Effect of pyrazinamide and probenecid on peritoneal urate transport kinetics during continuous ambulatory peritoneal dialysis.

OBJECTIVE: We administered pyrazinamide (PZA) and probenecid (PB) --two well-known modulators of urate transport via the proximal tubules - to evaluate their impact on urate transport through the peritoneal membrane and to clarify mechanisms affecting peritoneal transport. SETTING: A continuous ambulatory peritoneal dialysis (CAPD) unit in 2nd Hospital of IKA (Social Services Institute), Greece. PATIENTS: In 20 stable CAPD patients, on the study day, a 4-hour, 2-L, 1.36% glucose exchange was performed (control exchange). Pyrazinamide 3 g was given orally and another identical exchange was performed (study exchange). The same protocol was repeated with 2 g PB. KtN, peritoneal clearances of urea, creatinine, and urate for each exchange, and mass transfer area coefficients (MTAC) for the three solutes and their dialysate-to-plasma concentration (D/P) ratios were used to estimate peritoneal transport. RESULTS: Administration of PZA resulted in decreased clearances and MTAC values for the three solutes. The D/P ratio decreased significantly only for urate, indicating a more intense influence of PZA on urate. After PB administration, clearances of urea, creatinine, and urate were increased. MTAC and DIP ratio increased significantly only for urate (p < 0.05), demonstrating an action similar to that exerted on renal tubules. CONCLUSIONS: These findings provide evidence that unrestricted diffusion is not the only transport mechanism in the case of urate, and demonstrate the existence of an active mechanism in peritoneal urate transport with a reabsorptive and, probably, a secretive component that resembles that of renal tubule urate transport. Attention should be given in the case of CAPD patients undergoing antituberculous (PZA) treatment: it might have a negative impact on urea, creatinine, and urate peritoneal transport rates.

The effect of mannitol and secretin on the biliary transport of urate in humans.

No evidence is available on the transport of biliary urate and the possible role of choleretic agents in the regulation of biliary urate elimination in humans. To test this hypothesis we studied the following: (1) 45 cholecystomized patients to determine urate levels in hepatic bile and gallbladder bile, and (2) 13 cholecystomized patients fitted with T-tubes to determine the effects of secretin injection (either 70 U of porcine secretin or 0.02 mg.kg-1 of synthetic human secretin, as a single dose) and/or mannitol infusion (5 cm3.min-1 for 90 minutes) on biliary urate excretion. In the latter group, samples of bile and serum were analyzed for urate under basal state and after the administration of both agents. In our first approach, results showed that urate concentrations present in hepatic as well as in gallbladder bile were much lower than the corresponding values in serum (P < .001). The mean gallbladder bile urate concentration was not significantly increased over the concentration in hepatic bile. When compared with basal state values, procine and synthetic secretin induced a significant increase in mean urate clearance (P < .001) because of a significant increase in mean bile flow (P < .001), whereas the mean biliary urate concentration significantly decreased (P < .001) with a concomitant decrease in the mean serum urate concentration (P < .02). Mannitol also induced a significant increase in the mean urate clearance (P < .002) because of a significant increase in the mean biliary urate concentration (P < .01) with a concomitant decrease in the mean serum urate concentration (P < .01) and without changes in the mean bile flow (P > .05). Therefore, it appears that a substantial amount of urate is eliminated by biliary route. The load of biliary urate excreted may be modified by mannitol and secretin and possibly other factors, a finding that could have an application in some pathological conditions associated with decreased renal urate excretion.

Value of ascitic fluid ferritin in the differential diagnosis of malignant ascites.

The ascitic fluid ferritin concentrations were compared with serum-ascites albumin gradient (SAAG), in their diagnostic ability for detection of malignancy in 60 patients with ascites: 29 with chronic liver disease alone (CLD) and 31 patients with various neoplasms. Of the patients with malignancy, 12 had liver metastases, 9 had no evidence of liver involvement, and 10 had hepatocellular carcinoma (HCC) with or without coexisting liver cirrhosis. Analysis of our data confirms that the ascitic ferritin is a more accurate indicator of malignant ascites (MA) than the SAAG. This new parameter is particularly helpful in distinguishing MA associated with HCC and/or metastatic liver disease from nonmalignant ascites due to CLD alone.

Single kidney function: early and late changes in urate transport after nephrectomy.

Renal urate transport was studied by means of pyrazinamide (PZA) and probenecid (PB): (a) before and at 2, 6, 24 weeks (24 patients), (b) 1 to 30 years after uninephrectomy in 27 and 12 patients with Ccr greater than 80 and 30 to 70 ml/min, respectively. Uninephrectomy was followed by important tubular urate transport modifications during at least two weeks, which lead to a marked uricosuria as indicated by significant increase in FEur (mean value +/- SD, 0.228 +/- 0.059 vs. 0.097 +/- 0.014 and 0.099 +/- 0.019 in normals and chronically diseased solitary kidneys). Reduced response to PZA and PB suggests a diminished reabsorptive capacity for urate mainly at the presecretory site which persisted after FENa normalization. Tubular compensations were presumably complete at six weeks, since pattern of urate transport returned to normal with an almost complete reabsorption of filtered urate load (99%) and a percentage of postsecretory reabsorption (80%) very close to those seen in normal subjects with a pair of kidneys. The adjustment in urate excretion in solitary kidneys was achieved by a significant increase of secreted urate as compared with 50% of pre-uninephrectomy values. Thus, increased urate secretion by the remaining intact organ is sufficient to maintain urate balance with a normal serum level.

Cholangiocarcinoma and severe renal hypouricemia: a study of the renal mechanisms.

Hypouricemia in malignant neoplasms is rarely reported. We present a previously unreported case of cholangiocarcinoma associated with severe persistent hypouricemia (serum uric acid levels ranged from 0.07 to 0.08 mmol/L [1.16 to 1.40 mg/100 mL], and increased urate clearance (50.90 to 57.33 mL/min v a mean value in 20 normal subjects of 9.75 +/- 1.65 mL/min). High fractional urate clearance (Cus/Ccr = 0.50 to 0.58 v 0.09 +/- 0.01 in normals) was suppressed only slightly following pyrazinamide (PZA), to 0.29 versus 0.007, and was surprisingly enhanced by probenecid (PB) to 1.78 versus 0.63 in normals. No other renal tubular or metabolic abnormalities were detected. This previously unreported association of a high PZA-nonsuppressible urate excretion with a postprobenecid urate clearance exceeding glomerular filtration rate suggests that a combined renal tubular defect is responsible for hypouricemia. The patient described here provides evidence to support the presence of a presecretory reabsorptive defect in association with a "relatively high" urate secretion by the renal tubule. This report adds to the list of hypouricemic conditions and presents an important clue to elucidate urate handling mechanisms in man.

Insulin-dependent diabetes and renal hypouricemia.

We studied 14 patients (11 women and 3 men) from 18 to 33 years old, suffering from type I diabetes mellitus with normal renal function (creatinine clearance 106.91 +/- 28.73 ml/min) and serum uric acid below 2.5 mg/dl (2.34 +/- 0.11 mg/dl) as well as a high uric acid clearance (23.04 +/- 5.92 ml/min) and fractional urate excretion (21.4 +/- 2.6) versus urate clearance 9.82 ml/min and fractional urate excretion 8.80 +/- 1.3 in 14 normal control subjects. The study of the uricosuric mechanisms was conducted by the combination of probenecid (PB) test which inhibits the reabsorption of secreted urate, and pyrazinamide (PZA) test, which inhibits its tubular secretion. The results of studies indicate that the increase in urate clearance was accounted for by increased PZA-nonsuppressible urate suggesting a decreased reabsorption of filtered urate. Increased PZA-suppressible urate excretion combined with impaired response to a uricosuric drug is consistent with impaired reabsorption of secreted urate. According to our findings, increased urate excretion in diabetic patients may be attributed to the inhibition of both filtered and secreted reabsorption. This reabsorptive tubular abnormality is consistent with the view of an interference of tubular reabsorption of glucose with the tubular capacity for uric acid reabsorption.

Monocyte locomotion in anergic chronic brucellosis patients: the in vivo effect of ascorbic acid.

In 14 patients suffering from relapsing chronic brucellosis who were anergic to brucella antigens, we have studied peripheral blood monocyte random migration and chemotaxis against non-specific and specific leukoattractants, as well as plasma and monocyte ascorbic acid levels. We found that all parameters studied, were significantly beneath normal, when compared to normal subjects. After the oral administration of ascorbic acid at a daily dose of 1gr for 15 consequetive days, random and directed migration against a non-specific stimulus (casein) returned to normal. Directed migration against disease associated leukoattractants (brucella melitensis and brucella abortus) antigens improved significantly, without reaching normal values. We concluded that ascorbic acid supplementation might partially restore peripheral, monocyte function and help the monocyte-macrophage system to mount an effective immune response against chronicity of brucella infection.

Rhabdomyolysis and acute renal failure associated with pyloric stenosis.

Rhabdomyolysis and acute tubular necrosis (ATN) are described in a patient with pyloric stenosis in whom severe hypokalemia developed due to repetitive vomiting. Furthermore, the importance of hypokalemia in the development of acute renal failure is emphasized.

Evaluation of the renal mechanisms for urate homeostasis in uremic patients by probenecid and pyrazinamide test.

The tubular transport of urate was studied in 47 uremic patients and in 20 normal subjects using probenecid and pyrazinamide tests. There was a marked increase in urate excretion per nephron as the renal function deteriorated. Presecretory reabsorption of urate per nephron, which was almost complete in normal subjects, showed a diminution with increasing severity of chronic renal failure. Until the creatinine clearance had decreased to less than 10 ml/min, the secreted urate per nephron remained almost constant, while in the end stage of renal failure it was markedly decreased. With the progression of renal disease, the postsecretory reabsorption of urate per nephron diminished. In patients with a creatinine clearance less than 10 ml/min, it was 4 times lower than in normal subjects. These findings indicate that urate secretion does not contribute to the increase of urate excretion per nephron at any level of renal failure, whereas the impairment of both reabsorptive components accounts for the augmented urate excretion per nephron in uremic patients.

Effect of peritoneal dialysis on plasma levels of ascorbic acid.

The effect of peritoneal dialysis on plasma ascorbate levels was investigated in 32 patients suffering from end-stage renal disease. Our studies demonstrated a high peritoneal clearance of ascorbic acid resulting in a significant loss into the dialysate. The quantity of ascorbic acid lost by patients undergoing peritoneal dialysis was proportional to the predialysis ascorbic acid levels. Since the ascorbic acid lost from the plasma during peritoneal dialysis is not adequately replaced by dietary consumption of vitamin C, patients undergoing chronic peritoneal dialysis should receive ascorbic acid supplementation as an important part of their therapeutic regimen.