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.     

Ambulatory blood pressure monitoring and progression in patients with IgA nephropathy.

BACKGROUND: Hypertension is a recognized marker of poor prognosis in IgA nephropathy. METHODS: The present study investigated the prevalence of white-coat hypertension, the diurnal rhythm of blood pressure (BP), the effectiveness of antihypertensive drug therapy, and the effect of the above on the progression of the kidney disease in IgA nephropathy. One hundred twenty-six IgA nephropathy patients were selected consecutively for 24-h ambulatory blood pressure monitoring (ABPM). Fifty-five patients were normotensive and 71 were treated hypertensives. Their antihypertensive drugs were angiotensin-converting enzyme inhibitors (ACEI) alone or in combination with calcium-channel blockers (CCB). RESULTS: The mean night-time BP of normotensives (108+/-9/67+/-6 mmHg) was significantly lower than their day-time BP (125+/-8/82+/-7 mmHg, P<0.05). There was no significant difference between the mean day-time and night-time BP in hypertensive patients (125+/-9/82+/-7 mmHg vs 128+/-10/85+/-9 mmHg). The circadian variation of BP was preserved ('dippers') in 82% of the normotensive and 7% of the hypertensive patients (P<0.001). There were 10 'white-coat hypertensives' among the patients classified as normotensives with ABPM (mean office blood pressure 149+/-7/96+/-8 mmHg, 24-h blood pressure 127+/-6/83+/-5 mmHg, P<0.05) and 14 among treated hypertensives (mean office BP 152+/-8/98+/-6 mmHg, 24-h BP 130+/-4/85+/-8 mmHg, P<0.05). There was no difference in mean day-time BP among normotensive and treated hypertensive patients (125+/-8/81+/-5 mmHg vs 128+/-10/85+/-9 mmHg). Hypertensives had significantly higher night-time BP (125+/-9/85+/-9 mmHg) than normotensives (108+/-9/67+/-6 mmHg, P<0.001). There was no difference in serum creatinine levels among the different groups at the time of the ABPM. However, thirty-six+/-4.1 months after the ABPM, hypertensive patients (n=52) had higher serum creatinine levels (124+/-32 micromol/l) than at the time of the ABPM (101+/-28 micromol/l). The serum creatinine of normotensive patients (n=43) did not change during the follow-up period. 'Non-dipper' normotensives (n=10) had significantly higher serum creatinine levels at the end of the follow-up period than at its beginning (106+/-17 micromol/l vs 89+/-18 micromol/l, P<0.05). There was no increase in serum creatinine of 'dipper' normotensives. The mean serum creatinine of 'white-coat hypertensives' was significantly higher at the end of the study period than at its beginning. CONCLUSIONS: There is no diurnal blood pressure variation in most of the hypertensive IgA nephropathy patients. ACEI and CCB treatment have better effect on day-time than night-time hypertension. The lack of the circadian rhythm and 'white-coat hypertension' seems to accelerate the progression of IgA nephropathy.     

Short-term effects of fish oil treatment on urinary excretion of high- and low-molecular weight proteins in patients with IgA nephropathy

AIMS: Recently, it was shown that fish oil treatment improved renal survival in patients with IgA nephropathy. The precise mechanisms of this protective effect remained unclear. Omega-3 polyunsaturated fatty acids (PUFAs), important active substances of fish oil, are able to attenuate inflammatory responses. Thus, the renoprotective effects of fish oil may be the result of mitigation of glomerular or tubulo-interstitial inflammation. We hypothesized that such a decrease in glomerular or tubulo-interstitial inflammation could result in an improvement of glomerular permselectivity as reflected by the urinary excretion of IgG, or of tubular reabsorption capacity as reflected by the urinary excretion of low-molecular weight proteins (LMWPs), or a decrease of the excretion of the inflammatory mediators MCP-1 and TNF-alpha. METHODS: Twelve patients with a biopsy-proven IgA nephropathy, a persistent proteinuria of > 0.5 g/24 h, and an impairment of renal function (creatinine clearance 44 ml/min/1.73 m2, range 19-72) were treated with fish oil for 6 months. The daily dosage of PUFAs amounted to 3.0 g. Before start of treatment (month 0), at the end of treatment (month 6), and 6 months off treatment (month 12), renal measurements were carried out. Creatinine clearance (ECC) was measured after pretreatment with cimetidine. In timed urine samples albumin, IgG, the LMWPs beta2-microglobulin and alpha1-microglobulin, and both MCP-1 and TNF-alpha were measured. RESULTS: Six months of fish oil treatment had no effect on creatinine clearance (44 ml/min/1.73 m2 vs 42 ml/min/1.73 m2), the urinary excretion of albumin (1,594 +/- 284 vs 1,370 +/- 337 microg/min), IgG (84 +/- 16 vs 82 +/- 20 microg/min), beta2-microglobulin (medians: 1.0 vs 0.8 microg/min), alpha1-microglobulin (38 +/- 9 vs 53 +/- 15 microg/min), MCP-1 (medians: 720 vs 782 microg/min), or TNF-alpha (medians: 31 vs 27 microg/min). Mean arterial pressure gradually decreased from 102 +/- 4 to 96 +/- 4 mmHg at the end of the treatment (n.s.), however, the lowest value was observed after fish oil had been stopped for 6 months (93 +/- 3 mmHg, p < 0.05). Changes in the excretion of the urinary proteins during the 12-month study period were correlated to changes in blood pressure (r = 0.57, p < 0.01), independent of fish oil treatment. The course of the disease over the 12-month study period in our fish oil-treated patients was comparable to that of an untreated control group. CONCLUSIONS: Fish oil treatment in patients with IgA nephropathy, renal insufficiency and proteinuria did not affect the excretion of low- or high-molecular weight proteins, MCP-1 or TNF-alpha. Our data do not provide arguments for beneficial effects of fish oil treatment on glomerular permselectivity of tubulo-interstitial inflammation.     

Steroid and cyclophosphamide therapy for IgA nephropathy associated with crescenteric change: an effective treatment

BACKGROUND: IgA nephropathy is the most common form of idiopathic glomerulonephritis. There is no current consensus on treatment for this condition. We report on the effect of immunosuppression with corticosteroids and cyclophosphamide for the treatment of IgA nephropathy associated with crescenteric change. METHODS: The effect of oral prednisolone (0.8 mg/kg initially, reducing to 0.4 mg/kg after 4 weeks) and cyclophosphamide (1.5 mg/kg) given until a plateau of response was obtained was studied in 9 patients with IgA nephropathy associated with severe inflammatory change and crescents. The initial diagnostic renal biopsies of these patients revealed 25-70% of the glomeruli effected with active cellular crescents. When response to therapy, plateaued cyclophosphamide was discontinued and prednisolone reduced from 0.4 mg/kg. Follow-up renal biopsy was performed in 8 of the 9 patients. Patients were maintained on prednisolone (5- 7.5 mg) and azathioprine (1 mg/kg) for further 2 years. RESULTS: The mean time until discontinuation of cyclophosphamide was 17.8 weeks (+/-1.23, range 12-25 weeks). There were no serious complications of therapy. There was an improvement in renal function in all patients with serum creatinine falling from a mean of 149.6+/-16.5, range 81-227 micromol/l to 116.4+/-8.6, range 80-158 micromol/l, p=0.01. Creatinine clearance improved from a mean of 57.1+/-9.9, range 21-104 ml/min to 87.2+/-10.1, range 39-125 ml/min, p=0.004. 24-hour urinary total protein fell over the same time m period from a mean of 4.54+/-1.1, range 1.0-11.27 g to 1.2+/-0.27, range 0.01-2.65 g, p=0.004. There were no significant differences in blood pressure during this time. Repeat renal biopsies showed significant degrees of histological improvement with healing of crescents and a reduction in acute inflammatory change in all except one patient. The mean period of follow-up after cessation of cyclophosphamide was 17.4+/-2.8 months, range 10-36 months. There was no significant change over this period in serum creatinine, creatinine clearance or urinary protein losses. CONCLUSION: These data suggest that IgA nephropathy associated with severe inflammatory and crescenteric change can be effectively and safely treated with a low-cost regime based on oral corticosteroids and cyclophosphamide tailored to a plateau of treatment response in individual patients.     

Lercanidipine in patients with chronic renal failure: the ZAFRA study

OBJECTIVE: The objective was primary to evaluate the safe use of a new calcium channel blocker, lercanidipine, in patients with chronic renal failure (CRF). The secondary objective was to study the protective effect of calcium channel blocker on renal function in CRF patients previously treated with ACE inhibitors or angiotensin receptor blockers. DESIGN AND METHODS: The study recruited 203 CRF patients (creatinine >1.4 mg/dL for males, creatinine > 1.2 mg/dL for females, or creatinine clearance <70 mL/min). All patients were receiving ACE inhibitors (63.4%) or angiotensin II antagonist (36.6%) therapy, but they had higher blood pressure than recommended for CRF (130/85 mmHg). No patients were under diuretic treatment. Patients were clinically evaluated 1, 3, and 6 months after starting treatment with lercanidipine. Samples for urine and blood examination were taken during the examination. When needed, a third drug was added to the treatment, excluding diuretics. Creatinine clearance was measured using 24 h urine collection. RESULTS: 175 patients rendered valuable for the study (age 63.9+/-11.9 years, 52.9% males and 47.1% females). Blood pressure (BP) significantly decreased from 162+/-17/93+/-8.3 mmHg to 132+/-12/78+/-6 mmHg. 89.2% of patients showed a significant BP reduction, and 58.1% achieved optimal BP control (<130/85 mmHg). Seven patients (3.4%) showed untoward effects. Not one case of edema was detected, and the prevalence of adverse effects related to vasodilatation was extremely low (three patients, 1.48%). Plasmatic creatinine did not change (1.9+/-0.5 baseline versus 1.9+/-0.6 mg/dL), but creatinine clearance increased at the end visit (41.8+/-16.0 baseline versus 45.8+/-18.0 mL/min, p=0.019). Plasmatic cholesterol also decreased from 221+/-46 to 211+/-35 mg/dL (p=0.001). CONCLUSIONS: Lercanidipine showed a high antihypertensive effect in CRF patients. It has a good tolerability profile and showed an interesting effect on plasmatic lipids. An improvement in renal function, measured through creatine clearance, was detected.     

Treatment of IgA nephropathy with eicosapentanoic acid (EPA): a two-year prospective trial

Thirty-seven patients with biopsy proven mesangial IgA nephropathy were prospectively allocated to either two years of treatment with eicosapentanoic acid (EPA) 10 g per day or no treatment. At entry treated and untreated patients with renal dysfunction (Group A) or patients with normal serum creatinine less than 0.12 mmol/l (Group B) did not differ in serum creatinine, creatinine clearance, urinary protein excretion, or quantitative urinary red cell counts. Compliance with EPA therapy was excellent as assessed by plasma fatty acid profiles. At the end of the trial creatinine clearance in treated patients had gone from 80 +/- 16 to 57 +/- 17 ml/min (p less than 0.05) and in untreated patients from 76 +/- 18 to 55 +/- 14 (p less than 0.05). There were no beneficial effects in either Group A or Group B patients. The only two patients who had improvement in renal function were in the EPA treatment group. Although no side effects of treatment were noted, EPA does not alter the course of established mesangial IgA nephropathy.     

Renal handling of enalaprilat.

Most converting enzyme inhibitors share a predominantly renal dual elimination pathway consisting of glomerular filtration and tubular secretion. Since enalaprilat has two functional acidic groups, it is likely that it may be secreted via the proximal tubule organic acid system and, thus, its clearances would exceed that of glomerular filtration rate markers. We therefore examined the renal clearance of enalaprilat in normal volunteers and compared it with simultaneously measured inulin and creatinine clearances to explore the contribution of tubular secretion to the renal elimination of the drug. Twelve healthy male subjects with an age range of 24 to 58 years (mean +/- SE, 33.1 +/- 2.8) were studied. They had representative height (178.6 +/- 1.99 cm) and weight (73.3 +/- 2.1 kg) and had normal renal function as judged by blood urea nitrogen (BUN) (6 +/- 0.3 mmol/L [17 +/- 0.8 mg/dL]), plasma creatinine (88 +/- 3 mumol/L [1.0 +/- 0.03 mg/dL]), and creatinine clearance determined by a prestudy 24-hour urine collection (123.2 +/- 6.2 mL/min). Results are as follows: mean creatinine clearance, 2.12 mL/s (127 mL/min); mean inulin clearance, 119.1 ml/min mean creatinine clearance/inulin clearance, 1.07 mean enalaprilat protein binding, 37.9% unbound enalaprilat clearance, 222.4 ml/min; and the mean fractional enalaprilat clearances were: enalaprilat clearance/creatinine clearance, 1.72 (P less than 0.05, difference from 1.0); enalaprilat clearance/inulin clearance, 1.85, (P less than 0.05, difference from 1.0). Our results demonstrate that the clearance of free enalaprilat exceeds that of inulin and creatinine, suggesting that elimination of the drug proceeds through two complementary pathways, namely glomerular filtration and tubular secretion.     

Steroid therapy in IgA nephropathy: a retrospective study in heavy proteinuric cases

29 patients with IgA nephropathy whose proteinuria persisted at a level of 2.0 g/day or more and who received prednisolone treatment for 1-3 years were retrospectively evaluated on their clinical courses. 13 of 14 patients with renal dysfunction of less than 70 ml/min in initial creatinine clearance (Ccr) values subsequently entered a progressive course during a follow-up period of 47 months, leading to end-stage renal failure in 8 cases. On the other hand, only 1 of the other 15 patients with preserved renal function of 70 ml/min or more ended up with end-stage renal failure during a follow-up period of 74 months, although 7 underwent a progressive course. Three patients in the latter group experienced a prominent reduction in proteinuria to less than 1.0 g/day and maintained renal function. Meanwhile, the steroid group of moderate proteinuric patients with a creatinine clearance greater than 70 ml/min had a benign course, while the nonsteroid group had an unfavorable one. These results suggest that steroid therapy in IgA nephropathy may be able to stabilize a progressive course, especially in the early stage of the disease, although, because they come from an uncontrolled study, a definite conclusion cannot be drawn.     

Long-term results in renal transplant patients with allograft dysfunction after switching from calcineurin inhibitors to sirolimus.

BACKGROUND: Switching from calcineurin inhibitors (CNIs) to sirolimus might improve renal function in chronic renal transplant patients. METHODS: In a prospective study, we assessed long-term efficacy and safety parameters in 43 renal transplant recipients who were switched from a CNI (cyclosporin A, 65%; and tacrolimus, 35%) to sirolimus for either chronic allograft dysfunction (n = 38) or recurrent cutaneous cancers (n = 5). A kidney biopsy was done in 79% of patients prior to conversion, and showed either chronic allograft nephropathy (n = 26) or CNI nephrotoxicity (n = 7). Conversion was either abrupt or progressive, with CNI withdrawal over 3 weeks. All patients also received steroids with or without mycophenolate mofetil or azathioprin. Patient data were recorded at baseline (D0), at 1 (D30) and 6 months (D180), and at 1, 1.5 and 2 years post-conversion. RESULTS: After a mean post-conversion follow-up of 27+/-1.5 months, 58% of the patients were still on sirolimus. The survival of intent to treat patients and grafts was 95.3 and 93%, respectively. Overall, there was significant improvement in renal function, creatinine clearance increasing from 49.4+/-14.9 to 53+/-16.3 ml/min at D30 (P = 0.01), and to 54.7+/-20 ml/min at D180 (P = 0.01). Thereafter, creatinine clearance was not different from baseline, i.e. 54.7+/-21.7, 52.8+/-20 and 51.7+/-20.3 ml/min at years 1, 1.5 and 2, respectively. We divided the patients into two groups: responders (n = 29), those with an increase in creatinine clearance at 6 months post-conversion compared with D0, and non-responders (n = 14), those with a decrease in creatinine clearance at 6 months post-conversion compared with D0. In univariate analysis, factors predictive of response included proteinuria at D0 and the magnitudes of the differences between D30 and D0 for serum creatinine and lactate dehydrogenase. The conversion was associated with (i) significant decreases in serum calcium, phosphorus and uric acid, and in haemoglobin levels; (ii) significant increases in serum alkaline phosphatase, total cholesterol, parathyroid hormone, and the number of patients on statin and recombinant erythropoietin therapies; and (iii) the appearance of de novo proteinuria of >1 g/day in 28% of patients (P < 0.0009), which was >2 g/day in 12% of the entire cohort. Kidney biopsies in 17 patients 2 years after conversion showed the same Banff scores as observed at baseline. We identified three independent predictive factors for a renal response to the switch: absence of proteinuria, presence of antihypertensive therapy at D0 and serum lactate dehydrogenase level at D30. CONCLUSION: Conversion from CNIs to sirolimus in renal transplant patients with chronic allograft nephropathy was associated with improved renal function; however, 33% of the patients developed overt proteinuria.     

Effect of Lisinopril on the progression of renal insufficiency in mild proteinuric non-diabetic nephropathies.

BACKGROUND: The aim of the study was to determine whether Lisinopril, an ACE-inhibitor (ACEi), was more effective than other antihypertensive agents in slowing the progression of non-diabetic chronic renal diseases in patients with baseline proteinuria < or =1.0 g/day. METHODS: In an open, multicentre study all eligible patients entered a 3 months run-in phase during which antihypertensive therapy (with exclusion of ACEi) was adjusted in order to obtain a supine diastolic blood pressure < or =90 mmHg and urinary protein excretion and renal function stability were verified. One hundred and thirty-one patients with chronic renal insufficiency (Clcr between 20-50 ml/min) because of primary renoparenchymal diseases and proteinuria < or =1.0 g/day, were randomized to Lisinopril (L=66) or alternative antihypertensive therapy (C=65). Changes in renal function were assessed by inulin (Clin) clearance. RESULTS: During the follow-up period of 22.5+/-5.6 months, Clin did not change significantly in group L (-1.31+/-0.6 ml/min/1.73 m(2)) differing significantly from group C in which it declined markedly (-6.71+/-3.6 ml/min/1.73 m(2)) (P<0.04). Seven patients experienced adverse events that prompted discontinuation of treatment: four in group L and three in group C; in addition seven patients showed severe deterioration in renal function requiring dialysis: two in group L and five in group C. The overall risk of the combined end-points: need for dialysis or halving of GFR was significantly higher in group C versus group L. During the study the mean value for systolic blood pressure was 137.8+/-14.6 SD mmHg in group L and 140.8+/-14.1 SD mmHg in group C; the mean difference between groups, during and at the end of the study, was 2 mmHg (NS). The mean diastolic blood pressure during the study was 83.8+/-8.6 SD mmHg in group L and 84.3+/-7.56 SD mmHg in group C; during and at the end of the study the mean diastolic difference between groups was 1 mmHG: CONCLUSION: This study, employing a sensitive measurement of renal function and with similar blood pressure in both groups, provides support to the hypothesis that ACEi have a specific renoprotective effect, in addition to blood pressure control, also in patients with mild proteinuria.     

Long-term follow-up of ACE-inhibitor versus β-blocker treatment and their effects on blood pressure and kidney function in renal transplant recipients

Hypertension and nephrotoxicity are frequent complications of cyclosporine-induced immunosuppression in renal transplant recipients. Long-term antihypertensive treatment is obligatory for hypertensive transplant patients, to protect allograft function. The use of angiotensin-converting enzyme (ACE) inhibitors in the anti-hypertensive treatment of renal transplant recipients who receive immunosuppression with cyclosporine has long been discussed controversially. The aim of this prospective study, with a duration of 2 years and a follow-up of another 3 years, was to estimate the long-term antihypertensive potential of quinapril compared with that of the beta-blocker atenolol and to compare their effects on renal allograft function and proteinuria in 96 hypertensive renal transplant recipients who received cyclosporine A as immunosuppressive therapy. Patients were randomly assigned to receive either quinapril (group Q) or atenolol (group A) as anti-hypertensive treatment. Forty patients of each group completed the 5-year observation period according to protocol. Intention-to-treat and according-to-protocol analyses were performed. With the patients starting at similar baseline blood pressure values, both agents, atenolol and quinapril, decreased systolic and diastolic blood pressure (SBP, DBP) as well as middle arterial pressure (MAP) and pulse pressure (PP) to a similar extent (Delta SBP: group Q: -8+/-3 vs group A mmHg: -5+/-3; Delta DBP: -5+/-2 vs -4+/-2 mmHg; Delta MAP: -6+/-2 vs -5+/-2 mmHg; Delta PP: -2+/-2 vs -1+/-3 mmHg; mean +/- SEM). Neither serum creatinine levels nor Cockcroft-Gault clearance had changed significantly in either group after the 5-year period (Delta creatinine: 0.1+/-0.1 vs 0.2+/-0.2 mg/dl; Delta Cockcroft-Gault clearance: 3.9+/-4.6 vs 2.8+/-4.3 ml/min; mean +/- SEM). Urinary protein excretion remained stable among the quinapril-treated patients, whereas a significant increase was observed in the atenolol group during the 5-year study period (group Q: from 0.52+/-0.08 to 0.54+/-0.14 g/24 h; group A: from 0.34+/-0.03 to 0.72+/-0.13 g/24 h, P<0.02; mean +/- SEM). Albuminuria increased comparably in both groups, while the excretion of alpha-microglobuline increased slightly in the atenolol group, but decreased slightly in the quinapril group. The difference between the groups failed to be statistically significant (ANOVA, P<0.056). In conclusion, quinapril and atenolol may be considered suitable and safe substances in the long-term treatment of hypertensive renal transplant recipients, since both agents prove to be effective in anti-hypertensive treatment, and keep allograft function stable over a period of 5 years.     

The effects of dual blockade of the renin-angiotensin system on urinary protein and transforming growth factor-beta excretion in 2 groups of patients with IgA and diabetic nephropathy

AIMS: The therapeutic benefits of dual blockade of the renin-angiotensin system (RAS) have been inconsistent on renal function and proteinuria. To know the contribution of the heterogeneity of study subjects to such inconsistency, we evaluated the effects of dual blockade of RAS in 2 groups of selected renal diseases, IgA and diabetic nephropathy. To avoid confounding by the blood pressure-reducing effects, angiotensin II receptor antagonists (ATRAs) were added on the patients with long-term, optimally controlled blood pressure taking ACE inhibitors. Twenty-four-hour urinary protein excretion rate and urinary TGF-beta1 level were measured as surrogate markers of renal injury. METHODS: We conducted a prospective crossover trial with 14 IgA and 18 type-2-diabetic nephropathy patients showing moderate degree of proteinuria (> or = 1.0 g/day) and renal dysfunction (creatinine clearance 25 - 75/ml/min). Four to 8 mg once-daily dose of candesartan and placebo were alternatively added on ramipril dose of 5 - 7.5 mg/day for 16 weeks. RESULTS: All baseline data except for the age factor were statistically the same between the 2 disease groups. Twenty-four-hour mean arterial blood pressures were 91.2 +/- 1.6 and 92.3 +/- 1.8 mmHg in IgA and diabetic nephropathy patients respectively at baseline (p = NS). Mean arterial pressure did not change by the addition of candesartan or placebo in both groups. The addition of candesartan (combination) reduced 24-hour urinary protein excretion rate in IgA nephropathy patients with a mean change of -12.3 +/- 4.5%, which is significantly greater compared to a mean change of -0.1 +/- 3.3% after the addition of placebo (placebo) (mean difference 12.4 +/- 5.0, 95% CI 1.2 - 23.5; p < 0.05). Urinary TGF-beta1 level was reduced considerably by the combination therapy, with a -28.9 +/- 6.0% decrease, which was significantly different to that by the placebo, with +4.3 +/- 12.4% (33.3 +/- 13.5, 3.2 - 63.3; p < 0.05). In diabetic nephropathy patients, the addition of candesartan did not reduce 24-hour urinary protein excretion rate. Mean changes of 24-hour urinary protein excretion rate were -0.8 +/- 4.7% by the combination therapy and +0.5 +/- 6.1% by placebo (mean difference 1.3 +/- 4.7, 95% CI -6.8 - 13.5; p < NS). The level of urinary TGF-beta1 was reduced by the combination therapy, with -14.3 +/- 9.5% decrease, but it did not reach statistical significance compared to placebo of +0.7 +/- 15.5% (15.0 +/- 13.5, -14.4 - 44.5; p < NS). The changes in 24-hour urinary protein excretion rate and urinary TGF-beta1 level were neither correlated with each other, nor with the change in mean arterial pressure. Significant changes in the renal function were not detected during the study period. CONCLUSION: Definite beneficial effects of dual blockade of RAS on proteinuria and TGF-beta1 excretion were found in IgA nephropathy patients, which was independent of blood pressure-reducing effect. With our 16-week trial, such benefits were not observed in type 2 diabetic nephropathy. The reduction in urinary TGF-beta1 level suggests that the combination therapy may provide additional renoprotection through the antisclerosing effects. Based on our results, for a proper interpretation the therapeutic effects of the combination therapy should be evaluated separately according to the underlying renal disease.     

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.     

Effects of famotidine, a new histamine H2-receptor antagonist, on renal function

The effects of famotidine on renal function were investigated. Eight healthy men (N) and 8 renal patients with varying degrees of renal failure (R.F.) participated in the trial. They were given either famotidine (40 mg) or cimetidine (800 mg) for 7 days. Cimetidine produced a significant decrease in creatinine clearance (from 131.6 +/- 12.9 to 107.7 +/- 3.4 ml/min (N), and 22.2 +/- 3.9 to 18.1 +/- 3.5 ml/min (R.F.], and increase in serum creatinine (from 0.96 +/- 0.05 to 1.09 +/- 0.04 mg/dl (N), and 3.46 +/- 0.62 to 3.86 +/- 0.51 mg/dl (R.F.], and a decrease in creatinine excretion (from 24.0 +/- 1.1 to 22.6 +/- 0.8 mg/kg/24 hr (N], respectively, although the reduction in creatinine excretion in the renal failure group was small. On the other hand, the famotidine treatment produced no significant changes in renal function in both subjects (creatinine clearance, 136.5 +/- 5.7 to 133.6 +/- 6.0 ml/min (N), and 21.9 +/- 3.6 to 20.9 +/- 4.1 ml/min (R.F.); serum creatinine, 0.98 +/- 0.02 to 0.99 +/- 0.02 mg/dl (N), and 3.24 +/- 0.43 to 3.46 +/- 0.55 mg/dl (R.F.); and urinary creatine, 25.1 +/- 1.0 to 25.3 +/- 1.0 mg/kg/24 hr (N), and 17.2 +/- 1.4 to 16.6 +/- 1.5 mg/kg/24 hr (R.F.]. There were no changes in the percent sodium excretion, or the serum and urinary beta 2-microglobulin in both groups.     

Renal function and cardiopulmonary bypass: effect of perfusion pressure.

Controversy continues as to whether hypotension during cardiopulmonary bypass (CPB) impairs intraoperative and postoperative renal function. Therefore, 21 patients with normal renal function (plasma creatinine less than 1.2 mg/dL, creatinine clearance greater than 70 mL/min), aged 50 to 70 years, without associated pathology, scheduled for elective coronary surgery were studied prospectively. Patients were randomized into two groups: group 1 included 14 patients whose arterial blood pressure during CPB was left untreated, and group 2 consisted of 7 patients who received phenylephrine to maintain their arterial pressure above 70 mmHg. Plasma and urine creatinine, sodium, potassium, and osmolality were measured preoperatively, intraoperatively and postoperatively. Creatinine, osmolal and free water clearances, and excreted sodium fraction were calculated. Plasma creatinine remained normal throughout the study in all patients. Creatinine clearances were similar preoperatively (101.9 +/- 36.7 in group 1 and 120.6 +/- 50.7 mL/min in group 2). In group 1, creatinine clearance decreased during CPB to 88.7 +/- 39.7 mL/min, whereas in group 2 it increased to 157.6 +/- 79.5 mL/min; the difference between groups was significant. Early postoperatively, there was no difference: 136.2 +/- 86.6 mL/min in group 1 and 100 +/- 21.4 mL/min in group 2. One week postoperatively, values were 100.5 +/- 37.9 and 101.9 +/- 18.4, respectively. There was a significant correlation between the creatinine clearance and perfusion pressure intraoperatively, but not postoperatively. Osmolal clearance also correlated with perfusion pressure intraoperatively, but it was significantly lower in the phenylephrine group postoperatively. Postoperative renal function was normal in all patients; no deleterious effect of a low arterial pressure during bypass could be identified.     

Serum uric acid and renal prognosis in patients with IgA nephropathy

BACKGROUND/AIMS: This study was designed to elucidate the clinical significance of serum uric acid (SUA) and the relationship between hyperuricemia and renal prognosis in IgA nephropathy. METHODS: The correlation between SUA and other clinical parameters were examined in 748 IgA nephropathy patients (432 males and 316 females). Among these patients, 226 (144 males and 82 females) who were followed for more than 5 years were examined for the relationship between hyperuricemia and renal prognosis. RESULTS: In IgA nephropathy, SUA correlated negatively with creatinine clearance (Ccr), and positively with urinary protein and tubulointerstitial damage. SUA was higher in patients with hypertension or diffuse proliferative glomerulonephritis. Hyperuricemia was a risk factor for renal prognosis, both in terms of serum creatinine (p = 0.0025) and Ccr (p = 0.0057). In 56 patients with normal Ccr at renal biopsy, the change of Ccr after more than 8 years was -22.3 +/- 20.8% in 13 patients with hyperuricemia, compared with +2.6 +/- 39.4% in 43 patients without hyperuricemia (p = 0.0238). Hyperuricemia was related independently to deterioration of Ccr (p = 0.0461). CONCLUSION: Hyperuricemia in IgA nephropathy is derived from both glomerular and tubulointerstitial damage, and correlated with hypertension. Hyperuricemia is a risk factor for renal prognosis in IgA nephropathy.     

What is the best hydration regimen to prevent contrast media-induced nephrotoxicity?

BACKGROUND: Hydration is a commonly used method to prevent the decline in GFR after contrast media (CM) application. So far, there have been no controlled, randomized trials investigating the most effective route of fluid administration. METHODS: Thirty-nine patients with normal renal function (65 +/- 9 years, serum creatinine 0.9 +/- 0.2 mg/dl, GFR = 110 +/- 31 ml/min/1.73 m2) receiving at least 80 ml of low-osmolality CM during an angiographic procedure were randomized to one of the following hydration regimens: Group 1: volume expansion with 300 ml saline during CM administration (n = 20, serum creatinine 0.8 +/- 0.1 mg/dl, GFR 119 +/- 27 ml/min/1.73 m2); Group 2: intravenous administration of at least 2,000 ml saline within 12 h before and after CM application (n = 19, serum creatinine 0.9 +/- 0.2 mg/dl, GFR 101 +/- 32 ml/min/1.73 m2). GFR was measured by CM clearance (Renalyzer) at baseline and 48 hours after CM administration. The primary end point was the mean change in the GFR after 48 hours, the secondary one was the incidence of CM-induced nephropathy (CMIN), defined as a decrease in GFR of more than 50% from the baseline GFR within 48 hours. RESULTS: Patients of group 1 showed a significantly (p < 0.05) higher decline in GFR (delta GFR 34.6 +/- 25.7 ml/min/1.73 m2) compared to patients receiving the intravenous prehydration regimen (delta GFR 18.3 +/- 25.0 ml/min/1.73 m2). The incidence of CMIN was lower in prehydrated patients (5.3%) compared to the other group (15%). CONCLUSION: In patients with normal renal function, intravenous prehydration seems to be a very effective and feasible method to prevent the decline in GFR after contrast media exposure. Volume expansion given only during the CM exposure appears not to be sufficient enough to prevent renal damage.     

Long-term beneficial effects of angiotensin-converting enzyme inhibition in patients with nephrotic proteinuria.

Angiotensin-converting enzyme inhibitors (ACEI) can reduce proteinuria in diabetic and nondiabetic nephropathy. However, no studies have determined whether this antiproteinuric effect modifies the progression of renal insufficiency. We studied the evolution of 46 nondiabetic patients with nephrotic proteinuria treated with captopril for a minimum of 12 months. The follow-up period before captopril treatment was 12 to 18 months. At the end of follow-up, after captopril introduction (24.4 +/- 7.6 months), proteinuria had decreased from 6.3 +/- 2.5 to 3.9 +/- 3.1 g/24 h (P less than 0.001), with a mean decrease of 45% +/- 28%. The proteinuria decrease was higher in patients with reflux nephropathy, proteinuria associated with reduction of renal mass, inactive crescentic glomerulonephritis, nephroangiosclerosis, and IgA nephropathy, whereas patients with membranous glomerulonephritis and idiopathic focal glomerulosclerosis showed a poorer response. Patients were separated according to a proteinuria reduction greater (group A, 23 patients) or lower (group B, 23 patients) than 45% of the initial value. At the end of follow-up, renal function had not significantly changed in group A with respect to values at the start of treatment: serum creatinine (SCr) was 229 +/- 167 mumol/L (2.6 +/- 1.9 mg/dL) versus 203 +/- 97 mumol/L (2.3 +/- 1.1 mg/dL), and creatinine clearance (CrCl) was 0.80 +/- 0.52 mL/s (48 +/- 31 mL/min) versus 0.87 +/- 0.47 mL/s (52 +/- 28 mL/min). The slope of the reciprocal of Scr (1/SCr) showed a significantly beneficial change after captopril introduction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prospective study on renal outcome of IgA nephropathy superimposed on diabetic glomerulosclerosis in type 2 diabetic patients.

BACKGROUND AND METHODS: In order to examine the clinical outcome of IgA nephropathy (IgAN) superimposed on diabetic glomerulosclerosis in type 2 patients we studied 36 Chinese patients (26 men, 10 women), who were recruited for renal biopsy when they had proteinuria of more than 1 g/day. Twenty-seven had isolated diabetic glomerulosclerosis and nine had IgAN superimposed on diabetic glomerulosclerosis (combined). Renal function was assessed by serial serum creatinine, 24-h urine protein and creatinine measurements. Patient survival rate, incidence of end-stage renal disease (ESRD), blood pressure, and glycaemic control status were determined. RESULTS: The age at the time of renal biopsy was younger for the combined group when compared with the diabetic glomerulosclerosis group (44+/-3.6 vs 58+/-2.1 years, P=0.006). The duration of diabetes was, however, similar for the two groups (8.0+/-2.3 vs 6.7+/-1.2 years, P=NS). After a mean follow-up of 31.6+/-15.3 months, 15 patients (one in the combined group and 14 in the diabetic glomerulosclerosis group) developed ESRD. Nine patients (all in the diabetic glomerulosclerosis group) died during follow-up. With similar glycaemic and blood pressure control, the two groups had comparable rate of decline of creatinine clearance (CrCl) (-0.73+/-0.26 vs -0.73+/- 0.18 ml/min/1.73 m(2)/month, P=NS), final serum creatinine (363+/-134 vs 426+/-52 micromol/l, P=NS) and proteinuria levels (4.3+/-0.9 vs 4.4+/-0.6 g/day, P=NS), as well as CrCl (44.1+/-19.0 vs 33.4+/-6.9 ml/min/ 1.73 m(2), P=NS). CONCLUSION: It is concluded that the superimposed IgAN does not significantly alter the medium-term clinical outcome of patients with diabetic glomerulosclerosis.     

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.