Treatment of Proteinuria with Lercanidipine Associated with Renin-Angiotensin Axis-Blocking Drugs

Objective. Most calcium antagonists do not seem to reduce microalbuminuria or proteinuria. We have tried to assess the antiproteinuric effect of a calcium channel blocker, lercanidipine, in patients previously treated with ACE inhibitors or angiotensin receptor blockers. Design and Methods. The study included 68 proteinuric (> 500 mg/day) patients (age 63.1 ± 12.9 years, 69.1% males and 30.9 females). All patients were receiving ACE inhibitors (51.4%) or angiotensin II receptor blockers (48.6%) therapy but had higher blood pressure than recommended for proteinuric patients (<130/80 mmHg). Patients were clinically evaluated one, three, and six months after starting treatment with lercanidipine (20 mg/day). Samples for urine and blood examination were taken during the examination. When needed, a third drug was added to treatment. Creatinine clearance was measured using 24 h urine collection. Results. BP significantly decreases from 152 ± 15/86 ± 11 mmHg to 135 ± 12/77 ± 10 mmHg at six months of follow-up (p < 0.001). After six months of treatment, the percentage of normalized patients (BP < 130/80 mmHg) was 42.5%, and the proportion of patients whose BP was below 140/90 mmHg was 58.8%. Plasmatic creatinine did not change nor did creatinine clearance. Plasmatic cholesterol also decreased from 210 ± 48 to 192 ± 34 mg/dL (p < 0.001), as did plasma triglycerides (from 151 ± 77 to 134 ± 72 mg/dL, p = 0.022). Basal proteinuria was 1.63 ± 1.34 g/day; it was significantly (p < 0.001) reduced by 23% at the first month, 37% at three months, and 33% at the last visit. Conclusions. Lercanidipine at 20 mg dose, associated to renin-angiotensin axis-blocking drugs, showed a high antihypertensive and antiproteinuric effect. This antiproteinuric effect seems to be dose-dependent as compared with previous reports and proportionally higher than blood pressure reduction.     

Enalapril and losartan reduce sympathetic hyperactivity in patients with chronic renal failure

The aim of this study was to compare the effects on BP and sympathetic activity of chronic treatment with an angiotensin (Ang)-converting enzyme (ACE) inhibitor and an AngII receptor blocker in hypertensive patients with chronic renal failure (CRF). In ten stable hypertensive CRF patients (creatinine clearance, 46 +/- 17 ml/min per 1.73 m(2)), muscle sympathetic nerve activity (MSNA), plasma renin activity (PRA), baroreceptor sensitivity, and 24-h ambulatory BP were measured in the absence of antihypertensive drugs (except diuretics) after 6 wk of enalapril (10 mg orally) and after 6 wk of losartan (100 mg orally). The order of the three phases was randomized. Normovolemia was controlled with diuretics and confirmed with extracellular fluid volume measurements throughout the study. Both enalapril and losartan reduced MSNA (from 33 +/- 10 to 27 +/- 13 and 27 +/- 13 bursts/min, respectively; P < 0.05) and average 24-h BP (from 141 +/- 8/93 +/- 8 to 124 +/- 9/79 +/- 8 and 127 +/- 8/81 +/- 9 mmHg; P < 0.01). PRA was not different during the treatments. The change in BP and the change in MSNA during the treatments were correlated (r = 0.70 and r = 0.63, respectively; both P < 0.05). Baroreceptor sensitivity was not affected by the treatments. This is the first study to compare the effects of ACE inhibition and AngII blockade on MSNA. In hypertensive CRF patients, enalapril and losartan equally reduced BP and MSNA. Differences in modes of action of the two drugs did not result in differences in effects on MSNA, supporting the view that AngII-mediated mechanisms contribute importantly in the pathogenesis of sympathetic hyperactivity in these patients.     

Moxonidine normalizes sympathetic hyperactivity in patients with eprosartan-treated chronic renal failure

Enalapril and losartan reduce but not normalize sympathetic hyperactivity in patients with hypertensive chronic renal failure (CRF). This study assessed the effect of chronic eprosartan on BP and sympathetic activity, and assessed the effect of moxonidine during chronic eprosartan treatment. In 11 stable patients with CRF (creatinine clearance 47 +/- 10 ml/min), muscle sympathetic nerve activity (MSNA; peroneal nerve), BP, and baroreceptor sensitivity were measured in the absence of antihypertensive drugs (except diuretics) during chronic eprosartan therapy (600 mg for 6 wk) and in 9 patients after moxonidine (0.2 mg for 6 wk) was added. Normovolemia was controlled by diuretics and confirmed by extracellular fluid volume measurements. BP, heart rate, and MSNA were higher in patients than in 22 controls. During eprosartan therapy, mean arterial pressure (111 +/- 9 to 98 +/- 7 mmHg, P < 0.001), heart rate (71 +/- 10 to 65 +/- 8 bpm, P < 0.001), and MSNA (35 +/- 10 to 27 +/- 8 bursts/min, P < 0.001) decreased. After the addition of moxonidine (n = 9), a further reduction of mean arterial pressure to 89 +/- 7 mmHg (P < 0.05) and of MSNA to 20 +/- 10 bursts/min (P < 0.05) occurred. Sympathetic activity in patients with CRF can be normalized, and angiotensin II-independent sympathetic hyperactivity contributes to the pathogenesis of renal hypertension. Sympathetic hyperactivity is associated with poor cardiovascular outcomes, implying that reduction might be beneficial to the patients. The addition of moxonidine to angiotensin II antagonist treatment might be appropriate.     

Renin-angiotensin gene polymorphism in children with uremia and essential hypertension

The M235T polymorphism of the angiotensinogen (ANG) gene, the I/D polymorphism of the angiotensin converting enzyme (ACE) gene, and the A1166C polymorphism of the angiotensin II type 1 receptor (AT1R) gene were identified in 70 patients with end-stage renal disease [20 pediatric ESRD, aged 14.9+/-3.1, years blood pressure (BP) 139+/-14/91+/-13 mmHg, 50 adult ESRD, aged 48.7+/-18.7 years, BP 149.1+/-24/96.9+/-12 mmHg], 35 with juvenile essential hypertension (JEHT, aged 14.4+/-2.7 years, 24-h mean BP 135.37+/-7.37/72.4+/-7.68 mmHg), 130 adult healthy normotensive controls (aged 34.9+/-8.1 years, BP 117.8+/-8.7/78.7+/-8.5 mmHg), and 20 pediatric controls (aged 13.2+/-1.2 years, BP 109+/-6.5/71+/-5.9 mmHg). The ACE gene polymorphism was determined by polymerase chain reaction and the ANG and AT1R gene polymorphisms by single-step LightCycler technology. The ACE gene distribution of the Hungarian controls did not differ from the results of the other Caucasian populations. In JEHT and pediatric ESRD patients, the MT genotype of ANG was more frequent than in controls (JEHT 80%, pediatric ESRD 74% versus controls 50%, P<0.02). The DD genotype of ACE was over-represented in pediatric ESRD compared with controls (ESRD 45% versus controls 22%, P<0.05). There was a non-significant increase in the CC genotype frequency of AT1R in adult patients with ESRD compared with controls. In conclusion, there was an increased frequency of the ACE DD genotype in pediatric ESRD, which could be a genetic risk factor for the development of ESRD. Furthermore, there was a significant increase in MT genotype frequency of ANG M235T polymorphism in pediatric ESRD and JEHT. The role of AT1R gene polymorphism needs further investigation.     

ACE gene D/D genotype as a risk factor for chronic nephrotoxicity from calcineurin inhibitors in liver transplant recipients

BACKGROUND: Chronic renal failure (CRF) is a major cause of morbidity and mortality after orthotopic liver transplantation (OLTX) and is predominantly caused by calcineurin inhibitors (CI)-induced nephrotoxicity. The activation of the renin angiotensin system (RAS) has been implicated in the pathogenesis of chronic nephrotoxicity from CI. METHODS: We retrospectively investigated the genes coding for components of the RAS (ACE gene, Angiotensin II receptor 1 gene, Angiotensinogen gene) in 233 liver transplant recipients receiving Cyclosporine (CsA) or Tacrolimus (Tac) as maintenance immunosuppressant. All patients with serum creatinine (sCr) <1.0 mg/dL (n=143) before orthotopic liver transplantation (OLTX) were included in the final analysis. Patients were than categorized into two groups based upon their most recent postliver transplant sCr level: Group 1 (n=83) with sCr <1.5 mg/dL (mean 1.1+/-0.2) and group 2 (n=60) with sCr > or =1.5 mg/dL (mean 2.5+/-1.3) RESULTS: ACE D/D genotype was found in 57% of patients with sCr > or =1.5 mg/dL compared to 20% of patients with sCr <1.5 mg/dL (P<0.0001) CONCLUSIONS: Our analysis strongly suggests that liver transplant patients with ACE gene D/D genotype are at a significant higher risk of developing CI-induced chronic nephrotoxicity.     

Randomized placebo-controlled study on the effects of losartan and carvedilol on albuminuria in renal transplant recipients

BACKGROUND: The renoprotective effects of agents inhibiting the renin-angiotensin system in renal transplant recipients have been supposed but not finally proven. To shed more light on this issue, we performed a double-blind, placebo-controlled, crossover study to evaluate the influence of the AT-1 angiotensin II receptor blocker, losartan, on the surrogate marker of kidney injury, albuminuria, in patients after renal transplantation. The safety of this therapy was also evaluated. METHODS: Fourteen of 16 patients (nine male, five female), age 45.36 +/- 3.04 years, 65.5 +/- 10.0 months after kidney transplantation, with hypertension and stable serum creatinine 123 +/- 4 micromol/L without proteinuria, completed the protocol. Each patient underwent two 8-week treatment periods (one with losartan 50-100 mg and one with carvedilol 12.5-25 mg) in random order, allowing an 8-week placebo washout between treatments. The target office trough blood pressure was below 130/85 mmHg. RESULTS: The ambulatory blood pressure did not differ in the treatment periods. Losartan significantly reduced albuminuria relative to placebo and carvedilol (27.62+/-17.58 vs. 49.55 +/- 25.33 v. 44.77 +/- 21.9 mg/g creatinine; P < 0.01). A significant but not clinically relevant decrease in hemoglobin level after losartan was observed (losartan: 129 +/- 3.1 g/l, placebo: 134.2 +/- 3.2, carvedilol: 137.1 +/- 3.7; P < 0.001). Serum potassium, creatinine, creatinine clearance, and trough blood cyclosporine levels were unaffected. CONCLUSION: Losartan decreases microalbuminuria in renal transplant recipients with clinically minimal side effects.     

The clinical status of cadaveric renal transplant patients treated for 10 year with cyclosporine therapy

In this paper we assessed the clinical status of 150 cadaveric renal transplant patients who received cyclosporine without interruption for 10 yr. The mean creatinine clearance was 59.2 +/- 15.71 at 1 yr and 55.6 +/- 24.91 mL/min at 10 yr (p = 0.039). Patients were subdivided into four quartiles according to the mean creatinine clearance at 1 yr. The 14 patients with the lowest quartile showed a significant decrease of creatinine clearance from the 1st to 10th year (from 31.5 +/- 5.83 to 24.8 +/- 14.00 mL/min; p = 0.038) while no difference between the mean creatinine clearance at 1 and at 10 yr was found in the other three quartiles. At 10 yr, 84.6% patients needed antihypertensive therapy, a rate similar to that seen at 1 yr (81.4%). The mean plasma cholesterol (253 +/- 57.8 mg/dL) and triglyceride (197 +/- 113.1 mg/dL) at 10 yr were similar to those found at +/- yr (243 +/- 48.2 and 201 +/- 143.0 mg/dL, respectively). Most patients have a high degree of rehabilitation 10 yr after uninterrupted cyclosporine therapy and all patients but 3 were able to work.     

Prednisolone co-administered with losartan confers renoprotection in patients with IgA nephropathy

BACKGROUND: Treatment options for progressive IgA nephropathy are limited. METHODS: We performed a small, randomized controlled trial to evaluate the effects of prednisolone (PSL, 30 mg/dL, gradually tapered to 5 mg/dL over two years) plus 50 mg/day of losartan (LST, an angiotensin II receptor blocker) or PSL alone on IgA nephropathy. We separated 38 patients (age, 33 +/- 11 years; creatinine clearance, 103 +/- 31 mL/min; proteinuria, 1.6 +/- 0.5 g/day) into two groups that were treated with either PSL plus LST or PSL alone, and compared the proteinuria and creatinine clearance after two years. Baseline and histopathological data did not significantly differ between the two groups. RESULTS: Two years of treatment in both groups significantly decreased proteinuria compared with baseline, and PSL plus LST (from 1.6 +/- 0.6 to 0.3 +/- 0.1 g/day, p < 0.05) was more effective than PSL alone (from 1.6 +/- 0.3 to 0.5 +/- 0.1 g/day, p < 0.05). Creatinine clearance in both groups was similar at the start of study but significantly differed at the end of the study (PSL plus LST, 104.3 +/- 36.4 to 100.4 +/- 38.9 mL/min; PSL alone, 103.4 +/- 28.5 to 84.8 +/- 34.3 mL/min, p < 0.05). CONCLUSIONS: Combined therapy with PSL plus LST appears to be more effective than PSL alone in reducing proteinuria and protecting renal function in patients with IgA nephropathy.     

The plasma creatinine concentration is not an accurate reflection of the glomerular filtration rate in stable renal transplant patients receiving cyclosporine

We studied 31 stable renal cadaver kidney transplant patients receiving cyclosporine (CyA) and prednisone for immunosuppression to determine what reduction in true glomerular filtration rate (GFR) was reflected by their mild elevation in plasma creatinine concentration (1.8 +/- 0.11 mg/dL). We measured both the creatinine clearance (60 +/- 4.32 mL/min/1.73 m2) and the true GFR using Technetium 99m-DTPA (44 +/- 2.72 mL/min/1.73 m2). The creatinine clearance overestimated true GRF by a mean of 38%, indicating that this percentage of creatinine reached the urine by tubular secretion rather than glomerular filtration. A similar degree of overestimation was found in a separate group of 14 patients receiving imuran for immunosuppression. In 23 patients receiving CyA in whom the serum creatinine concentration was less than 2.0 mg/dL, the mean DTPA clearance was 49.5 +/- 2.83 mL/min/1.73 m2. In stable renal transplant patients receiving CyA, a serum creatinine concentration at, or close to, the upper limit of the normal range may reflect markedly impaired renal function.     

mTOR inhibitors: do they help preserve renal function?

BACKGROUND: Renal function deterioration is one of the main problems facing heart transplant recipients. The mammalian target of rapamycin (mTOR) inhibitors, in combination with or replacing calcineurin inhibitors, may help preserve renal function. The aim of this study was to evaluate the progression of renal function after switching the immunosuppressive regimen. PATIENTS AND METHODS: We studied 23 heart transplant recipients (5.5 +/- 4.5 years since transplantation). An mTOR inhibitor was introduced to replace cyclosporine (everolimus, 65%; sirolimus, 35%). Patient clinical characteristics and renal function were studied after switching. The statistical analysis used Student t test for paired data. RESULTS: The reason for the transplantation was ischemic cardiopathy (52%), dilated myocardiopathy (39%), or other causes (9%). Mean age at time of transplantation was 52 +/- 9 years. Comorbidities were as follows hypertension (43%), insulin-dependent diabetes (22%), hypercholesterolemia (39%), and ex-smokers (70%). The reason for the switch was increased creatinine (65%), appearance of tumors (26%), or others (8%). Previous creatinine level was 1.89 +/- 0.6 mg/dL with clearance of 61.7 +/- 23 mL/min and at the end of follow-up (mean follow-up, 11 +/- 6 months) creatinine level was 2.0 +/- 1.45 mg/dL with clearance of 68.3 +/- 35 mL/min, namely, no significant difference (P = .49 and P = .57, respectively). In the subgroup of patients who switched treatment due to renal dysfunction, initial creatinine level was 2.38 +/- 0.4 mg/dL with clearance of 42.3 +/- 10 mL/min and at the end of follow-up it was 2.28 +/- 0.2 mg/dL and 43.6 +/- 11 mL/min, respectively (P = .68 for creatinine and clearance). CONCLUSIONS: The introduction of mTOR inhibitors to the immunosuppressant regimen may be useful to delay renal functional deterioration caused by calcineurin inhibitors.     

Beneficial effects of fluvastatin on progressive renal allograft dysfunction

To assess the time-dependent changes in renal function in relation to antioxidant and lipid-lowering effects of fluvastatin in hyperlipidemic renal transplant recipients, 20 patients were treated with fluvastatin 40 mg/d for 12 months, after failure of a dietary program. Plasma malondialdehyde (MDA) levels and lipid profiles were evaluated in relation to serum creatinine and calculated creatinine clearances 18 months before and during the fluvastatin treatment. Mean baseline lipid values were: total cholesterol 318 mg/dL, triglycerides 212 mg/dL, LDL cholesterol 219 mg/dL, HDL cholesterol 58 mg/dL, apolipoprotein A 176 mg/dL, and apolipoprotein B 145 mg/dL. During 12 months of treatment, fluvastatin produced consistent and significant reductions in total and LDL cholesterol (-18.4% and -24.1%), triglycerides (-17.7%), and apolipoprotein B (-22.7%) as well as an increase in HDL cholesterol (12.3%) and apolipoprotein A (9.2%). Plasma MDA levels decreased by 41.8% (from 3.5 +/- 0.3 to 1.8 +/- 0.1 nmol/mL, P =.00002). Creatinine clearance, which had been declining at a rate of 0.32 mL/min/month during the previous 18 months before treatment, progressively improved during treatment, giving a positive slope of the creatinine clearance, which increased by 0.35 mL/min/month, (P =.016; 53.3 +/- 4.2 mL/min vs 49.8 +/- 4.1 mL/min pretreatment). Multiple linear regression analysis revealed that MDA was the parameter most closely associated with the variability in creatinine clearance. In conclusion, renal transplant patients with lipid abnormalities display renoprotective activity of fluvastatin, possibly due to its lipid-lowering and antioxidant effects.     

Antiproteinuric effect of losartan in non-diabetic renal disease is not dependent on ACE insertion/deletion polymorphism

BACKGROUND: The antiproteinuric effect of angiotensin-converting enzyme (ACE) inhibitors appears to vary depending on the ACE insertion (I)/deletion (D) genotype in non-diabetic nephropathy. This interaction may be overcome by using an angiotensin II receptor blocker. We evaluated the short-term antiproteinuric effect of losartan according to the ACE I/D genotype in patients with non-diabetic proteinuric renal diseases. METHODS: Ninety-nine (II/ID/DD: 36/52/11) non-diabetic patients with overt proteinuria were enrolled. The patients received losartan 50 mg daily followed by 100 mg in two treatment periods each lasting 12 weeks. Clinical parameters including proteinuria were measured at baseline and at the end of each period. RESULTS: At baseline each genotype (II/ID/DD) had comparable mean arterial blood pressure (mean +/- SD) 103.2 +/- 11.1/102.7 +/- 10.6/104.1 +/- 15.3; proteinuria (geometric mean, 95% CI, mg/day) 1,839 (1,518-2,227)/1,998 (1,683-2,372)/1,613 (1,072-2,427), and creatinine clearance (ml/min/1.73 m(2)) 65.7 +/- 28.4/63.2 +/- 27.8/68.8 +/- 25.3, respectively. Both doses of losartan significantly lowered blood pressure and proteinuria (p < 0.05 vs. baseline), and losartan 100 mg was more effective than 50 mg in reducing proteinuria (52.5 +/- 29.0 vs. 40.5 +/- 30.8%, respectively, p = 0.001). No differences in the antiproteinuric effect of losartan was observed among the ACE I/D genotype. Losartan 100 mg demonstrated a comparable degree of mean arterial pressure (mean +/- SD, %) (II/ID/DD, 13.3 +/- 7.6/10.8 +/- 9.8/13.0 +/- 11.6, respectively, p = NS) and proteinuria reduction (mean, 95% CI) among the three genotypes (51.4% (40.3-62.5%)/53.4% (45.5-61.4%)/51.4% (40.0-63.8%), respectively, p = NS). CONCLUSION: Our data suggest that losartan provides a similar short-term antiproteinuric response for all three genotypes of ACE I/D genotype in non-diabetic proteinuric chronic renal disease.     

Cyst decompression surgery for autosomal dominant polycystic kidney disease.

A prospective study was undertaken to evaluate the efficacy of surgical cyst decompression for retarding the progression of renal failure and for the management of chronic pain associated with autosomal dominant polycystic kidney disease (ADPKD). Thirty patients with ADPKD and pain (14 patients), renal insufficiency (4 patients), or both (12 patients) underwent unilateral (19 patients) or bilateral (11 patients) cyst reduction surgery. The patients were monitored for 21 +/- 2 months postoperatively. The probability of being painfree was 80% at 1 yr and 62% at 2 yr. Preoperative and 1-to 3-month postoperative serum creatinine levels and GFR (clearance of insulin or (125I) iothalamate) were not significantly different (2.2 +/- 0.3 versus 2.2 +/- 0.3 mg/dL and 49 +/- 8 versus 54 +/- 9 mL/min/1.73 m2, respectively). One-year serum creatinine levels remained unchanged in patients with normal preoperative renal function (1.0 +/- 0.07 versus 1.0 +/- 0.05 mg/dL), whereas those with preoperative progressive renal insufficiency had no difference in the mean slope of reciprocal serum creatinine plots preceding and after surgery (-0.008 +/- 0.001 versus -0.009 +/- 0.002 dL/mg/month). In patients who underwent unilateral surgery, split function isotope scans showed no change in function of the operated kidney when compared with the nonoperated kidney. Surgical cyst decompression provides effective relief of chronic pain without compromising renal function. However, the data in this article do not support the use of this procedure to slow progression of renal insufficiency in ADPKD.     

Effect of low-dose dual blockade of renin-angiotensin system on urinary TGF-beta in type 2 diabetic patients with advanced kidney disease.

BACKGROUND: We evaluated the renoprotective effects of dual blockade of renin-angiotensin system (RAS) by using a low-dose combination of ACE inhibiter and angiotensin II receptor blocker in type 2 diabetic patients with advanced kidney disease. The amount of proteinuria and the urinary levels of bioassayable TGF-beta1 were used as surrogate markers of renal injury and sclerosis. METHODS: We performed a prospective double-blinded randomized crossover trial consisting of three 16-week treatment periods with ramipril alone (10 mg/day), candesartan alone (16 mg/day), and ramipril (5 mg/day) plus candesartan (8 mg/day) combination therapy. Twenty-one type 2 diabetic patients with overt nephropathy with a 24 h urinary protein excretion rate (UPER) of > 1.0 g/24 h and creatinine clearance (Ccr) of 30 to 59 ml/min/1.73 m2 completed the entire study. RESULTS: Subjects consisted of 10 female and 11 male patients with a mean age of 49 +/- 8 years and duration of diabetes ranging from 4 to 13 years. At baseline, 24-h blood pressures (BPs) were 133 +/- 6/81 +/- 7 mmHg, Ccr 40.6 +/- 4.1 ml/min/1.73 m2, 24-h UPER 4.1 +/- 1.9 g/24 h, and urinary TGF-beta1 level 28.4 +/- 16.1 pg/mg creatinine (cr). Although there was no comparable change in BP and plasma/urinary biochemical parameters, 24-h UPER was significantly reduced by the combination therapy (2.9 +/- 1.4 g/24 h) compared with that of ramipril (3.5 +/- 1.8 g/24 h) and of candesartan (3.3 +/- 2.0 g/24 h) single therapy (P < 0.05). Urinary TGF-beta1 level was reduced in all three therapies compared with that of the control (28.4 +/- 16.1 pg/mg cr) (P < 0.05). However, the combination therapy showed the most significant change (combination 19.6 +/- 10.6 pg/mg cr; ramipril 24.7 +/- 13.3 pg/mg cr; candesartan; 23.4 +/- 11.7 pg/mg cr). No significant or irreversible adverse effect was observed in the 21 patients who completed the entire study. CONCLUSIONS: The dual blockade of RAS with low-dose ramipril plus candesartan was found to be safe and offered additive benefits with respect to reducing proteinuria and urinary TGF-beta1 excretion in diabetic patients with advanced kidney disease. These benefits were evident as compared with single ramipril and candesartan therapies at doses two-fold greater. Further study on the dose-titration is mandatory in terms of safety and especially for maximizing renoprotection in this patient population.     

Differentiation of acute renal failure and chronic renal failure by 2-dimensional analysis of urinary dipeptidase versus serum creatinine

The differential diagnosis of acute renal failure (ARF) and chronic renal failure (CRF) may be possible by measuring urinary dipeptidase (Udpase) activity and serum creatinine (Scr) concentration. When the mass test of 246 individuals was examined on a 2-dimensional plot of Udpase (y-axis) versus Scr (x-axis) with the data obtained from healthy volunteers (n = 189), ARF (n = 19) and CRF (n = 38) patients, the characteristic distribution of each group was obvious. It is summarized by the mean values of healthy volunteers (1.44 +/- 0.39 mg/dL, 1.19 (0.59 mU/mL), ARF (6.04 +/- 5.04 mg/dL, 0.12 +/- 0.08 mU/mL), and CRF patients (8.72 +/- 2.93 mg/dL, 0.81 +/- 0.44 mU/mL). The healthy volunteers are distributed along the y-axis and the ARF patients the x-axis, thus separating the two groups 90 degrees apart. The CRF patients are scattered away from both x-, and y-axis. This 2-dimensional approach is thought to be very useful for the differential diagnosis of ARF suggesting Udpase as a new member of the marker enzymes of renal disease.     

Prognosis of malaria associated severe acute renal failure in children

Between January and December 1996, we observed 64 children (mean age 8.3 years range 4.2 to 11.2 years) who required dialysis for severe acute renal failure secondary to Falciparum Malaria. All received anti malarial therapy and other supportive therapy as well as peritoneal dialysis. Out of these 28 died (43.8%). The children who died (Group I) compared to those who survived (Group II) differed significantly in age (mean +/- SD) (7.2 +/- 1.3 years vs. 9.2 +/- 2.1 years P < 0.05), plasma creatinine at presentation (645 +/- 104 mumol/L vs. 438 +/- 87 mumol/L P < 0.05), plasma bilirubin (2.1 +/- 0.3 mg/dL vs. 1.2 +/- 0.2 mg/dL P > 0.02) systolic BP (50 +/- 11 mmHg vs. 90 +/- 12 mmHg P0 < 0.01), diastolic BP (20 +/- 4 mmHg vs. 60 +/- 9 mmHg P < .01) .Hb level 5.3 +/- 0.4 g/dL vs. 8 +/- 1.3 gm/dL P < .02), time from diagnosis to referral (5.3 +/- 1.3 days vs. 8.9 +/- 2.1 days P < .05) and urine output (200 +/- 49 mL/24 h vs. 600 mL +/- 131 mL P < .01). There was no significant difference in gender, alanine transaminase (ALT) level, degree of fever, plasma Na or plasma K. Diarrhea was present in 29% of the children who died and in only 11% of those who survived (P > 0.05) and splenomegaly was found in 3% and 18% respectively (PO > .05).     

Effect of whole bone marrow cell infusion in the progression of experimental chronic renal failure

INTRODUCTION: The therapeutic potential of adult stem cells for the treatment of chronic diseases is becoming increasingly evident over the last few years. In the present study, we sought to assess whether the infusion of bone marrow-derived mononuclear cells (MoSCs) and mesenchymal cells (MSCs) could reduce/stabilize the rate of progression of chronic renal failure (CRF) in rats. METHODS: We used the 5/6 renal mass reduction model to induce chronic renal failure in male Wistar rats. Renal function was assessed by measurements of serum creatinine (sCr), creatinine clearance (Clcr), and 24-hour proteinuria at baseline as well as 60 and 120 days after surgery. MoSCs and MSCs obtained from bone marrow aspirates were separated by the Ficoll-Hypaque method. After a 12- to 14-day culture, 1.5 x 10(6) MSCs and the same number of MoSCs were injected into the renal parenchyma of the remanant kidney of rats with CRF on the day of surgery. RESULTS: Among the control group, at day 120, the results were sCr = 1.31 +/- 0.5 mg/dL, Clcr = 0.64 +/- 0.35 mL/min, and proteinuria = 140.0 +/- 57.7 mg/24 h. Rats treated with MoSCs at day 120 had sCr = 0.81 +/- 0.20 mg/dL, Clcr = 1.05 +/- 0.26 mL/min, and proteinuria = 61 +/- 46.5 mg/24 h, while rats injected with MSCs had sCr = 0.95 +/- 0.1 mg/dL, Clcr = 0.68 +/- 0.24 mL/min, and proteinuria = 119.2 +/- 50.0 mg/24 h. Analysis of the progression to CRF showed that the treatment significantly reduced the rate of decline in Clcr after treatment with MoSc: control: -0.0049 +/- 0.0024 mL/min/d versus MSC: - 0.0013 +/- 0.0017 mL/min/d versus MoSC: +0.0002 +/- 0.0016 mL/min/d (P = .017). Proteinuria tended to be lower among the treated groups. Histological scores of chronic damage were not different, but distinct patterns of chronic lesions were observed among treated rats. CONCLUSION: Our results showed that progression of CRF in rats could be slowed/stabilized by intrarenal parenchymal injection of MoSCs. A trend toward reduction in the progression rate of CRF was also observed with injection of MSCs.     

Cyclosporine versus tacrolimus in kidney transplantation: are there differences in nephrotoxicity?

Cyclosporine and tacrolimus, two calcineurin inhibitors, show different side effects and toxicities. The data concerning their nephrotoxicity are few and conflicting. A retrospective study was performed in 2 groups of renal transplant recipients treated with cyclosporine or tacrolimus to evaluate graft function and side effects. All patients had completed at least 6 months of follow-up before inclusion in the study. Group I included 10 patients who were converted from cyclosporine to tacrolimus, due to cosmetic problems or due to chronic graft dysfunction with creatinine values <3 mg/dL. After conversion, there was a significant reduction in creatinine values (from 2.43 +/- 1.21 to 1.86 +/- 0.72 mg/dL; P =.023) and an improvement in creatinine clearance (from 47.5 +/- 19.2 to 56.1 +/- 18.9 mL/min; P =.047). The lipid profile did not change, but there was a trend to better blood pressure control with less antihypertensive drugs. Group II compared 2 subgroups of patients receiving kidneys from the same donor, one treated with cyclosporine and the other with tacrolimus. Tacrolimus patients showed better renal function; namely, creatinine was 1.15 +/- 0.27 versus 1.44 +/- 0.33 mg/dL (P =.029) and creatinine clearance was 87.7 +/- 27.1 versus 60.3 +/- 25.9 mL/min (P =.043). Lipid and blood pressure values were not different between the 2 subgroups, but tacrolimus patients tended to need a lower number of antihypertensive medications. The incidence of de novo diabetes mellitus was approximately 20% among patients using tacrolimus. We concluded that tacrolimus may be less nephrotoxic than cyclosporine. Tacrolimus patients showed better graft function and easier blood pressure control, but a high incidence of posttransplantation diabetes mellitus.     

Blood pressure reduction associated with preservation of renal function in hypertensive patients with IgA nephropathy: a 3-year follow-up

BACKGROUND: The relative importance of hypertension in the progression of renal failure is well understood. Recently, several studies have provided evidence that antihypertensive therapy enhances renal survival. However, the specific antihypertensive drug regimens that are most effective in generating such long-term effects remain controversial. PATIENTS AND METHODS: Forty-nine hypertensive IgA nephropathy (IgAN) patients (39 +/- 7 years old, serum creatinine 1.1 +/- 0.2 mg/dl) with proteinuria received antihypertensive therapy with angiotensin-converting enzyme inhibitors (ACEi: 2.5-10 mg of benazapril daily) and calcium channel blockers (CCBs: 2.5-10 mg amlodipine daily) for 3 years. The patients' blood pressures in group one were controlled below 140/85 mmHg by increases in their first drug dose or by addition of the second drug in group 1. Blood pressures for patients in group 2 were controlled using the same two options, except to levels below 130/70 mmHg. Patients within the two groups were selected and controlled with regard to sex, age, and serum creatinine. The renal protective effects of each protocol were evaluated in terms of reductions in creatinine clearance. After 3 years of the above outlined blood pressure control regimens, the reductions in creatinine clearance were compared. RESULTS: Creatinine clearances decreased in group 1 patients (from 85.7 +/- 2.4 ml/min to 72.9 +/- 2.4 ml/min, p < 0.05). On the other hand, creatinine clearance remained essentially unchanged for patients in group 2 (from 87.2 +/-4.7 ml/min to 85.9 +/- 5.9 ml/min). Although creatinine clearance in both groups was almost the same at the start of study, there was a significant difference between them by the conclusion of the study (p < 0.05). Proteinuria and hematuria did not change significantly throughout the study and there were no significant differences in these respects between these two corresponding groups. There were no significant differences between the groups with reference to side-effects or complications. CONCLUSION: These data provide evidence that reducing blood pressure has protective renal effects in cases of mild renal insufficiency with hypertension in IgA nephropathy.     

Randomized, double-blind, placebo-controlled trial to evaluate efficacy of ketodiet in predialytic chronic renal failure.

OBJECTIVE: To assess whether a ketodiet, a combination of ketoanalogs of essential amino acids (KAs) and a very low-protein diet, retards progression of chronic renal failure and maintains nutritional status. DESIGN: A prospective, randomized, double-blind, placebo-controlled trial. SETTING: Nephrology outpatient department in Northern Railways Central Hospital, New Delhi, India. PATIENTS: Thirty-four patients in predialytic stages of chronic renal failure (CRF), randomized to 2 comparable groups in terms of age, sex distribution, blood pressure control, etiology, use of angiotensin converting enzyme inhibitors, serum creatinine, glomerular filtration rate (GFR), and body mass index (BMI). INTERVENTION: Subjects randomly received either 0.6 g/kg/d protein plus placebo (n = 16) or 0.3 g/kg/d protein plus tablets of KAs (Ketosteril; Fresenius Kabi, Germany) (n = 18) for 9 months. A dietician administered the diet as well as the KAs or the placebo to the patients. OUTCOME MEASURES: Changes in GFR and renal and nutritional parameters were measured. RESULTS: Mean (+/- SD) GFR measured by the 99mTc-DTPA (99 m technetium diethylenetri-aminepenta-aceticacid) plasma sample method was unchanged in the ketodiet group: 28.1 +/- 8.8 (before) and 27.6 +/- 10.1 mL/min/1.73 m2 (after the study) (P =.72). However, it significantly decreased from 28.6 +/- 17.6 to 22.5 +/- 15.9 mL/min/1.73 m2 in the placebo group (P =.015). Serum creatinine before and after the study in the ketodiet group was 2.26 +/- 1.03 mg/dL and 2.07 +/- 0.8 mg/dL (P =.90) and in the placebo group was 2.37 +/- 0.85 and 3.52 +/- 2.9 mg/dL (P =.066), respectively. In both groups the mean BMI did not change from 25.4 +/- 4.2 to 24.5 +/- 4.2 kg/m2 (P =.46) for ketodiet and from 25.0 +/- 6.8 to 23.9 +/- 4.1 kg/m2 (P =.39) for the placebo group. Serum total proteins decreased significantly (P =.038) in the placebo group, and serum albumin showed a trend (P =.061) toward reduction, whereas both of these parameters were maintained in the ketodiet group. CONCLUSION: Over a 9-month period, very low-protein diet supplemented with ketoanalogs helped CRF patients to preserve GFR and maintain BMI. KAs were safe and efficacious in retarding the progression of renal failure and preserving the nutritional status of CRF patients.