects on uremic toxicity and did not compromise nutritional status. The results do not, however, establish a favorable influence on residual renal function and emphasize the need for reliable methods for studying dietary effects on renal function in uremia.     

Renal excretion of pyruvate, lactate and alpha-ketoglutarate in kidney donors before and after nephrectomy and in patients with terminal uremia

The excretional patterns of lactate, pyruvate and alpha-ketoglutarate have been investigated in 7 patients with terminal uremia and in 10 kidney donors with normal renal function before and after unilateral nephrectomy. Methods for analysis of the three substances in urine were elaborated. In all patients, the levels of renal excretion of lactate and pyruvate were very low, and clearance values were independent of the glomerular filtration rate (GFR). alpha-ketoglutarate clearance varied to some extent with renal function, but no correlation to GFR was found, and exceeded the GFR in uremic patients, indicating that the net result of renal handling of alpha-ketoglutarate may be a tubular secretion.     

Moderate amplifications of the c-myc gene correlate with molecular and clinicopathological parameters in colorectal cancer

Advanced glycation end product (AGE) formation is related to hyperglycemia in diabetes but not in uremia, because plasma AGE levels do not differ between diabetic and nondiabetic hemodialysis patients. The mechanism of this phenomenon remains elusive. Previously, it was suggested that elevation of AGE levels in uremia might result from the accumulation of unknown AGE precursors. The present study evaluates the in vitro generation of pentosidine, a well identified AGE structure. Plasma samples from healthy subjects and nondiabetic hemodialysis patients were incubated under air for several weeks. Pentosidine levels were determined at intervals by HPLC assay. Pentosidine rose to a much larger extent in uremic than in control plasma. Pentosidine yield, i.e., the change in pentosidine level between 0 and 4 wk divided by 28 d, averaged 0.172 nmol/ml per d in uremic versus 0.072 nmol/ml per d in control plasma (P < 0.01). The difference in pentosidine yield between uremic and control plasma was maintained in samples ultrafiltrated through a filter with a 5000-Da cutoff value and fortified with human serum albumin (0.099 versus 0.064 nmol/ml per d; P < 0.05). Pentosidine yield was higher in pre- than in postdialysis plasma samples (0.223 versus 0.153 nmol/ml per d; P < 0.05). These results suggest that a large fraction of the pentosidine precursors accumulated in uremic plasma have a lower than 5000 Da molecular weight. Addition of aminoguanidine and OPB-9195, which inhibit the Maillard reaction, lowered pentosidine yield in both uremic and control plasma. When ultrafiltrated plasma was exposed to 2,4-dinitrophenylhydrazine, the yield of hydrazones, formed by interaction with carbonyl groups, was markedly higher in uremic than in control plasma. These observations strongly suggest that the pentosidine precursors accumulated in uremic plasma are carbonyl compounds. These precursors are unrelated to glucose or ascorbic acid, whose concentration is either normal or lowered in uremic plasma. They are also unrelated to 3-deoxyglucosone, a glucose-derived dicarbonyl compound whose level is raised in uremic plasma: Its addition to normal plasma fails to increase pentosidine yield. This study reports an elevated level of reactive carbonyl compounds ("carbonyl stress") in uremic plasma. Most have a lower than 5000 Da molecular weight and are thus partly removed by hemodialysis. Their effect on pentosidine generation can be inhibited by aminoguanidine or OPB-9195. Carbonyl stress might contribute to AGE modification of proteins and thus to clinically relevant complications of uremia.     

Surgically curable and incurable scirrhous carcinomas of the stomach

In the present study we investigated the direct effects of potential uremic toxins on the energy metabolism of cultured cardiac myocytes. High-energy phosphates were extracted with perchloric acid and determined by high performance liquid chromatography. Energy charge (calculated from the ratio of [ATP], [ADP] and [AMP] was significantly reduced by 20 mM urea and the combination of creatinine (5 mM) plus urea (200 mM). On the other hand, perfusion with culture media containing clinically relevant amounts of urea (20 mM) or creatinine (1 mM) increased the PCr/ATP ratio. This effect was more pronounced after application of an artificial uremic medium (consisting of uremic serum, urea, creatinine and cytokines) or high amounts of creatinine (5 mM) plus urea (200 mM). As contractility of myocytes is reduced due to application of uremic compounds or uremic serum, we attribute changes in contraction frequency or inotropy to dysregulation of calcium availability within the cell. In fact, the cardiodepressive action of uremic serum (2.5%) could be completely reversed by the calcium agonist, Bay K 8644, thus indicating disturbances in myocardial calcium homeostasis in uremia. Altered calcium regulation by uremic toxins might therefore be responsible for the observed changes in myocardial energy metabolism. These results might contribute to the understanding of the pathogenesis of cardiac damage in end-stage renal disease.     

Increased lipase inhibition in uremia: identification of pre-beta-HDL as a major inhibitor in normal and uremic plasma

The hypertriglyceridemia commonly observed in uremia has been attributed to an abnormally high inhibitor activity in plasma for lipoprotein lipase (LPL) and hepatic lipase (HL), both of which have a key role in lipoprotein metabolism. The purpose of this investigation was to establish a relationship between plasma lipase inhibitor activity and hypertriglyceridemia, identify the main plasma lipase inhibitor, and determine the basis for the greater inhibitor activity in uremia. In a mixed population of normal (N = 8) and uremic subjects (N = 12), log-transformed plasma triglycerides correlated with both inhibitor activity and uremic status. However, inhibitor activity was the only retained predictor variable for triglycerides in a multiple linear regression model (r = 0.91; P < 0.0001). An inhibitor isolated from normal plasma was identified as a particle containing apolipoprotein A-I (apo A-I) and 3% phospholipid. This particle, which has pre-beta electrophoretic mobility and a Stokes' radius of 54 A, therefore corresponds to a form of the previously described pre-beta-HDL (free apo A-I) in the non-lipoprotein fraction of plasma. Comparison of normal and uremic plasma indicated that the greater lipase inhibitor activity in the latter could be attributed to an increased concentration of apo A-I in the non-lipoprotein fraction of plasma (pre-beta-HDL), as well as to increased inhibition by the uremic lipoproteins. The increased plasma lipase inhibitor activity may be important in the pathogenesis of hypertriglyceridemia in chronic renal failure.     

Evaluation of cardiac 31P magnetic resonance spectroscopy: reviewing NMR principles

Methylguanidine, guanidinoacetic acid and guanidinosuccinic acid are endogenous substances in body tissues. Extremely high levels of these substances are known to be related to the pathogenesis of epilepsy and renal failure such as uremia. In this study it was demonstrated that methylguanidine, guanidinoacetic acid and guanidinosuccinic acid, and arginine generate hydroxyl radicals in aqueous solution. These findings suggest that a high level of guanidino compounds accumulating near or within cells such as neurons (in an epileptogenic focus) or nephrons (in uremic patients) may cause free radical damage leading to these clinical disorders. Arginine may have a similar role in the pathogenesis of hyperarginemia.     

Uremic medium increases cytokine-induced PAI-1 secretion by cultured endothelial cells

The overall fibrinolytic activity is depressed in patients with chronic renal failure where a prothrombotic state is described, thereby enhancing the risk of vascular occlusive events. The mechanism responsible for fibrinolysis derangement has not yet been elucidated. To evaluate the effect of the uremic environment on the fibrinolytic activity of endothelial cells, we studied plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) production by human umbilical vein endothelial cells (HUVEC) in culture, exposed either to uremic or normal sera, before and after cytokine stimulation. Twenty uremics were studied: 11 were on conservative dietary treatment and nine were on maintenance hemodialysis. Eight healthy subjects served as controls. Before cytokine stimulation, no difference in the HUVEC supernatant concentration of t-PA and PAI-1 was found among the groups studied. After stimulation with interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha, the HUVEC supernatant levels of PAI-1 in the uremics were higher than in the controls, whereas the supernatant levels of t-PA did not differ. Our data provide evidence that uremic serum, in concert with IL-1 or TNF-alpha, can enhance PAI-1 secretion by endothelial cells, thereby depressing the fibrinolytic system. This impaired endothelial fibrinolytic response to hypercoagulation could favor vascular events, which are the major cause of morbidity and mortality in patients with chronic uremia.     

Pulmonary complications of azotemia. A case of uremic lung

The authors studied the problem of pulmonary complications in acute and chronic uremia. They recalled the main characteristics of haemodynamic oedemas which can accompany the periods of left ventricular insufficiency during the evolution of uremia. They analized the characteristicsof the classic uremic lung representing in fact only a variety of lesional oedema in which the toxic effect of urea is controversial. Ventilatory consequences of chronic uremia were briefly exposed.     

Prevention of phosphate-induced progression of uremia in rats by 3-phosphocitric acid

Male Sprague-Dawley rats were rendered uremic by surgical removal of 70% of functioning renal mass. This produced a rapid threefold rise in serum creatinine to 0.87 +/- 0.067 (SEM) mg/dl at 2 weeks postoperatively which declined subsequently to a value of 0.64 +/- 0.06 (SEM) and remained stable thereafter for an additional 4 weeks in animals maintained on a diet with normal phosphate content. Increase of dietary phosphate content to 2.2% at 2 weeks after surgery produced a significant and progressive increase in serum creatinine to values fourfold higher than the mean values in comparable partially nephrectomized control animals maintained on a diet with normal phosphate content (P less than 0.001). This deterioration in renal function was associated with extensive nephrocalcinosis, tubular dilatation, cellular necrosis, and marked interstitial inflammation. 3-phosphocitric acid, a compound which has been shown to prevent calcium phosphate crystal growth as well as to prevent in vivo nephrocalcinosis, was very effective in preventing this phosphate-induced deterioration of renal function and in preventing any significant increase in renal calcium content in animals fed a high phosphate diet. This compound was also effective in preventing the renal histologic changes associated with phosphate-induced uremia.     

Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure

We previously demonstrated the presence of advanced oxidation protein products (AOPP), a novel marker of oxidative stress in the plasma of uremic patients receiving maintenance dialysis. The present study in a cohort of 162 uremic patients showed that plasma concentrations of AOPP increased with progression of chronic renal failure and were closely related to advanced glycation end products (AGE)-pentosidine (r = 0.52, p < 0.001), taken as a marker of AGE. In vivo, the relevance of AOPP and AGE-pentosidine in monocyte-mediated inflammatory syndrome associated with uremia was evidenced by close correlations between AOPP or AGE-pentosidine and monocyte activation markers, including neopterin, IL-1R antagonist, TNF-alpha, and TNF soluble receptors (TNF-sR55 and TNF-sR75). To determine the mechanisms by which AOPP and AGE could be directly involved in monocyte activation, AOPP-human serum albumin (HSA) and AGE-HSA were produced in vitro by treating HSA with oxidants or glucose, respectively. Spectroscopic analysis confirmed that AOPP-HSA contains carbonyls and dityrosine. Both AOPP-HSA and AGE-HSA, but not purified dityrosine, were capable of triggering the oxidative burst of human monocytes in cultures. The AOPP-HSA-induced respiratory burst was dependent on the chlorinated nature of the oxidant and on the molar ratio HSA/HOCI. Collectively, these data first demonstrate that AOPP act as a mediator of oxidative stress and monocyte respiratory burst, which points to monocytes as both target and actor in the immune dysregulation associated with chronic uremia.     

Reproducibility of the acetylene rebreathe technique for determining cardiac output

Acute and subacute extrapyramidal movement disorders are rarely reported in uremic patients. We report three such cases with basal ganglia lesions. All three had advanced renal failure with high serum creatinine levels. One of the patients had a history of ischemic heart disease and acute pulmonary edema with hypoxemia. Another patient had experienced arterial hypotension during previous hemodialysis. The third had prominent metabolic acidosis. One of the patients developed generalized dyskinesias, whereas the other two developed gait disturbances. Neuroimaging studies in all three cases showed bilateral changes in the basal ganglia. The natural history was self-limiting with gradual improvement. Diminution of the basal ganglia lesions was demonstrated on follow-up imaging in two of the three cases. We conclude that acute or subacute movement disorders with bilateral basal ganglia lesions may occur in uremia. Hypoperfusion with global brain ischemia and selective vulnerability of the basal ganglia to uremic toxins may account for these lesions.     

The roles of renal catabolism and uremia in modifying the clearance of fibrinogen and its degradative fragments D and E

Elevated levels of fibrinogen/fibrin degradation products (FDP) occur in uremia, and have been thought to be in part related to intravascular coagulation in the kidney. More recent data indicated that delayed catabolism of fibrinogen fragment D occurred in anephric animals. To further evaluate FDP catabolism in the kidney, turnover studies of purified dog 131I-Fg-D and 125I-Fg-E were performed on dogs before and after acute subtotal nephrectomies, and later during chronic uremia. 131I-fibrinogen clearances were also perfomed. Slowed catabolism of Fg-D and Fg-E was observed in both the acute and chronic uremic stages. Altered urinary excretion was not a factor as only minimal amounts of Fg-D and Fg-E were excreted in the urine of the control animals. In the 131I-fibrinogen studies, there were significant changes in plasma volume, fibrinogen t 1/2, and intravascular/extravascular distribution, but not in fractional catabolic rate. To differentiate fully, the effects of uremia from those of loss of catabolic renal tissue, the Fg-D and Fg-E turnover studies were repeated on other animals with intact kidneys whose ureters were diverted into the peritoneum and compared to subsequent studies after total nephrectomy. The control and ureter-severed studies had the same clearance pattern, whereas decreased catabolism occurred in the nephrectomized dogs. The results demonstrate uremia per se does not have a major effect upon the catabolism of fibrinogen, Fg-D, and Fg-E. Loss of renal tissue does impair the clearance of Fg-D and Fg-E, indicating these proteins are normally catabolized in part by the kidneys. Thus elevated plasma FRA in uremic patients may reflect decreased Fg-D and Fg-E catabolism rather than increased FDP production from primary or secondary fibrinolysis.     

Plasma catecholamines, neuropeptide Y and leucine-enkephalin in uremic patients before and after dialysis during rest and handgrip

We have studied the effects of handgrip on plasma levels of catecholamines, neuropeptide Y (NPY), and leu-enkephalin before and after hemodialysis of uremic patients. A cuprophan dialyzer was used. We found, that dopamine level was higher in uremia group before hemodialysis both during rest (0.38 +/- 0.39 pmol/ml) and handgrip (1.13 +/- 1.00 pmol/ml) compared to control (0.17 +/- 0.19, and 0.66 +/- 0.83 pmol/ml respectively). Hemodialysis leads to further increase of its level (0.49 +/- 0.35 pmol/ml) at rest. Epinephrine level was almost the same in uremic patients before (0.43 +/- 0.51 pmol/ml) and after dialysis (0.46 +/- 0.60) as in control subjects (0.41 +/- 0.37 pmol/ml) during the rest. Its level measured after the handgrip was the highest in uremic group after dialysis (2.10 +/- 2.00 pmol/ml), significantly lower before dialysis (1.26 +/- 0.85 pmol/ml), and the lowest in control group (0.78 +/- 0.43 pmol/ml). Norepinephrine level were very similar in uremic group before dialysis (1.54 +/- 1.05 pmol/ml), after dialysis (1.79 +/- 1.29 pmol/ml) and in control group (1.46 +/- 1.06 pmol/ml) during the rest. During the handgrip test its level was higher in uremic group after hemodialysis than before it (adequate values 8.78 +/- 4.61 and 6.70 +/- 4.74 pmol/ml). The difference between uremia group before dialysis and control group did not reach significance. The level of NPY has the tendency to increase in uremic patients. Dialysis leads to following increase of its level, but the changes did not reach the significance both in rest and handgrip. Leu-enkephalin level was higher in uremic group (9.21 +/- 7.62 pmol/ml) compared to control (5.22 +/- 1.53 pmol/ml). We observed non-significant fall of this level after dialysis (6.79 +/- 4.76 pmol/ml). We found the same tendency during the handgrip, and the changes were significant. In conclusion: uremia per se leads to increase the level of dopamine and leu-enkephaline during the rest and handgrip, but the level of epinephrine only during the handgrip; dialysis leads to further increase of dopamine during the rest, but epinephrine, norepinephrine and leu-enkephaline only during the handgrip.     

Autoxidation products of both carbohydrates and lipids are increased in uremic plasma: is there oxidative stress in uremia?

BACKGROUND: Advanced glycation end products (AGEs), formed by non-enzymatic glycation and oxidation (glycoxidation) reactions, have been implicated in the pathogenesis of several diseases, including normoglycemic uremia. AGE research in uremia has focused on the accumulation of carbohydrate-derived adducts generated by the Maillard reaction. Recent studies, however, have demonstrated that one AGE, the glycoxidation product carboxymethyllysine (CML), could be derived not only from carbohydrates but also from oxidation of polyunsaturated fatty acids in vitro, raising the possibility that both carbohydrate and lipid autoxidation might be increased in uremia. METHODS: To address this hypothesis, we applied gas chromatography-mass spectrometry and high performance liquid chromatography to measure protein adducts formed in uremic plasma by reactions between carbonyl compounds and protein amino groups: pentosidine derived from carbohydrate-derived carbonyls, malondialdehyde (MDA)-lysine derived from lipid-derived carbonyls, and CML originating possibly from both sources. RESULTS: All three adducts were elevated in uremic plasma. Plasma CML levels were mainly (>95%) albumin bound. Their levels were not correlated with fructoselysine levels and were similar in diabetic and non-diabetic patients on hemodialysis, indicating that their increase was not driven by glucose. Pentosidine and MDA-lysine were also increased in plasma to the same extent in diabetic and non-diabetic hemodialysis patients. Statistical analysis indicated that plasma levels of CML correlated weakly (P < 0.05) with those of pentosidine and MDA-lysine, but that pentosidine and MDA-lysine varied independently (P > 0.5). CONCLUSIONS: These data suggest that the increased levels of AGEs in blood, and probably in tissues, reported in uremia implicate a broad derangement in non-enzymatic biochemistry involving alterations in autoxidation of both carbohydrates and lipids.     

Mechanism of erythrocyte accumulation of methylation inhibitor S-adenosylhomocysteine in uremia

We have recently demonstrated that methyl esterification of erythrocyte membrane proteins, a reaction involved in recognition and repair of specifically damaged proteins, is impaired in uremia. This is accompanied by a significant increase in intracellular S-adenosylhomocysteine (AdoHcy), a potent inhibitor of methyltransferases. AdoHcy accumulation is normally prevented by its enzymatic hydrolysis to homocysteine (Hcy) and adenosine, a reversible reaction catalyzed by AdoHcy hydrolase. To assess the contribution that Hcy offers in the elevation of AdoHcy, we measured plasma and red blood cell Hcy, AdoHcy, adenosine, and S-adenosylmethionine (AdoMet) intracellular concentrations, as well as RBC AdoHcy hydrolase specific activity, in standard hemodialysis patients and normal subjects. Plasma and red blood cell Hcy levels are significantly higher in the dialysis group, and are positively correlated to AdoHcy levels. Adenosine and AdoMet levels, and AdoHcy hydrolase specific activity are not significantly different between the two groups. The enzymatic formation of labeled AdoHcy from Hcy and tracer adenosine appears to be significantly increased, in vitro, in erythrocytes from both control and uremic patients, when 50 microM Hcy (concentration comparable to plasma levels actually found in vivo in uremic patients) is added to the incubation medium. When erythrocytes from uremic patients are incubated in vitro in absence of Hcy, a significant reduction of intracellular AdoHcy is observed with time compared to identical samples incubated in presence of 50 microM Hcy, with a T1/2 of approximately 270 minutes. The results allow us to conclude that plasma and red cell Hcy levels actually found in uremia can be effectively responsible for the intracellular accumulation of the toxic compound AdoHcy.     

Morphine reverses the inhibitory effects of repeated saline injections on peritoneal inflammation in mice

AIMS: The lipid composition of platelets and the function of these cells in patients with uremia were studied. METHODS: Fourteen patients and 14 normal volunteers were studied. Platelet lipids including phospholipids and cholesterol, as well as the platelet aggregation response to agonists, were studied. RESULTS: The amount of platelet phospholipids was decreased in patients compared to controls (338.0 +/- 79 vs. 511.6 +/- 125 nmol/10(9) cells; p < 0.001), while the percentage of the five main specimens of these compounds was normal. The content of platelet cholesterol in patients (97.8 +/- 17.0 microg/10(9) cells) was similar to that in controls (91.7 +/- 26.0 microg/10(9) cells). Consequently, the cholesterol:phospholipid ratio in uremic platelets was increased (0.75 +/- 0.1 vs. 0.46 +/- 0.1; p < 0.01). Although this feature is associated with hyperreactive platelets, the aggregation tests were defective for adenosin diphosphate (p < 0.01), arachidonic acid (p < 0.01), epinephrine (p < 0.01) and collagen (p < 0.001). This behavior is probably due to the multifactorial platelet defect described in uremia.     

Uremia in the rat affects gastric cell growth and differentiation

The aim of this study was to determine if hypertrophy of different tissues seen in uremic rats included gastrointestinal hypertrophy and an increase in parietal cell mass that might explain the increased acid secretion we previously reported. Chronic renal failure was induced by subtotal nephrectomy. Despite a lower total body weight, uremic rats had a significantly greater stomach weight (33%), corpus area (13%), corpus mucosal height (19%), and parietal (32%) and enterochromaffin-like (ECL, 54%) cell density, but a 16% decrease in mucous neck cell region height. These findings suggest that uremia leads to gastric stem cell stimulation with differentiation favoring parietal and ECL cells over mucous cells. In addition, in uremic rats there was an increase in height of the duodenal mucosa, but not of the ileal or transverse colon mucosa. In conclusion, the present study shows that uremia in the rat promotes hypertrophy of the stomach with cell differentiation favoring parietal cells over mucus cells. The increase in parietal cell mass may explain the increased acid secretion in these rats.