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To determine whether the renal nitric oxide (NO) system has a role in the pathogenesis of polycystic kidney disease (PKD) in Han:Sprague-Dawley (SPRD) rats, the NO synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), 70 mg/L, or L-arginine, 0.5 g/L, was administered to heterozygous diseased (cy/+) and homozygous normal animals. Urine nitrate and nitrite excretion was reduced by L-NAME treatment and, in the male cy/+ rats, increased by L-arginine administration. The administration of L-NAME significantly increased blood pressure in all groups, whereas L-arginine had no effect. L-NAME and L-arginine had a modest but significant overall effect on the severity of cystic disease in male rats, reflected by relative kidney weights and cyst volume densities. This effect was gender dependent because it was not observed in female animals. The administration of L-NAME resulted in a significant increase in plasma creatinine concentration of the cy/+ rats, which was more marked in male than female animals. These observations support the recently reported gender differences in the renal NO system and a small role for NO synthesis that can be inhibited by L-NAME in the pathogenesis of PKD in Han:SPRD rats. These observations do not exclude a more important role for the endogenous renal NO production in the pathogenesis of PKD in view of a recent report of a major NOS resistant to conventional inhibitors in the rat kidney.

Urinary tract infections (UTI) due to gram-negative bacteria are a serious complication in patients with polycystic kidney disease (PKD). Endotoxin, a component of the cell wall of gram-negative bacteria, has been reported to be pro-cystogenic in experimental animals. Because endotoxin levels in urines (endotoxiuria) from PKD patients have not been reported, the Limulus amebocyte lysate (LAL) assay, which detects picogram quantities of endotoxin, was used to probe for this cyst-promoting chemical. Fifteen PKD patients (seven females, eight males), asymptomatic for UTI, were tested and compared with 10 female and 10 male controls. All urines were assessed for (1) evidence of aerobic bacteria by routine quantitative cultures, (2) bacteria and pyuria by microscopic examination of gram-stained urine, and (3) bacterial endotoxin by the LAL assay. LAL tests were positive in 73% (11/15) of PKD patients, but only 25% (5/20) of controls (P = 0.0058). There was no significant difference in test positivity between PKD females (71%) and males (75%). There was no correlation of age, degree of renal dysfunction, or urine osmolality with endotoxiuria. Routine quantitative cultures were negative for gram-negative bacteria in PKD patients and all controls (except one female), as were microscopic findings for intact bacteria and pyuria. Thus endotoxiuria, in the absence of classical signs, symptoms, and microbiological findings of UTI, raises the possibility that endotoxin is available intrarenally to promote cystogenesis even before a potential susceptibility of PKD patients to classical UTI is manifested. Sources of urinary endotoxin observed in PKD patients, such as cryptic intrarenal sites or leakage from the gastrointestinal (GI) tract, remain to be defined.

Infections involving cysts of patients with autosomal-dominant polycystic kidney disease (PCKD) are often refractory to therapy possibly because of poor penetration of antibiotics into cyst fluid. Ten patients with PCKD had blood urine and cyst fluid sampled at surgery or autopsy for antibiotic concentrations. Cysts were categorized as to their nephron site of origin by cyst fluid sodium concentrations. Drugs active against anaerobes such as metronidazole and clindamycin were present in therapeutic concentrations in both proximal and distal cysts. Ampicillin and trimethoprim-sulfamethoxazole had the best profiles considering likely infecting organisms and the antibiotic concentrations achieved in both type of cysts. It is likely that prolonged therapy with both of these drugs is necessary to insure therapeutic success. Other drugs that can be detected in cysts are lipid soluble, undergo tubular secretion, or have high pKa values. These include erythromycin, vancomycin, and cefotaxime. Aminoglycosides because of their predominant glomerular filtration and thus low filtration rate per single cystic nephron are undetectable in both proximal and distal cysts. Clinically, alternatives to aminoglycosides should be chosen for infected cysts in PCKD.

Urinary doubly refractile lipid bodies (oval fat bodies) are observed most frequently in patients with heavy proteinuria resulting from glomerular disease. We observed doubly refractile lipid bodies (DRLB) in the urine sediment of 60% of 35 patients with autosomal dominant polycystic kidney disease (ADPKD). All patients had clinical courses typical of ADPKD, and none exhibited the features of a second, unrelated renal disease. DRLB in the urine were correlated with a urine dipstick protein reading exceeding trace. Age, sex, BP, and serum creatinine concentration were not associated with the presence of DRLB in the urine. Examination of cyst fluid obtained from kidneys of six ADPKD patients revealed DRLB in 80% of cyst fluid samples that contained degraded blood (so-called chocolate cysts). The DRLB in cyst fluid were morphologically indistinguishable from those observed in urine, and DRLB from both sources were stained with oil red O. We conclude that urinary DRLB are a clinical feature of ADPKD.