Effect of pitavastatin on urinary liver-type fatty-acid-binding protein in patients with nondiabetic mild chronic kidney disease

BACKGROUND/AIM: Urinary liver-type fatty-acid-binding protein (L-FABP) is a useful clinical marker in the monitoring of chronic kidney disease (CKD) associated with tubulointerstitial damage. Statins have been shown to be effective in the treatment of renal disease. The aim of the present study was to determine whether pitavastatin, a newly developed statin, modulates the urinary L-FABP levels in normolipidemic patients with CKD. METHODS: Thirty normolipidemic mild CKD patients (18 males and 12 females, mean age 40 years, mean serum creatinine level 1.0 mg/dl) were randomly assigned to two groups: (1) pitavastatin (1 mg/day, n = 15) and (2) placebo (n = 15). Urinary protein and urinary L-FABP levels were measured before the initiation of treatment and 3 and 6 months thereafter. Twenty age-matched healthy subjects were also studied as controls. RESULTS: Before treatment, the urinary L-FABP levels in 30 CKD patients (84.0 +/- 68.5 microg/g creatinine) were significantly higher than those of healthy subjects (6.4 +/- 4.2 mug/g creatinine; p < 0.001). Pitavastatin slightly reduced serum total cholesterol and triglyceride levels, but this was not statistically significant. However, pitavastatin reduced the urinary protein excretion from 1.8 to 1.0 g/day (p < 0.01), while the urinary L-FABP levels fell from 88.5 +/- 70.5 to 28.0 +/- 16.5 mug/g creatinine (p < 0.01). CONCLUSION: The present data suggest that pitavastatin ameliorates tubulointerstitial damage in CKD patients independent of the lipid-lowering effect.     

Beneficial effect of aspirin on renal function in patients with renal insufficiency postcardiac surgery

AIM: Renal function is one of the most important prognostic factors following cardiac surgery. Whether aspirin affects cardiopulmonary bypass related renal injury is investigated in this study. METHODS: Ninety-four patients with impaired renal function (creatinine = or >1.5 mg/dl) undergoing coronary artery bypass grafting (CABG) were categorized into 2 groups according to aspirin administration before surgery. Serum creatinine, urinary output and creatinine clearance along with other perioperative factors were compared between the 2 groups prior to surgery, 24 hours and 48 hours following cardiopulmonary bypass. RESULTS: Creatinine levels increased significantly in the second postoperative day only in the non-aspirin (control) group (3.7+/-1.6 vs 2.9+/-1.7 mg/dl, p=0.03). Aspirin (study) group had lower creatinine levels in day 1 (p=0.03) and day 2 (p=0.001). Furthermore, in the study group creatinine clearance was higher in day 1 (34.3+/-14.3 vs 30.9+/-13.1 ml/min, p=0.01) and in day 2 (32.6+/-13.8 vs 26.4+/-9.8 ml, p<0.0001). Creatinine levels at discharge were elevated compared to the preoperative levels in the control group (p=0.01). However, the study group had lower creatinine levels at discharge (2.6+/-1.4 vs 3.8+/-1.6 mg/dl, p<0.0001). Urinary output was higher in the study group in the first postoperative day compared to the control group (p=0.01). Postoperative bleeding was slightly increased in the study group compared to the control group (760+/-230 ml vs 530+/-210 ml, p=0.01). CONCLUSIONS: Continuation of aspirin administration until the day of surgery may have a protective effect against renal injury resulting from cardiopulmonary bypass, with only a negligible increase in bleeding. Possible explanations for this effect are antiplatelet activity of aspirin during cardiopulmonary bypass causing inhibition of vasoconstrictive agents like thromboxane, and improvement of renal perfusion by reducing blood viscosity.     

Frequency of urolithiasis in individuals seropositive for human immunodeficiency virus treated with indinavir is higher than previously assumed

PURPOSE: Indinavir was approved by the Food and Drug Administration in 1996 as a human immunodeficiency type 1 protease inhibitor to treat human immunodeficiency virus infection. Prompted by the high number of patients receiving indinavir who present with renal colic at our institution, we performed a detailed investigation of the true frequency of urolithiasis during indinavir treatment. MATERIALS AND METHODS: We evaluated 105 patients with a mean age of 38.1 years who were treated with indinavir from 1996 to 1997. Before indinavir treatment was initiated all patients underwent renal ultrasonography, urinalysis, and determination of serum sodium, potassium, calcium, uric acid and creatinine. It was recommended that all patients drink 2 l of fluids daily, and all remained under continuous surveillance. RESULTS: Metabolic evaluation and ultrasonography showed no abnormality in any case. A stone episode occurred in 13 men (12.4%) as renal colic during observation. Colic recurred in 1 patient after 2 and 5 months, and in 1 after 2 months. Median duration of indinavir treatment until an acute stone episode was 21.5 weeks (range 6 to 50). A total of 12 stones passed spontaneously. Three patients underwent ureteroscopic calculous removal and 1 was treated with extracorporeal shock wave lithotripsy. CONCLUSIONS: Despite adequate patient information and compliance the rate of nephrolithiasis during indinavir therapy was 12.4%.     

Renal toxicity of interleukin-2 administration in patients with metastatic renal cell cancer: effect of pre-therapy nephrectomy

Systemic administration of interleukin-2 and lymphokine-activated killer cells is a new approach to the immunotherapy of advanced cancer. Metastatic renal cell cancer is one of the histological types of tumors particularly susceptible to this treatment approach although renal toxicity often is a dose-limiting side effect. We compared the renal functional changes observed during interleukin-2 therapy in 52 consecutive patients with advanced renal cancer to that of 83 consecutive patients with metastatic nonrenal cancer. Of the 52 patients with renal cancer 41 had recently undergone nephrectomy. The over-all peak serum creatinine values and the percentage increase of serum creatinine over baseline for all patients studied were significantly higher in cycle 2 of interleukin-2 therapy than in cycle 1: 3.8 +/- 0.2 versus 2.6 +/- 0.1 mg. per dl. and 241.7 +/- 16.5 versus 140.3 +/- 11.0 per cent, respectively. In patients with pre-therapy serum creatinine values of 0.4 to 0.9 mg. per dl. there were no significant differences in the mean peak serum creatinine nor in the percentage increase over baseline between renal and nonrenal cancer patients during cycle 1. In cycle 2 of therapy these values were higher in the renal cancer group (3.6 +/- 0.8 versus 2.4 +/- 0.2 mg. per dl. and 310.4 +/- 103.5 versus 214 +/- 30.4 per cent, respectively) but they did not reach statistical significance (P2 = 0.08 and 0.25, respectively). Renal and nonrenal cancer patients with pre-therapy serum creatinine levels of 1.0 to 1.4 mg. per dl. achieved similar high values in cycle 2 of interleukin-2 therapy (3.9 +/- 0.3 versus 3.9 +/- 0.4 mg. per dl. and 222.7 +/- 23.2 versus 248.7 +/- 33.5 per cent, respectively), although the initial increase (cycle 1) was higher in the renal cancer patients (3.3 +/- 0.3 versus 2.4 +/- 0.2 mg. per dl. and 172.3 +/- 25.9 versus 116.1 +/- 18.0 per cent, respectively). Baseline serum creatinine greater than or equal to 1.5 mg. per dl. was associated with an over-all higher peak serum creatinine and higher percentage increase of serum creatinine over baseline than that below 1.5 mg. per dl. baseline: 4.4 mg.per dl. and 171.1 +/- 36.3 per cent in cycle 1 and 6.5 +/- 0.7 mg. per dl. and 296.1 +/- 44.0 per cent in cycle 2, respectively (p less than 0.01). There was no association between peak serum creatinine and interval from nephrectomy to interleukin-2 therapy.(ABSTRACT TRUNCATED AT 400 WORDS)     

Characteristics of the patients with diabetic nephropathy with relatively low serum creatinine at the initiation of dialysis

Clinical feature and creatinine metabolism were studied in 86 diabetic patients who had newly initiated dialysis treatment. In 32.5% of the patients, serum creatinine was below 8.0 mg/dl at the initiation of dialysis treatment. Gastrointestinal symptoms, general malaise, pulmonary edema and uremic encephalopathy were the causes which required dialysis treatment in those patients, and the frequency of pulmonary edema was significantly higher than in patients whose serum creatinine was above 8.0 mg/dl at the initiation of dialysis (p less than 0.05). There were no significant differences in serum urea nitrogen, potassium, sodium, albumin levels and hematocrit between low serum creatinine group (3.0-7.9 mg/dl) and high serum creatinine group (8.0-11.9 mg/dl) at the initiation of dialysis. Serum creatinine levels were highly correlated with creatinine generation rate (r = 0.788, p greater than 0.01). There was a significant correlation between creatinine generation rate and muscle volume (r = 0.863, p less than 0.001). Muscle volume of diabetic dialyzed patients was 29.5 +/- 7.0 cm3/cm in males and 26.9 +/- 5.0 cm3/cm in females, and those values were lower than those of non-diabetic dialyzed patients (p greater than 0.005). Frequency of the patients whose creatinine generation rate was below 1500 mg/day was 81.3% in diabetic hemodialyzed patients and this was significantly higher than in non-diabetic hemodialyzed patients (p less than 0.005). In conclusion, in patients with diabetic nephropathy who have to initiate dialysis treatment, uremic symptoms have progressed though serum creatinine levels are relatively low. This low serum creatinine levels in patients with diabetic end-stage renal disease are resulted from their low muscle volume.     

Low risk of contrast nephropathy in high-risk patients undergoing spiral computed tomography angiography with the contrast medium iopromide and prophylactic oral hydratation

BACKGROUND: Spiral computed tomography angiography (CTA) is a sensitive and specific technique for visualizing renal arteries and diagnosing renal artery stenosis (RAS). Whether spiral CTA is associated with increased risk of contrast nephropathy (CN) in patients with impaired renal function is unknown. METHODS: We prospectively studied 50 patients with chronic renal insufficiency (serum creatinine concentration greater than 1.58 mg/dl) who underwent spiral CTA with iopromide, a nonionic, low-osmolar contrast agent. Fourteen patients had diabetes mellitus. Patients were encouraged to drink 1 l of water 12 hours before and 2 l over 24 hours after the procedure. The presence of CN was defined by an increase of 20% or more in the baseline serum creatinine level within or 72 hours after administration of the radio-contrast agent. RESULTS: In the entire group, mean serum creatinine levels increased significantly from 2.92 +/- 1.39 to 3.06 +/- 1.55 mg/dl (p = 0.02) and mean creatinine clearance decreased from 29.8 +/- 12.9 to 28.9 +/- 12.8 ml/min (p = 0.009) 72 h after administration of the contrast medium. Two patients experienced an increase in serum creatinine level of 20%. Renal function returned to baseline within seven days in the 2 patients. Absolute changes in creatinine clearance after the administration of radiocontrast medium were similar in nondiabetic and diabetic patients and in the subgroup of patients, with a baseline serum creatinine of < 3 mg/dl and > or = 3 mg/dl. CONCLUSIONS: In patients with chronic renal insufficiency, spiral CTA performed with iopromide, a nonionic, low-osmolar contrast medium and a prophylactic oral hydratation, is a minimally invasive technique with low risk of contrast nephropathy.     

Prevalence of nephropathy in black patients with type 2 diabetes mellitus

The prevalence of nephropathy in black patients with type 2 diabetes mellitus is poorly defined. We performed a cross-sectional analysis of 98 unrelated and unselected black type 2 diabetic patients treated in indigent care internal medicine clinics to determine the prevalence of proteinuria and nephropathy. Serum creatinine, blood urea nitrogen, urine albumin and urine creatinine concentrations were measured. A Spearman's rank correlation was computed to test for a relationship between diabetes duration and continuous outcomes. For binary outcomes, an odds ratio and 95% confidence interval were computed for a change of 10 years diabetes duration based on logistic regression. Cases were 61% female, and had mean (+/- SD) age 59.9 +/- 12.5 years, diabetes duration 12.6 +/- 9.4 years, body mass index 32.4 +/- 9.3 kg/m(2), hemoglobin A1C (HbA1C) 9.2 +/- 2.3%, and serum creatinine concentration 1.60 +/- 1.1 mg/dl. For continuous variables, diabetes duration was positively associated with albuminuria (r = 0.31; p = 0.0017), serum creatinine (r = 0.36; p = 0.0003) and blood urea nitrogen concentration (r = 0.36; p = 0.0003). For binary variables, cases with longer diabetes duration were at increased risk for urinary albumin:creatinine >300 microg/mg (p = 0.006), elevated serum creatinine concentration (> or = 1.4 mg/dl in women or > or = 1.6 mg/dl in men; p = 0.045), elevated blood urea nitrogen concentration (> or = 20 mg/dl; p = 0.026), and clinical cerebrovascular disease (p = 0.028). HbA1C, body mass index, and blood pressure did not correlate with diabetes duration in this population. Among the cases, 33.7% had elevated serum creatinine concentration and 71.5% had abnormal levels of albuminuria (27.6% > 300 microg albumin/mg Cr and 43.9% 30-300 microg albumin/mg Cr). Abnormal proteinuria was seen in the majority of black patients with poorly controlled type 2 diabetes mellitus treated in indigent care clinics. This prevalence may be conservative, due to the widespread use of angiotensin-converting enzyme inhibitor therapy and exclusion of cases treated only by nephrologists. Approximately 70% of black patients with type 2 diabetes cared for in indigent care clinics have abnormal proteinuria and are at heightened risk for ESRD and death.     

Pre-operative renal function predicts development of chronic renal insufficiency after orthotopic heart transplantation.

BACKGROUND: Risk factors for the development of chronic renal insufficiency after solid-organ transplantation remain unclear. METHODS: We conducted a 5-year retrospective analysis of all adult patients (n = 160) who survived >1 year after orthotopic heart transplantation at our institution from 1985 through 1992. Study subjects were classified into 3 groups based on peri-operative renal function: (1) pre-operative creatinine concentration <1.5 mg/dl and a post-operative (first 4 days) creatinine <2.0 mg/dl (n = 75); (2) pre-operative creatinine of <1.5 mg/dl but a post-operative creatinine of >2.0 mg/dl (n = 47); (3) pre-operative creatinine of >1.5 mg/dl (n = 38). The association between development of chronic renal insufficiency and peri-operative renal dysfunction was evaluated using the Cox proportional hazard model. RESULTS: A total of 47 (29.4%) patients experienced chronic renal insufficiency (serial serum creatinine >2.0 mg/dl on 2 or more monthly examinations). The mean pre-operative serum creatinine was 1.6 mg/dl in patients who experienced chronic renal insufficiency, whereas it was 1.3 mg/dl in patients who did not (p < 0.01). The fraction of patients in whom chronic renal insufficiency developed was highest in Group 3 (55.3%), lower in Group 2 (25.5%), and lowest in Group 1 (18.7%) (p < 0.01). After adjusting for multiple potential confounding variables, including cyclosporine dosage, the risk of chronic renal insufficiency linearly decreased in the 3 groups, stratified by peri-operative renal function (relative risk, 1.82; 95% confidence interval, 1.23-2.7). However, the difference in relative risk of renal insufficiency was not statistically significant between Group 2 and Group 1. CONCLUSION: Pre-operative serum creatinine concentration predicts development of renal insufficiency after heart transplantation.     

Acute rapamycin nephrotoxicity in native kidneys of patients with chronic glomerulopathies.

BACKGROUND: Based on its success as a transplant immunosuppressor, there is intense interest in using rapamycin in the treatment of progressive glomerulopathies involving native kidneys. However, we call attention to the potential toxicity associated with the use of rapamycin in this setting. METHODS: We conducted a study to examine the efficacy and safety of rapamycin in patients with progressive chronic renal failure. Eleven patients with either focal segmental glomerulosclerosis, immunoglobulin A nephropathy, membranous nephropathy or membrano-proliferative glomerulonephritis and progressive renal failure (defined as an increase in >25% of baseline serum creatinine over the last year or loss of glomerular filtration rate > or =5 ml/min/year as determined by the Cockcroft-Gault formula), proteinuria > or =1.0 g/24 h and with a creatinine clearance of > or 20 ml/min/1.73 m(2) were entered into a 12 month study. Patients were treated with rapamycin, starting at 5 mg/day, orally, aiming for target blood levels of 7-10 ng/dl. All patients were on treatment with an angiotensin-converting enzyme inhibitor and/or an angiotensin receptor blocker, aiming to control blood pressure < or =145/90 mmHg. RESULTS: Six patients developed acute renal failure, defined as an increase in serum creatinine > or =0.5 mg/dl (baseline: 3.2+/-0.9 mg/dl; peak: 5.6+/-1.6 mg/dl; P<0.01, paired t-test). In four patients, discontinuation of the drug resulted in improvement of renal function close to baseline levels. One patient required haemodialysis and had no subsequent recovery of renal function. In another patient, renal function recovered after discontinuation of the drug and then rapamycin was resumed at a lower dose when creatinine returned to baseline. This resulted in a second acute increase in serum creatinine that failed to return to baseline when the medication was discontinued. Four other patients had the following adverse events: skin rash, severe hypertriglyceridaemia, diarrhoea and hyperkalaemia. In none of the subjects were rapamycin levels >15 ng/dl. CONCLUSIONS: Rapamycin can cause nephrotoxicity in some patients with chronic glomerulopathies. Whether the toxicity is solely related to rapamycin, due to the combination of proteinuria and rapamycin, or other unknown factor use is presently undetermined.     

Does furosemide prevent renal dysfunction in high-risk cardiac surgical patients? Results of a double-blinded prospective randomised trial.

OBJECTIVE: Renal dysfunction following cardiac surgery is more apparent in high-risk patients with pre-existing renal dysfunction, diabetes and impaired left-ventricular function, and following complicated procedures involving prolonged cardiopulmonary bypass (CPB). The aim of this prospectively randomised double-blinded placebo-controlled study was to evaluate reno-protective effect of low-dose furosemide infusion in this high-risk group. METHODS: Patients with preoperative serum creatinine >130 micromol/l (1.4 mg/dl), left-ventricular ejection fraction <50%, congestive heart failure, diabetes, or procedures involving prolonged CPB were randomised to receive either saline at 2 ml/h (n=21), or furosemide at 4 mg/h (n=21). Infusion was commenced after induction of anaesthesia and continued for 12h postoperatively. Renal dysfunction was defined as >50% increase in serum creatinine postoperatively, or >130 micromol/l (1.4 mg/dl), or requirement for haemodialysis, or all of these. In patients with preoperative serum creatinine >130 micromol/l, >50% increase over preoperative levels was used to define postoperative renal dysfunction. RESULTS: Following cardiac surgery, patients receiving furosemide had a higher urine output (3.4+/-1.2 ml/kg/h in furosemide group and 1.2+/-0.5 ml/kg/h in placebo group; p<0.001), higher postoperative fluid requirement (4631+/-1359 ml in furosemide group and 3714+/-807 ml in placebo group, p=0.011), and lower urinary-creatinine (2+/-1.3 micromol/l in furosemide group and 5.9+/-2.5 micromol/l in placebo group p<0.001). Both groups had significant increase in retinol binding protein/creatinine ratio (7.2+/-6 to 3152+/-1411 in furosemide group; 4.9+/-2.1 to 2809+/-1125 in placebo group; p<0.001) and peak serum creatinine (98+/-33 to 177+/-123 micromol/l in furosemide group; 96+/-20 to 143+/-87 micromol/l in placebo group; p<0.001), and a significant decrease in peak creatinine-clearance (64.3+/-29.4 to 39.1+/-16.6 ml/min in furosemide group; 65.5+/-38.6 to 41.8+/-17.8 ml/min in placebo group; p<0.001) following cardiac surgery, implying significant renal injury following cardiac surgery. Peak creatinine levels (177+/-123 micromol/l in furosemide group and 143+/-87 micromol/l in placebo group; p=0.35) and peak creatinine-clearance (39.1+/-16.6 ml/min in furosemide group and 41.8+/-17.8 ml/min in placebo group; p=0.61) were similar in the two groups. Importantly, there was no difference in incidence of renal dysfunction between the furosemide group (9/21) and the control group (8/21) (relative risk 1.1, 95% confidence interval 0.6-2.2; p=0.99). CONCLUSIONS: Our randomised trial did not demonstrate any benefit of furosemide-infusion postoperatively in high-risk cardiac surgical patients. Although urinary output increased with furosemide, there was no decrease in renal injury, and no decrease in incidence of renal dysfunction.     

Analysis of factors affecting the course of renal disease progression in patients with established renal insufficiency

All renal diseases ultimately progress to end-stage renal disease after renal dysfunction develops except for acute renal failure or rapidly progressive glomerulonephritis. However, renal function can be preserved for long periods in patients with mild renal insufficiency. We examined the factors affecting the progression of renal disease in patients with established renal insufficiency. We enrolled 38 patients with renal insufficiency diagnosed at the first visit and who were followed up for at least 3 years. We retrospectively recorded all information relating to serum creatinine and blood pressure levels during the follow-up periods. The patients were categorized as group A(n = 11), long-term renal survivors(at least 8 years), group B(n = 22), short-term renal survivors(3 to 8 years) and others(n = 5). Basal renal diseases were variable, and included IgA nephropathy, membranous nephropathy, focal segmental glomerulosclerosis, hypertensive glomerulosclerosis, tubulo-interstitial disease and lupus nephritis. Except for the degree of urinary occult blood, no other clinical data obtained at the first visit differed between groups A and B. Overall blood pressure levels throughout the entire clinical course also did not differ between the two groups. However, mean blood pressure levels before serum creatinine had reached the level of 2.0 mg/dl were significantly lower in group A compared with group B (96 +/- 7.8 vs. 103 +/- 6.3 mmHg, p < 0.05). We considered that the serum creatinine level of the so-called "point of no return" might be 2.0 mg/dl. In conclusion, blood pressure should be strictly controlled before serum creatinine levels reach 2.0 mg/dl.     

Prognosis of renal amyloidosis: a clinicopathological study using cluster analysis

Progression of renal amyloidosis is associated with severe proteinuria or nephrotic syndrome, and various mechanisms have been postulated to explain these complications. We studied the acceleration of proteinuria and reduced renal function by cluster analysis using clinical parameters, renal histological findings, type of renal amyloidosis and follow-up data. We divided 97 cases into three groups of renal amyloidosis. Accelerated progression correlated with serum creatinine (s-Cr) levels at renal biopsy and histological grade of renal damage by amyloid deposition (p < 0.0001). The most influential prognostic factors (s-Cr level > or =2.0 mg/dl) were tubulointerstitial and vascular damage induced by amyloid deposition at biopsy (odds ratio 96.9 and 69.2, respectively). In addition, we found amyloidosis type amyloid associated (AA) correlated with more amyloid-mediated vascular and tubulointerstitial damage than amyloidosis type amyloid light chain (AL) (p < 0.001, p < 0.01, respectively). Proteinuria and nephrotic syndrome were more severe in cases of amyloidosis AL than in amyloidosis AA (p = 0.076). In conclusion, less tubulointerstitial and vascular damage was caused by amyloid deposition; this was slowly progressive. Amyloid AA was detected in tubulointerstitial tissue and vessels more frequently than amyloid AL. Heavy proteinuria and/or nephrosis were not indicators of rapid progression.     

Incidence of acquired renal cysts in biopsy specimens

AIMS: This study investigated whether or not acquired renal cysts develop in patients with mild chronic renal failure. METHODS: A retrospective study was carried out using renal biopsy specimens from 720 patients. A renal cyst was defined as a tubule dilated >200 microm. RESULTS: Renal cysts were found in 21 of 720 renal biopsy specimens. Serum creatinine of 21 patients with renal cysts was significantly higher than that of 699 patients without cysts (2.59 +/- 2.64 vs. 1.09 +/- 0.79 mg/dl) (p < 0.0001). Poor renal function (serum creatinine >1.6 mg/dl) reveals more cyst formation on biopsy specimens than good renal function (serum creatinine <1.5 mg/dl). Cysts were observed in 11 of 607 (1.8%) patients less than 50 years of age and in 10 of 113 (8.8%) patients over 51 years. To exclude simple cysts which are commonly observed in older subjects, 11 patients under 50 years of age were extensively examined. Mean serum creatinine was 2.98 +/- 3.06 mg/dl (0.7-10.4 mg/dl). These 11 patients revealed low creatinine clearance of 47.5 +/- 25.6 ml/min (5-71 ml/min). Creatinine clearances in 7 patients were 52-71 ml/min (serum creatinine 0.7-2.0 mg/ dl). One of 11 biopsy specimens with cysts was examined by immunohistochemistry on lectin. This specimen was positive for tetragonolobus lectin and negative for peanut lectin, suggesting that the epithelial cells lining the cyst were derived from proximal tubules, unlike those of simple cysts. CONCLUSION: These results suggest that low normal renal function such as creatinine clearances 52-71 ml/min due to nephron loss is sufficient to induce acquired cyst development in various renal diseases.     

Increased prevalence and analysis of risk factors for indinavir nephrolithiasis

PURPOSE: Indinavir is a protease inhibitor used for treating HIV-1. The drug is lithogenic and was thought to cause a 3% incidence of kidney stones. We evaluated a cohort of patients positive for HIV on indinavir to determine the incidence of indinavir nephrolithiasis and identify risk factors for indinavir stone formation. MATERIALS AND METHODS: Our cohort study of the prevalence of indinavir nephrolithiasis included 155 patients with HIV for 5,732 patient-weeks. The same cohort was then used for a retrospective chart review to assess patient age, weight, duration of drug use, time to stone formation, CD4 count, creatinine, alanine transaminase, and urinary pH and specific gravity as risk factors for stone formation. RESULTS: We estimated the cumulative incidence of indinavir stone formation by the Kaplan-Meier product limit estimator method. At 78 weeks 43.2% of patients had stones (95% confidence interval [CI] 0.292 to 0.543). Increasing age was the only variable that was a statistically significant predictor of indinavair urolithiasis (relative risk 0.955, 95% CI 0.918 to 0.993, p = 0.0159). The mean duration plus or minus standard deviation of indinavir use was statistically the same in each group (42.5 +/- 27. 2 and 40.3 +/- 27.1 weeks in those without and with stones, respectively) despite the observed mean time to stone formation of 23.0 +/- 19.8 weeks. CONCLUSIONS: The clinical prevalence of indinavir nephrolithiasis is much greater than initially reported. Nephrolithiasis during indinavir use does not appear to induce patients to withdraw from the drug.     

Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease.

In patients with uremia, increased blood concentrations of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) have been linked to the severity of atherosclerosis and to excess cardiovascular mortality. The ADMA levels and several traditional cardiovascular risk factors were assessed in 44 untreated nonsmoking patients with confirmed primary chronic renal disease at different stages of renal disease. True GFR was assessed by means of the inulin-clearance technique. For comparison, nonsmoking subjects matched with respect to age, gender, and body-mass index were examined. Mean plasma ADMA concentration was markedly higher (P < 0.0001) in all patients combined (4.2 +/- 0.9 micromol/L) than in control subjects (n = 16; age 45 +/- 10 yr; serum creatinine 1.0 +/- 0.1 mg/dl; ADMA 1.4 +/- 0.7 micromol/L). However, mean ADMA levels were similar in patients with normal renal function (n = 16; age 41 +/- 9 yr; serum creatinine 1.1 +/- 0.1 mg/dl; GFR 120 +/- 14 ml x min(-1) x 1.73 m2; ADMA 4.0 +/- 0.7 micromol/L), in patients with moderate renal failure (n = 15; 47 +/- 7 yr; 1.8 +/- 0.3 mg/dl; 65 +/- 10 ml x min(-1) x 1.73 m2; 3.8 +/- 0.6 micromol/L) and in patients with advanced renal failure (n = 13; 46 +/- 9 yr; 4.2 +/- 0.9 mg/dl; 25 +/- 4 ml x min(-1) x 1.73 m2; 4.7 +/- 1.2 micromol/L). Furthermore, ADMA levels were increased to the same extent in normotensive (n = 17; 4.0 +/- 0.8 micromol/L) and in hypertensive (n = 27; 4.2 +/- 0.9 micromol/L) patients. In contrast to ADMA, mean total plasma homocysteine concentration were similar in control subjects (10.6 +/- 2.9 micromol/L) and in patients with normal GFR (11.0 +/- 2.9 micromol/L), but were significantly higher in patients with moderate renal failure (17.7 +/- 4.1 micromol/L) and particularly in patients with advanced renal failure (28.2 +/- 10.6 micromol/L). Finally, mean total serum cholesterol concentrations were comparable in the control group and in the three groups of patients with renal disease. In contrast to several traditional cardiovascular risk factors, markedly increased blood concentrations of ADMA, a putative biochemical marker of atherosclerosis, are present even in nonsmoking patients without diabetes with incipient primary renal disease. Thus, the early increase of ADMA levels may be of relevance for the excess cardiovascular morbidity and mortality due to arterio- and atherosclerotic complications in patients with renal disease.     

Potassium citrate administration ameliorates tubulointerstitial lesions in rats with uric acid nephropathy

Although controversial, chronic uric acid nephropathy is a tubulointerstitial disease capable of developing renal function loss. On the other hand, potassium citrate (KCi) administration has demonstrated to be effective in calcium as well as uric acid nephrolithiasis therapy. Therefore, the aim of the present study was to evaluate the possible benefit of KCi treatment in the prevention or amelioration of renal interstitial damage in uric acid nephropathy. Two-month-old male Sprague-Dawley rats were divided into 3 groups: G1 hyperuricemic (HU), G2 hyperuricemic + KCi (HU+KCi), and G3 KCi. G1 and G2 were fed on oxonic acid (inhibitor of rat liver uricase), and a uric acid supplement, during 4 weeks. G2 and G3 were given 2% KCi in drinking water, and G1 regular tap water and standard rat chow. At the end of the study, renal tissue was processed for light and electron microscopy and immunostaining by alpha-smooth muscle actin (SMA). Tubulointerstitial lesions and the amount of alpha-SMA immunostaining in renal tissue were evaluated by histomorphometric quantitation. Rats belonging to the hyperuricemic groups treated with KCi (G2) showed fewer tubulointerstitial lesions as follows: % tubular atrophy: 1.7 +/- 0.3 versus 7.2 +/- 1.2, p < 0.05; inflammatory cells infiltrate (number of cells/area): 0.6 +/- 0.1 versus 2.4 +/- 0.2, p < 0.01; % interstitial fibrosis (cortex): 3.3 +/- 0.3 versus 9.3 +/- 0.5, p < 0.05; % interstitial fibrosis (medulla): 5.2 +/- 0.3 versus 21.9 +/- 1.2, p < 0.01, lower albuminuria (32.8 +/- 11.2 mg/day versus 128.5 +/- 10.4, p < 0.01), higher creatinine clearance ( 1.36 +/- 0.02 ml/min versus 0.74 +/- 0.01, p < 0.01 ) and less percentage of alpha-SMA in renal tissue (1.8 +/- 0.1 versus 10.5 +/- 1.4, p < 0.05), when compared with the hyperuricemic group not treated with KCi (G1). These data suggest that KCi administration could provide a substantial benefit in the regard to tubulointerstitial lesion and progressive renal damage.     

Effects of H2-receptor antagonists on renal function in cyclosporine-treated renal transplant patients

H2-receptor antagonists have been frequently avoided in cyclosporine-treated transplant patients because of concern regarding possible exacerbation of nephrotoxicity. To determine whether the reported increase of serum creatinine levels in cyclosporine-treated transplant patients receiving H2-receptor antagonists was due to a true decrease in glomerular filtration rate or was secondary to altered renal tubular handling of creatinine, simultaneous inulin and creatinine clearances were analyzed in 11 cyclosporine-treated renal transplant recipients before and after H2-receptor antagonist administration. Seven patients received one week of cimetidine 300 mg p.o. four times daily and eight received one week of ranitidine 150 mg p.o. two times daily. Prior to study, all patients had stable renal function and were maintained on prednisone (mean dose 0.2 +/- 0.01 mg/kg/day) and cyclosporine (mean dose 5 +/- 0.6 mg/kg/day). Four patients were also receiving azathioprine (2 mg/kg/day). Cimetidine administration resulted in a significant increase (P less than 0.05) in mean serum creatinine concentration from 2.0 +/- 0.3 mg/dl to 2.4 +/- 0.3 mg/dl and a significant reduction (P less than 0.05) in mean creatinine clearance remained unchanged during this same period. Serum creatinine levels returned to baseline values for all patients following discontinuation of the drug. Ranitidine administration had no consistent effect on serum creatinine concentration, creatinine clearance or inulin clearance. Cyclosporine trough levels and BUN were unchanged by either drug. These results confirm previous observations demonstrating an increase in serum creatinine and a reduction in creatinine clearance following administration of H2 receptor antagonists, especially cimetidine. Failure to document a simultaneous reduction in inulin clearance is consistent with the hypothesis that H2-receptor antagonists do not exacerbate cyclosporine nephrotoxicity and lower GFR, but rather compete with creatinine for tubular secretion.     

Renal autotransplantation: an alternative to standard renal revascularization procedures

From January 1978 through December 1987, 22 patients underwent 23 renal autotransplantation procedures for the treatment of renovascular hypertension through the retroperitoneal approach. The causes of the renal artery stenosis were as follows: atherosclerosis (15), fibromuscular dysplasia (6), and Takayasu's arteritis (1). Indications for renal autotransplantation were as follow: disease extending into the renal artery branches (10), stenosis of multiple renal arteries (6), atherosclerotic aorta in high-risk patients (4), and stenosis of renal artery in children (2). The mean preoperative blood pressure of 205 +/- 6/109 +/- 3 mm Hg decreased significantly to 139 +/- 4/77 +/- 2 mm Hg (p less than 0.001). The serum creatinine decreased significantly from a mean preoperative level of 2.2 +/- 0.8 mg/dl to a mean postoperative level of 1.4 +/- 0.4 mg/dl (p less than 0.05). Eleven patients with preoperative renal dysfunction had a significant decrease in the serum creatinine from a mean preoperative level of 3.4 +/- 0.3 mg/dl to a mean postoperative level of 1.9 +/- 0.2 mg/dl (p less than 0.001). One operative death occurred as a result of myocardial infarction. There were three postoperative complications, none of which affected the ultimate result in blood pressure or renal function. This experience demonstrates that in selected patients, renal autotransplantation is an excellent alternative in the surgical treatment of renovascular hypertension.     

Early Prognostic Value of Serum Creatinine Levels in Children With Posterior Urethral Valves

Purpose

We evaluated the prognostic value of serum creatinine level at initial treatment for future renal function in children with posterior urethral valves.

Materials and Methods

We reviewed the records of 35 patients with posterior urethral valves presenting in the first year of life and treated initially at our institution between 1973 and 1990 with valve ablation or vesicostomy. Initial assessment included serum creatinine determination, urine culture, renal ultrasonography and voiding cystourethrography. After 4 or 5 days of catheter bladder drainage renal ultrasound and serum creatinine measurement were repeated. At the end of followup patients were divided into 2 groups according to glomerular filtration rate calculated by the Schwartz formula: group 1-69 ml. or less per minute per 1.73 m.² (median 15) and group 2-greater than 70 ml. per minute per 1.73 m.² (median 110). Median followup was 102 months (8.5 years, range 50 to 219 months).

Results

Mean serum creatinine at diagnosis plus or minus standard deviation was 3.60 +/− 2.01 and 1.3 +/− 0.7 mg./dl. in groups 1 and 2, respectively (normal 0.1 to 0.6, p <0.01). Mean serum creatinine after catheterization was 2.4 +/− 1.1 and 0.6 +/− 0.2 mg./dl. in groups 1 and 2, respectively (p <0.01). Mean nadir creatinine during the first year of life was 1.7 +/− 0.6 and 0.4 +/− 0.2 mg./dl. in groups 1 and 2, respectively (p <0.01). All differences were statistically significant. Linear regression analysis of creatinine after catheterization and glomerular filtration rate at last followup demonstrated a correlation coefficient of -0.7 (p <0.01).

Conclusions

Although it is well known that nadir creatinine in the first year of life correlates with prognosis, the correlation of long-term renal function with creatinine at valve ablation or vesicostomy is more useful to the clinician. These data indicate that serum creatinine level 4 to 5 days after the initial diagnosis correlates strongly with long-term renal function in children with posterior urethral valves.     

Renal allograft rejection with normal renal function in simultaneous kidney/pancreas recipients: does dissynchronous rejection really exist?

BACKGROUND: Between July 1, 1994 and December 1, 1998, 147 simultaneous kidney/pancreas transplantations were performed at our center. Of 95 patients who experienced at least one acute renal allograft rejection episode after transplantation, 7 (7.4%) developed rejection in the presence of stable and normal or near-normal renal function. METHODS: The indication for renal allograft biopsy was a rising serum lipase, i.e., suspected pancreatic rejection. All seven patients were treated with steroids and augmentation of the tacrolimus dose, with a fall in the serum lipase and no change in the serum creatinine. RESULTS: The serum creatinine levels just before, at the time of, 1 week after the biopsy, and at most recent follow-up were 1.4+/-0.4, 1.3+/-0.3, 1.2+/-0.2, and 1.2+/-0.2 mg/dl. The serum lipase levels just before, at the time of, 1 week after the biopsy, and at most recent follow-up were 1022+/-1157 mg/dl, 874+/-996 mg/dl, 243+/-260 mg/dl, and 94+/-75 mg/dl. The tacrolimus dosages and levels at the time of the biopsy and 1 week later were 14.9+/-5.0 mg/day and 15.0+/-4.0 ng/ml, and 16.4+/-6.3 mg/day and 15.1+/-6.8 ng/ml. CONCLUSIONS: These findings suggest that, in patients undergoing simultaneous kidney/pancreas transplantation, the entity of dissynchronous pancreatic allograft rejection without renal allograft rejection may not really exist. These data also make an additional fundamental point that acute rejection may occur in patients with normal and stable renal function.