PO-03 - Khorana score and histotype predict the incidence of early venous thromboembolism (VTE) in Non Hodgkin Lymphoma (NHL). A pooled data analysis of twelve clinical trials of Fondazione Italiana Linfomi (FIL).

BACKGROUND: Recent studies show that the risk of VTE in NHL pts is similar to that observed in high risk solid tumors (i.e. pancreatic, ovarian cancer). VTE in NHL occurs in most cases within three months from diagnosis and can have substantial impact on treatment delivery and outcome as well as on quality of life. However few data are available on potential predictors. AIMS: To better clarify the epidemiology of early (within six months from treatment start) VTE in NHL we conducted a pooled data analysis of 12 clinical trials from FIL. Our analysis included basic demographic features, lymphoma-related characteristics as well the Khorana score (based on histology, BMI, platelets WBC and HB counts) which is extensively used in solid tumors to predict VTE risk. PATIENTS AND METHODS: From Jan. 2010 to Dec. 2014, all pts with B-cell NHL enrolled in prospective clinical trials from FIL for frontline treatment were included. For 9 studies study period included the entire trial population was included. The analyses were conducted based on CRFs as well as pharmacovigilance reports. VTE definition and grading was stated according to standard criteria of toxicity (CTCAE V4.0). Cumulative incidence of VTE from the study enrollment was estimated using the method described by Gooley et al. accounting for death from any causes as a competing risk. The Fine & Gray survival model was used to identify predictors of VTE among NHL pts. Factors predicting the grade of VTE were investigated using an ordinal logistic regression model. This pooled data analysis was approved by local IRB. RESULTS: Overall, 1,717 patients belonging to 12 studies were evaluated. Eight were phase I/II or II (25% of pts) and 4 phase III (75% of pts). M/F ratio was 1.41, Median age was 57, (IQ range (IQR) 49-66). Histologies were: DLCL-B 34%, FL 41%, MCL 18%, other 6%. Median BMI was 25 (IQR 22-28). Median Hb, WBC and platelets counts were 13g/dl) (IQR 11.5-14.2), 7.1*10^(9)/l (IQR 5.6-10.3), 224*10^(9)/l (IQR 169-298), respectively. 1189 pts were evaluable Khorana score: 58% low risk, 30% intermediate risk, 12% were high risk. Human erythropoetin support was given to 9% of patients. All pts received Rituximab. Planned therapeutic programs included ASCT in 27% of pts, conventional chemotherapy in 67% a conventional chemotherapy plus lenalidomide in 6%. Overall 59 any grade VTE episodes occurred in 51 pts (2.9%), including 21 grade III-IV VTE (18 pts). None was fatal. Median time from study enrolment to VTE was 63 days (IQR: 35-110). Considering death as a competitive event the 6 months cumulative incidence of VTE was 2,2% in low risk Khorana score, 4.5% (95%IC: 2.3-6.7) in intermediate and 6.6% (95%IC: 2.4-10.8) in high risk (p=0.012) (figure 1). Khorana score was predictive also for grade III-IV events as they were 0,7% (95% CI:0.1-1.4) in low risk and 2.0% (95% CI:0.8-3.3) in intermediate-high risk (p=0.048). The results were similar also after excluding lenalidomide containing studies. The Fine and Gray multivariate analyses, adjusted for age and stage, showed that Khorana score (intermediate risk adjHR=1.96; 95%IC: 0.84-4.56 and high risk adjHR=3.81; 95%IC: 1.51-9.58) and DLCL-B histotype (adjHR=2.58; 95% CI: 1.01-6.55) were independently associated to an increased risk of VTE. Moreover an ordinal logistical regression model indicated that the increase of one point in the Khorana score resulted in an increased risk of VTE (OR=1.85; 95% CI: 1.23-2.79). CONCLUSIONS: Our results suggest that DLCL-B histotype and Khorana score are predictors of VTE in NHL. The latter might become a simple and effective tool to assess the risk of VTE in NHL. Prospective validation including also patients not eligible for clinical trials is needed.

Prothrombin complex concentrates for urgent anticoagulation reversal in patients with intracranial haemorrhage.

BACKGROUND: Intracranial haemorrhage (ICH) is a serious and potentially fatal complication of oral anticoagulant therapy (OAT). Prothrombin complex concentrates (PCCs) produce a rapid and effective reversal of OAT effects, but little evidence exists on their efficacy and safety in the management of ICH in patients on OAT. AIM: To evaluate the efficacy and safety of PCCs for the rapid reversal of OAT in patients with ICH. METHODS: Patients suffering from acute ICH while receiving OAT were eligible for this prospective cohort study if their international normalized ratio (INR) was > or = 2.0. Stratified 35-50 IU kg(-1) PCC doses were infused based on initial INR. RESULTS: A total of 92 patients (50 males; mean age 74 years, range 34-92 years) were included. The median INR at presentation was 3.3 (range 2-9). At 30 min after PCC administration the median INR was 1.4 (range 0.9-3.1), declining to < or = 1.5 in 75% of patients. The benefit of PCC was maintained for a long time, since in 98% of all post-infusion time points through 96 h the median INR remained < or = 1.5 (median 1.19; range 0.9-2.3). During hospitalization neither thrombotic complications nor significant adverse events were observed and 11 patients died (11.9%). None of the deaths was judged to be related to PCC administration. CONCLUSIONS: PCC administration is an effective, rapid and safe treatment for the urgent reversal of OAT in patients with ICH. Broader use of PCC in this clinical setting appears to be appropriate.

Renoprotective effects of carvedilol in hypertensive-stroke prone rats may involve inhibition of TGF beta expression.

1. The effect of carvedilol on renal function, structure and expression of TGF beta and the matrix proteins fibronectin, collagen I and collagen III, was evaluated in spontaneously hypertensive stroke-prone (SHR-SP) rats fed a high fat, high salt diet. 2. Carvedilol treatment for 11 to 18 weeks did not alter systolic blood pressure in SHR-SP rats, however, it resulted in a significant reduction in heart rate. 3. Carvedilol treatment reduced renal fibrosis and total, active and chronic renal damage to levels approaching those of WKY rats on a normal diet. 4. Urinary protein excretion was higher in SHR-SP rats (51+/-10 mg day(-1)) than WKY rats (18+/-2 mg day(-1)) and this was further increased when SHR-SP rats were fed a high fat, high salt diet (251+/-120 mg day(-1)). Treatment with carvedilol resulted in significantly lower urinary protein excretion (37+/-15 mg day(-1)). 5. The expression of TGF beta mRNA was significantly higher in SHR-SP rats compared to WKY rats and a further increase was observed when rats were fed a high fat, high salt diet. Renal TGF beta expression was significantly reduced by treatment with carvedilol. The expression of fibronectin and collagen I and collagen III mRNA showed a pattern similar to that observed with TGF beta mRNA expression. Collagen I mRNA expression followed a pattern similar to renal fibrosis. 6. These data indicate that carvedilol can provide significant renal protection in the absence of any antihypertensive activity and that the mechanisms involved in this action may include reduced expression of profibrotic factors such as TGF beta.

Eprosartan reduces cardiac hypertrophy, protects heart and kidney, and prevents early mortality in severely hypertensive stroke-prone rats.

OBJECTIVE: Eprosartan is a selective angiotensin II type I receptor antagonist approved for the treatment of hypertension. In the present studies, eprosartan's ability to provide end-organ protection was evaluated in a model of cardiomyopathy and renal failure in stroke-prone rats (SP). METHODS: SP were fed a high fat (24.5% in food) and high salt (1% in water) diet (SFD). Eprosartan (60 mg/kg/day) or vehicle (saline control) (n = 25/group) was administered by intraperitoneally-implanted minipumps to these SP on the SFD for 12 weeks. Normal diet fed SP and WKY rats (n = 25/group) were also included for comparison (i.e. served as normal controls). Mortality, hemodynamics, and both renal and cardiac function and histopathology were monitored in all treatment groups. RESULTS: Eprosartan decreased the severely elevated arterial pressure (-12%; P < 0.05) produced by SFD but did not affect heart rate. Vehicle-treated SP-SFD control rats exhibited significant weight loss (-13%; P < 0.05) and marked mortality (50% by week 6 and 95% by week 9; P < 0.01). Eprosartan-treated SP-SFD rats maintained normal weight, and exhibited zero mortality at week 12 and beyond. Eprosartan prevented the increased urinary protein excretion (P < 0.05) that was observed in vehicle-treated SP-SFD rats. Echocardiographic (i.e. 2-D guided M-mode) evaluation indicated that SP-SFD vehicle control rats exhibited increased septal (+22.2%) and posterior left ventricular wall (+30.0%) thickness, and decreased left ventricular chamber diameter (-15.9%), chamber volume (-32.7%), stroke volume (-48.7%) and ejection fraction (-22.3%), and a remarkable decrease in cardiac output (-59.3%) compared to controls (all P < 0.05). These same parameters in eprosartan-treated SP-SFD rats were normal and differed markedly and consistently from vehicle-treated SP-SFD rats (i.e. treatment prevented pathology; all P < 0.05). Cardiac-gated MRI data confirmed the ability of eprosartan to prevent cardiac pathology/remodeling (P < 0.05). Histopathological analysis of hearts and kidneys indicated that eprosartan treatment significantly reduced end-organ damage (P < 0.01) and provided corroborative evidence that eprosartan reduced remodeling of these organs. Vehicle-treated SP-SFD rats exhibited a 40% increase in the plasma level of pro-atrial natiuretic factor that was reduced to normal by eprosartan (P < 0.05). CONCLUSION: These data demonstrate that eprosartan, at a clinically relevant dose, provides significant end-organ protection in the severely hypertensive stroke-prone rat. It preserves cardiac and renal structural integrity, reduces cardiac hypertrophy and indices of heart failure, maintains normal function of the heart and kidneys, and eliminates premature mortality due to hypertension-induced end-organ failure.

Parathyroid hormone-1 receptor down-regulation in kidneys from rats with chronic renal failure.

Although secondary hyperparathyroidism is a common complication of chronic renal failure, few studies have examined the characteristics of parathyroid hormone (PTH) binding to the kidney or the regulation of the PTH receptor in chronic renal disease. In this study we measured PTH binding to the PTH-1 receptor in renal cortical membranes from normal rats and from rats with experimentally induced chronic renal failure. In normal rats, analysis of saturation binding experiments using 125I PTH-related peptide (chicken, cPTHrP) revealed apparent Kd and Bmax values of 1.16 +/- 0.14 nmol/l and 338 +/- 22.7 fmol/mg, respectively. Three weeks following induction of renal failure there was no change in the affinity of the PTH-1 receptor (Kd = 1.51 +/- 0.24 nmol/l) but the Bmax was reduced by 45% (183 +/- 32.5). In normal rats which had undergone thyroparathyroidectomy, the Kd was unchanged (1.17 +/- 0.09) while the Bmax increased to 459 +/- 31 fmol/mg. We conclude that chronic renal failure is accompanied by a downregulation of renal PTH-1 receptors.

Gene expression in rats with renal disease treated with the angiotensin II receptor antagonist, eprosartan.

The role of ANG II on renal and cardiac gene expression of matrix proteins was studied in rats with progressive renal disease. Induction of renal failure by five-sixths nephrectomy of Sprague-Dawley rats resulted in hypertension (163 +/- 19 vs. control pressures of 108 +/- 6 mmHg), proteinuria (83 +/- 47 vs. 14 +/- 2 mg/day), and increased renal expression of fibronectin, thrombospondin, collagen I and III, transforming growth factor-beta (TGF-beta), and plasminogen activator inhibitor-1 (PAI-1) mRNA. Treatment with the ANG II receptor antagonist, eprosartan (60 mg. kg(-1).day(-1)), lowered blood pressure (95 +/- 5 mmHg) and proteinuria (19 +/- 8 mg/d) and abrogated the increased TGF-beta, fibronectin, thrombospondin, collagens I and III, and PAI-1 mRNA expression. An increase in left ventricular weight was observed in five-sixths nephrectomized rats (0.13 +/- 0.01 vs. 0.08 +/- 0.01 g/100 g body wt), a response that was inhibited by eprosartan treatment (0.10 +/- 0.01 g/100 g). Left ventricular expression of TGF-beta and fibronectin was also increased in rats with renal disease; however, the small decreases in expression observed in eprosartan-treated rats did not reach statistical significance. These data suggest that eprosartan may be beneficial in progressive renal disease and that the mechanism of action includes inhibition of cytokine production in addition to antihypertensive activity.

Identification of a novel kidney-specific gene downregulated in acute ischemic renal failure.

To gain further insights into the molecular mechanisms involved in acute renal failure, we have isolated a new gene from rat and human, named KSP32 (kidney-specific protein with a molecular mass of 32 kDa). KSP32 encodes a novel gene that shows little homology to other mammalian proteins. It, however, shares extensive homology with several proteins found in the nematode Caenorhabditis elegans and plants. The expression of KSP32 mRNA is highly restricted to kidney. In situ hybidization analysis revealed that the expression of KSP32 mRNA was prominent in the boundary of kidney cortex and outer medulla, exhibiting a raylike formation extending from the medulla into the cortex. Finally, KSP32 mRNA was dramatically downregulated in rat following induction of acute ischemic renal failure. Rapid loss of KSP32 mRNA expression was observed beginning at approximately 5 h following renal injury and mRNA levels remained depressed for at least 96 h. Both KSP32 mRNA levels as well as renal function recovered 14 days after injury. Administration of an endothelin receptor antagonist (SB-209670), known to restore renal function, significantly increased KSP32 expression.

Angiotensin-converting enzyme inhibition alters clusterin mRNA expression in the kidney following renal mass reduction.

The effect of the angiotensin-converting enzyme inhibitor captopril on clusterin mRNA was examined in partially nephrectomized male rats. Urine protein excretion was measured 3, 7, and 28 days after removal of five sixths of the renal mass. Nephrectomy caused a progressive increase in clusterin mRNA levels in the remnant kidney. Maximal clusterin mRNA levels occurred 7 days after nephrectomy and declined 28 days after nephrectomy. Captopril, 250 mg/ml in drinking water, prevented the injury-induced increase in clusterin mRNA at 7 and 28 days. Captopril had no effect on clusterin in sham-operated rats. As expected, the urine protein excretion increased progressively after nephrectomy, and this was attenuated by administration of captopril in the drinking water. Therefore, clusterin is a marker of renal injury which, along with proteinuria, is modulated by angiotensin-converting enzyme inhibition.

Angiotensin-converting enzyme inhibition attenuates proteinuria and renal TGF-beta 1 mRNA expression in rats with chronic renal disease.

Evidence suggests that transforming growth factor beta 1 (TGF-beta 1), a multifunctional cytokine, induces renal extracellular matrix production and glomerular hypertrophy. The aim of the present study was to investigate the effect of captopril on the expression of TGF-beta 1 mRNA in a rat model of chronic renal failure: five-sixths nephrectomy. Chronic renal disease was induced by removal of the right kidney and ligation of three blood vessels supplying the left kidney. Sham-operated animals were used as controls. RNA was extracted from the viable remnant kidney of rats 1 day and 1 and 2 weeks following five-sixths nephrectomy and from the kidneys of rats who underwent sham surgery. TGF-beta 1 mRNA was induced within 24 h of partial nephrectomy, similar to that reported for early-onset genes. Subsequently, TGF-beta 1 mRNA expression continued to increase over the next 2-4 weeks. The upregulation of TGF-beta 1 correlated with the degree of proteinuria. Both the increase in TGF-beta 1 mRNA and proteinuria were abrogated by captopril treatment. In addition, no change in expression of ALK-5 or type II TGF-beta receptors following five-sixths nephrectomy was observed. These data suggest that captopril may protect against development of glomerulosclerosis and proteinuria by reducing TGF-beta 1 expression and hence matrix production.

Involvement of nitric oxide synthase in proteinuria associated with chronic renal disease in rats.

The present study demonstrates that the nitric oxide synthase inhibitor, aminoguanidine, can attenuate the proteinuria observed in a predominantly noninflammatory model of chronic renal disease in the rat. These data suggest that nitric oxide synthase may be involved in progressive renal disease.

The age-related increase in renal clusterin mRNA is accelerated in obese Zucker rats.

Clusterin is a multifunctional glycoprotein associated with development and tissue injury. Because renal function decreases with advancing age in the obese Zucker rat, clusterin mRNA expression was examined in the kidney of young adult Zucker rats and compared with age-related changes in renal clusterin mRNA expression in Fischer 344 (F344) rats. Renal clusterin mRNA levels in the obese Zucker rat were 2.5-fold higher by 3 mo of age and fourfold higher at 5 mo of age compared with the lean strain. In comparison, renal clusterin mRNA in 12-mo-old F344 rats was twofold higher than in 3-mo-old animals and was tenfold higher at 24 mo of age. Clusterin mRNA was positively correlated with urinary protein excretion and negatively correlated with creatinine clearance in Zucker rats. Clusterin was increased in select nephrons of the obese Zucker rat kidney and in 24-mo-old F344 rat kidney as assessed by in situ hybridization. Increased expression of clusterin mRNA occurred mostly in the tubular epithelium of dilated, convoluted proximal tubules. These data indicate that renal clusterin mRNA levels increase as a function of age and that age-related increases in renal clusterin and the associated tubular abnormalities are accelerated in obese Zucker rats.

Phosphate excretion and phosphate transporter messenger RNA in uremic rats treated with phosphonoformic acid.

The prevention of phosphate retention in chronic renal disease may reduce both renal osteodystrophy and disease progression. We evaluated the expression of the sodium-dependent phosphate transporter, NaPi-2, and the response to phosphonoformic acid (PFA) in rats with 5/6 nephrectomy-induced renal failure. Partial nephrectomy resulted in a significant proteinuria and reduced renal function. In addition, there was an approximately 50% reduction in the expression of NaPi-2 mRNA. Treatment of rats for 48 hr with PFA (0.6% in glucose drinking fluid) had no effect on NaPi-2 mRNA; however, PFA resulted in a significant increase in fractional phosphate excretion in both normal (7 +/- 0.5% vs. 3 +/- 0.2%) and uremic (60 +/- 4% vs. 36 +/- 4%) rats. Plasma phosphate concentration was higher in uremic rats (2.5 +/- 0.1 mM) compared with normal rats (1.9 +/- 0.04 mM) but not in uremic rats treated with PFA (2.1 +/- 0.04 mM). These data suggest that PFA can increase renal phosphate excretion independent of changes in phosphate transporter expression and prevent phosphate retention.

Prevention of cyclosporine A-induced renal vasoconstriction by the endothelin receptor antagonist SB 209670.

Administration of endothelin to inactin-anesthetized rats resulted in a significant renal vasoconstriction as evidenced by a reduction in both renal plasma flow and glomerular filtration rate. Infusion of the novel nonpeptide endothelin ETA/ETB receptor antagonist, (+/-)-SB 209670, [(1RS-2SR,3RS)-3-(2-carboxymethoxy-4-methoxy-phenyl)-5 -(prop-1-yloxy)indane-2-carboxylic acid], significantly attenuated the renal vascular effects of endothelin-1. Intravenous administration of cyclosporine A (50 mg/kg) caused a significant reduction in renal plasma flow and glomerular filtration rate and urine flow and a dramatic increase in renal vascular resistance. Concomitant infusion of (+/-)-SB 209670 abolished the cyclosporine A-induced reduction in renal plasma flow and glomerular filtration rate and attenuated the cyclosporine A-induced fluid retention. The data indicate that endothelin is involved in the acute renal effects of cyclosporine A.

SB 203220: a novel angiotensin II receptor antagonist and renoprotective agent.

SB 203220, [(E)-alpha-[[2-butyl-1-[(4-carboxy-1-naphthalenyl)-methyl]-1H- imidazol-5-yl]-methylene]-2-thiophene-propanic acid], is a novel nonpeptide angiotensin II receptor antagonist with significant oral activity. In the present study, we compared the cardiovascular and renal effects of SB 203220 and captopril in rats with chronic renal failure induced by 5/6 nephrectomy. Preliminary studies indicated that SB 203220 (600 ppm in the diet) and captopril (250 mg/l in drinking water) significantly attenuated the pressor activity of exogenous angiotensin II and angiotensin I, respectively. After 5/6 nephrectomy, significant hypertension was observed such that at 6 weeks, systolic blood pressure had reached 176 +/- 9 mm Hg. Both SB 203220 (128 +/- 18 mm Hg) and captopril (131 +/- 7 mm Hg) significantly attenuated the hypertension. Urinary protein excretion increased progressively after renal ablation (from 7 to 124 mg/day), and this was attenuated by both SB 203220 (32 +/- 7 mg/day) and captopril (42 +/- 6 mg/day). Assessment of serum creatinine and urea nitrogen indicated that SB 203220 but not captopril resulted in maintenance of renal function, close to that observed in control rats. Both SB 203220 and captopril attenuated the renal and left ventricular hypertrophy associated with 5/6 nephrectomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Is the HELLP syndrome due to inherited factors? Report of two cases.

The etiology and pathogenesis of the HELLP syndrome, a multisystem disease occurring only in pregnancy, are still unclear. Curiously, very few authors have investigated whether inherited factors may be involved. We report two cases of HELLP syndrome in two unrelated women whose fetuses were relatives (first cousins). The first case concerned a woman aged 32 with a normal course pregnancy who was admitted to the hospital for fever, nausea and vomiting, low platelets, hemolysis and increased liver enzymes. Abruptio placentae with fetal death and severe disseminated intravascular coagulation with hemorrhages ensued within a few hours. Hysterectomy was then performed. After treatment with transfusions and drugs the patient slowly improved; 28 days later she left the hospital in good condition. The second case involved a woman aged 31 with a normal course pregnancy who was admitted to the hospital for epigastric pain, nausea, low platelets, hemolysis and increased liver enzymes. The patient underwent an immediate cesarean section and delivered a live infant; no bleeding occurred during or after delivery. The patient's condition rapidly improved and she left the hospital after 13 days. Until now, no author has proved that inherited fetal factors are at work in the HELLP syndrome. Our observations suggest a role for genetic factors, and this needs to be investigated in prospective studies.

Comparison between carvedilol and captopril in rats with partial ablation-induced chronic renal failure.

1. The effect of the novel beta-adrenoceptor antagonist and vasodilator, carvedilol (SK&F 105517, approximately 70 mg kg-1 daily in the food), and captopril (approximately 38 mg kg-1 daily in the drinking fluid) on the progression of chronic renal failure in rats was studied. 2. Six weeks following partial renal ablation, the urinary protein excretion of the carvediol- (60 +/- 21 mg day-1) and captopril-treated (35 +/- 9 mg day-1) animals was less than 50% that of control rats (133 +/- 27 mg d-1). 3. Serum creatinine (Scr) and urea nitrogen (SUN) concentrations of the carvedilol-(Scr, 0.63 +/- 0.09 mg dl-1; SUN, 11.3 +/- 1.2 mg dl-1) and captopril-treated (Scr, 0.82 +/- 0.05 mg dl-1; SUN, 14.1 +/- 1.5 mg dl-1) animals were also significantly (P < 0.05) lower than that observed in control animals (Scr, 1.4 +/- 0.3 mg dl-1; SUN, 19.2 +/- 3.9 mg dl-1), indicating that glomerular filtration rate was improved by both drugs. Plasma renin activity was significantly (P < 0.05) higher in captopril-treated rats (24.7 +/- 4.6 ng angiotensin I ml-1 h-1) than in either carvedilol-treated (7.9 +/- 1.4 ng angiotensin I ml-1 h-1) or control animals (7.4 +/- 1.0 ng angiotensin I ml-1 h-1). 4. Histological examination of the kidneys demonstrated a significantly reduced glomerular hypertrophy and glomerulosclerosis in those animals receiving carvedilol or captopril compared to controls. 5. Serum carvedilol concentration measured every 6 h for 24 h was variable and ranged on average from 57 +/- 13 ng ml-1 at 16 h 00 min to 121 +/- 31 ng ml-1 at 03 h 00 min. These data indicate that the rats probably had 24 h systemic exposure to carvedilol.6. The present study indicates that carvedilol is effective in attenuating the progression of chronic renal failure in rats.

Protein C and protein S levels in uremic patients before and after dialysis.

The inhibitory capacity of the natural protein C (PC)/protein S (PS) system was evaluated measuring both the functional activity and the antigen level of both these inhibitors in 30 uremic patients before and after a dialytic treatment and in 30 healthy normal volunteers. PC functional activity was determined by two methods, one clotting and one chromogenic. PS antigen level was measured both as free protein and as total content. Unlike previous authors, we found that PC functional activity and the antigen level were normal in patients before dialysis, with a significant increase after. PS functional activity and free and total antigen levels were all normal before dialysis, and all except free antigen showed a significant post-treatment rise.

Increased endothelin excretion in rats with renal failure induced by partial nephrectomy.

1. Six weeks following partial nephrectomy in rats, significant increases in serum urea nitrogen and serum creatinine concentration and a significant decrease in creatinine clearance were observed. 2. Measurement of systolic blood pressure by tail plethysmography indicated that animals that had undergone partial nephrectomy were hypertensive. 3. Compared to sham-operated animals, there were 4 fold increases in both urinary protein excretion and urinary endothelin excretion. 4. There was a significant correlation between urinary protein and urinary endothelin excretion (r = 0.77). There was also a correlation (r = 0.65) between urinary endothelin excretion and systolic blood pressure. 5. Plasma endothelin concentrations were not different in sham-operated and partially nephrectomized rats. 6. The data indicate that there is an increased renal endothelin production in rats with chronic renal failure.

Effect of nifedipine on cyclosporine A-induced nephrotoxicity, urinary endothelin excretion and renal endothelin receptor number.

The aim of the present study was to determine the effect of a calcium channel blocker on renal function, urinary endothelin excretion and endothelin receptor number in rats. Administration of cyclosporine resulted in a significant impairment of renal function when measured by either [14C]inulin or 24 h creatinine clearances. This nephrotoxicity was associated with statistically significant (P less than 0.05) increases in urinary endothelin excretion and renal endothelin receptor number. Treatment with nifedipine attenuated cyclosporine A-induced renal dysfunction and reduced urinary endothelin excretion. The data provide further evidence of a role for endothelin in cyclosporine A-induced nephrotoxicity.