Prevalence of microalbuminuria in a large population of patients with mild to moderate essential hypertension.

To determine the prevalence of increased urinary albumin excretion (UAE) in essential hypertension and to establish whether this abnormality is associated with deranged renal function, we have measured UAE in a group of 123 patients with essential hypertension and in 110 normal subjects. Mean arterial pressure (MAP) was 96 +/- 0.6 mm Hg in normal subjects and 121 +/- 0.3 mm Hg in patients with essential hypertension (p less than 0.01). Mean UAE was 8.6 +/- 0.5 in normal subjects and 32.9 +/- 3.3 mg/24 h in patients with essential hypertension (p less than 0.01). Forty percent of patients with essential hypertension manifested a UAE exceeding 30 mg/24 h and had an average UAE of 72.0 +/- 4.7 mg/24 h. MAP in patients with increased UAE was similar to that in subjects with normal UAE (121 +/- 0.5 vs. 121 +/- 0.4 mm Hg). Creatinine clearance was also not different between these two groups (91 +/- 1.8 vs. 94 +/- 1.5 ml/min). No correlation was found between UAE and MAP or creatinine clearance. Long-term prospective studies are needed to extablish whether an increase in UAE may predict future nephrosclerosis in essential hypertension.     

Effects of a protein load in patients with early chronic renal failure before and after angiotensin II blockade

We studied the effects of mid-term enalapril administration on protein-load-induced renal responses in 10 patients with early chronic renal failure (serum creatinine 2.70 +/- 1.0 mg/dl). The oral protein load was performed twice, before and after a 10-day therapy with enalapril. Glomerular filtration rate (125I-iothalamate clearance) rose from 22.5 +/- 10.6 to 60.1 +/- 32.8 ml/min after the protein load before enalapril; it did not change after the protein load during enalapril therapy. Percent fractional excretion of sodium, urinary osmolality and free water clearance were significantly affected only by the protein load before enalapril. Enalapril blunts the protein-load-induced changes in glomerular filtration rate and in tubular function; these effects might be mediated by angiotensin II blockade.     

PROTECTIVE ROLE OF ENALAPRIL FOR CHRONIC TUBULOINTERSTITIAL LESIONS OF HYPEROXALURIA

PURPOSE: Hyperoxaluria is a recognized cause of tubulointerstitial lesions and it may contribute to chronic renal failure. In previous studies we demonstrated that enalapril was effective against the progression of tubulointerstitial lesions in a 4-week hyperoxaluria rat model. We evaluated whether the action of enalapril on the tubulointerstitial lesions produced by hyperoxaluria persisted for a long period. MATERIALS AND METHODS: Two-month-old male Sprague-Dawley rats were divided into 4 groups of 12 each, including 1--control animals given tap water, 2--animals with hyperoxaluria, 3--animals with hyperoxaluria plus enalapril, 4--animals with enalapril. Hyperoxaluria in groups 2 and 3 rats was induced by administering 1% ethylene glycol, a precursor for oxalates, in the tap water continuously throughout the whole study. Meanwhile, groups 3 and 4 received 20 mg./l. enalapril in the drinking water. At the end of the study renal tubulointerstitial lesions were evaluated by immunostaining using monoclonal antibodies against macrophage infiltrates (ED1), tubulointerstitial alpha-smooth muscle actin and transforming growth factor-beta1. The lesions were quantified by semiquantitative scores. Creatinine clearance and urinary albumin excretion were also determined. RESULTS: There was no difference in urine oxalate excretion in groups 2 and 3. Group 3 rats treated with enalapril showed fewer tubulointerstitial lesions than nontreated group 2 rats, as indicated by the mean scores plus or minus standard error of mean for inflammatory infiltrate (2.16 +/- 0.2 versus 0.83 +/- 0.16), tubular atrophy (2 +/- 0.27 versus 0.66 +/- 0.14), interstitial fibrosis (2.5 +/- 0.15 versus 0.5 +/- 0.1), glomerular ED1 (1.75 +/- 0.25 versus 0.16 +/- 0.11), interstitial ED1 (2.33 +/- 0.18 versus 0.58 +/- 0.10) tubular transforming growth factor-beta1 (2.09 +/- 0.08 versus 0.91 +/- 0.14), interstitial transforming growth factor-beta 1 (2.33 +/- 0.22 versus 0.66 +/- 0.12), tubulointerstitial alpha-smooth muscle actin (2.91 +/- 0.22 versus 0.83 +/- 0.16), lower urinary albumin excretion (35.5 +/- 2.7 mg. daily versus 10.9 +/- 1) and higher creatinine clearance (2.29 +/- 0.04 ml. per minute versus 2.54 +/- 0.03, all p <0.05). CONCLUSIONS: Based on our results we believe that enalapril would provide a beneficial effect against chronic tubulointerstitial lesions caused by oxalates.     

ACE inhibitorenalapril diminishes albuminuria in patients with cystinosis

BACKGROUND/AIMS: Cystinosis, a rare autosomal recessive disease, manifests with renal Fanconi syndrome during the first year of life. Interstitial damage is a major cause of renal failure in patients with cystinosis. We presume that albuminuria contributes to the development of renal failure in these patients. The aim of this study was to examine whether the administration of ACE inhibitor enalapril diminishes albuminuria in patients with cystinosis. METHODS: Five patients with cystinosis aged 4 - 9 years were studied. All patients had Fanconi syndrome and were treated with cysteamine. Median creatinine clearance was 48 ml/min/1.73 m2 (range 21 - 61). The excretion of albumin and alpha1 microglobulin as well as arterial blood pressure and serum creatinine were evaluated before and at 3 months on oral administration of enalapril (0.15 mg/kg once daily). RESULTS: At 3 months on enalapril, albuminuria decreased in all patients (1,042 vs 629 mg per 24 h, p < 0.05). The median reduction of albuminuria was 43% (range: 4 - 72%, p < 0.05). Urinary excretion of alpha1 microglobulin remained constant. Systolic blood pressure decreased from median 110 - 100 mmHg (p < 0.05), while diastolic blood pressure remained stable (median 60 mmHg). Creatinine clearance decreased from median 48 - 45 ml/min/1.73 m2 (p < 0.05) and returned to previous values after discontinuation of enalapril. CONCLUSION: ACE inhibitor enalapril diminishes albuminuria in patients with cystinosis and might be used in these patients in order to slow the progression of renal insufficiency attributed to proteinuria.     

Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients

Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients. BACKGROUND: In hypertensive type 2 diabetic patients, treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with a lower incidence of cardiovascular events than those treated with calcium channel-blocking agents. However, the long-term renal effects of ACE inhibitors in these patients remain inconclusive. In 1989, we commenced a placebo-controlled, double-blind, randomized study to examine the anti-albuminuric effects of enalapril versus nifedipine (slow release) in 102 hypertensive, type 2 diabetic patients. These patients have been followed up for a mean trial duration of 5.5 +/- 2.2 years. We examined the determinants, including the effect of ACE inhibition on clinical outcomes in these patients. METHODS: After a six-week placebo-controlled, run-in period, 52 patients were randomized double-blind to receive nifedipine (slow release) and 50 patients to receive enalapril. After the one-year analysis, which confirmed the superior anti-albuminuric effects of enalapril (-54%) over nifedipine (+11%), all patients were continued on their previously assigned treatment with informed consent. They were subdivided into normoalbuminuric (N = 43), microalbuminuric (N = 34), and macroalbuminuric (N = 25) groups based on two of three 24-hour urinary albumin excretion (UAE) measurements during the run-in period. Renal function was shown by the 24-hour UAE, creatinine clearance (CCr), and the regression coefficient of the yearly plasma creatinine reciprocal (beta-1/Cr). Clinical endpoints were defined as death, cardiovascular events, and/or renal events (need for renal replacement therapy or doubling of baseline plasma creatinine). RESULTS: In the whole group, patients treated with enalapril were more likely to revert to being normoalbuminuric (23.8 vs. 15.4%), and fewer of them developed macroalbuminuria (19.1 vs. 30.8%) compared with the nifedipine-treated patients (P < 0.05). In the microalbuminuric group, treatment with enalapril (N = 21) was associated with a 13.0% (P < 0.01) reduction in 24-hour UAE compared with a 17.3% increase in the nifedipine group (N = 13). In the macroalbuminuric patients, enalapril treatment (N = 11) was associated with stabilization compared with a decline in renal function in the nifedipine group, as shown by the beta-1/Cr (0.65 +/- 4.29 vs. -1.93 +/- 2.35 1/micromol x 10-3, P < 0.05) after adjustment for baseline values. Compared with the normoalbuminuric and microalbuminuric patients, those with macroalbuminuria had the lowest mean CCr (75.5 +/- 24.1 vs. 63.5 +/- 21.3 vs. 41.9 +/- 18.5 mL/min, P < 0.001) and the highest frequency of clinical events (4.7 vs. 5.9 vs. 52%, P < 0. 001). On multivariate analysis, beta-1/Cr (R2 = 0.195, P < 0.001) was independently associated with baseline HbA1c (beta = -0.285, P = 0.004), whereas clinical outcomes (R2 = 0.176, P < 0.001) were independently related to the mean low-density lipoprotein cholesterol (beta = 2.426, P = 0.018), high-density lipoprotein cholesterol (beta = -8.797, P = 0.03), baseline UAE (beta = 0.002, P = 0.04), and mean CCr during treatment (beta = -0.211, P = 0.006). CONCLUSION: In this prospective cohort analysis involving 102 hypertensive, type 2 diabetic patients with varying degrees of albuminuria followed up for a mean duration of five years, we observed the importance of good metabolic and blood pressure control on the progression of albuminuria and renal function. Treatment with enalapril was associated with a greater reduction in albuminuria than with nifedipine in the entire patient group, and especially in those with microalbuminuria. In the macroalbuminuric patients, the rate of deterioration in renal function was also attenuated by treatment with enalapril.     

Urine calcium excretion, nephrogenous cyclic-adenosine monophosphate and serum parathyroid hormone levels in patients with essential hypertension.

To evaluate the role of calcium and the parathyroid gland in the pathophysiology of essential hypertension, creatinine clearance, urinary excretion of sodium, calcium and nephrogenous cyclic adenosine monophosphate (NcAMP) and serum parathyroid hormone (PTH) levels were measured in 25 newly diagnosed essentially hypertensive patients before institution of any treatment and in 25 age- and sex-matched normal volunteers. While no significant differences in creatinine clearance, serum total calcium levels or 24-hour sodium excretion existed between the two groups, hypertensives had a higher mean (+/- SD) 24-hour calcium excretion rate (199.0 +/- 44.7 vs. 152.8 +/- 33.6 mg, p less than 0.001), a higher mean NcAMP excretion rate (2.54 +/- 0.8 vs. 1.87 +/- 0.5 nmol/100 ml glomerular filtrate, p less than 0.001) and a higher mean serum PTH concentration (1.87 +/- 0.6 vs. 1.53 +/- 0.4 ng/ml, p less than 0.001) than the normotensives. A significant positive correlation existed between calcium and sodium excretion in both hypertensives (r = 0.66, p less than 0.001)) and normotensives (r = 0.67, p less than 0.001), but given the same levels of creatinine clearance and sodium excretion, hypertensives excreted more calcium than normotensives (p less than 0.001)). In both hypertensives and normotensives, serum PTH levels were positively correlated with NcAMP excretion (r = 0.42, p less than 0.05, and r = 0.41, p less than 0.05, respectively) and the ratio of urinary sodium to urinary calcium excretion (r = 0.59, p less than 0.001, and r = 0.75, p less than 0.001), respectively). The above results suggest that in essential hypertension, increased activity of parathyroid glands may occur as a consequence of increased urinary calcium losses which are presumably due to an intrinsic defect in renal calcium handling.     

Renal and metabolic effects of L-arginine infusion in kidney transplant recipients.

AIM AND METHODS: In order to investigate the role of kidney damage on renal response to L-arginine (L-Arg) infusion in transplant patients receiving cyclosporine A (CsA) treatment, we assessed systemic and glomerular hemodynamic variables, the fraction excretion of urinary sodium, albumin, cyclic GMP (as an index of nitric oxide (NO) production from L-Arg) and urea excretion (as an index of ureagenesis), and glucoregulatory hormone levels in five normal volunteers and 21 renal allograft recipients (aged 10-20 years) treated with CsA, 10 with normal renal function and 11 with chronic renal insufficiency. RESULTS: In the normal subjects, L-Arg infusion (290 mg/min/1.73 m2 for 1 h) significantly reduced mean arterial pressure (MAP) (76+/-7 to 70+/-5 mmHg) and renal vascular resistance (RVR), and increased GFR (103+/-9 to 122+/-7 min/1.73 m2), RPF, urinary cyclic GMP excretion (0.40+/-0.1 to 0.60+/-0.1 nmol/100 ml glomerular filtrate (GF)), and sodium and albumin excretion. Neither the patients with chronic graft dysfunction nor those with a normal graft responded to L-Arg infusion: RVR remained high, and MAP, GFR, RPF, fractional excretion of sodium and urinary excretion of albumin and cyclic GMP were unchanged in both groups of patients. Glucagon, insulin and urinary urea excretion rose significantly in controls and both patient groups. CONCLUSION: The hemodynamic effects of L-Arg infusion were inhibited in the patients, regardless of their degree of renal function, possibly because L-Arg-NO production was blunted.     

Protein-restricted diets in diabetic nephropathy

Low-protein diets in nondiabetic renal failure may slow the progressive loss of renal function in some patients, but few studies have detailed the nutritional consequences of these diets in patients with diabetic nephropathy. We studied 7 patients with insulin-dependent diabetes mellitus and chronic renal insufficiency [mean +/- SEM creatinine clearance (S, U): 28.3 +/- 6.5 ml/min (0.47 +/- 0.11 ml/s x 1.73/A)] for 15 weeks who were prescribed a diet of 0.6 g protein/kg ideal body weight. Midarm muscle circumference (24.1 +/- 1.8 at onset vs. 24.5 +/- 1.5 cm at completion), triceps skinfold thickness (21.6 +/- 3.1 vs. 21.0 +/- 1.5 mm), body weight (71.8 +/- 4.1 vs. 71.2 +/- 4.6 kg), and serum albumin [3.0 +/- 0.1 vs. 3.2 +/- 0.1 g/dl (30 +/- 1 vs. 32 +/- 1 g/l)] remained stable. Based on urinary nitrogen excretion, diet diaries overestimated the degree of dietary protein restriction; there was good adherence to the diet as evidenced by a reduction in urinary urea nitrogen (average 32%). Blood glucose control was maintained despite increased carbohydrate intake. On average, creatinine clearance did not change significantly, but proteinuria diminished slightly (1.8 +/- 0.2 vs. 1.5 +/- 0.6 g/day). These results indicate that 0.6 g/kg/day protein diets did not cause protein depletion in insulin-dependent diabetic patients. Longer-term studies are indicated to assess more fully the efficacy of these dietary regimens in reducing proteinuria or benefiting diabetic nephropathy.     

Relationship of systemic blood pressure to nephropathology in insulin-dependent diabetes mellitus.

Although hypertension is an important complication of diabetes it is unclear whether its association with other diabetic complications represents cause or consequence. Our study is a cross sectional evaluation of the relationship of blood pressure to renal structural and functional parameters. In 139 patients with insulin dependent diabetes for 18.9 +/- 7.4 years (mean +/- SD), we divided the patients into those with markedly increased mesangial volume fraction [Vv(mes/glom) greater than or equal to 0.37] and those with less [Vv(mes/glom) less than 0.37]. Hypertension (systolic BP greater than or equal to 160 and/or diastolic BP greater than 90 mm Hg or receiving BP medications) occurred in 29/40 with Vv(mes/glom) greater than or equal to 0.37. All 40 had clinical nephropathy with urinary albumin excretion (UAE) greater than 200 mg/24 hr. By two-way ANOVA creatinine clearance was lower and albuminuria was increased with both hypertension and the expanded mesangium. Also other measures of renal structure including filtration surface, index of interstitial fibrosis and index of arteriolar hyalinosis were increased by hypertension and mesangial expansion. Most patients with hypertension had other criteria for clinical nephropathy. Since, in these studies, we could not determine if hypertension contributed to or resulted from the renal lesions, we developed an estimate of the rate of mesangial expansion. We found that patients with normal BP (119 +/- 11/78 +/- 7 mm Hg) can be rapidly developing mesangial expansion. These studies support the view that the development of serious renal lesions can be independent of hypertension in IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical profiles and outcomes of end-stage renal failure patients with late initiation of renal replacement therapy based on uremic symptoms under intensive renoprotective therapies

AIM: This study describes the clinical profiles and outcomes of renal failure patients with late initiation of renal replacement therapies (RRT) based on uremic symptoms under intensive treatment prior to the start of RRT (IT). METHODS: Thirteen patients (male 10, female 3) with end-stage renal disease who preferred to wait for the initiation of RRT until uremic symptoms appeared regardless of serum creatinine (s-Cr) and 24-hour creatinine clearance (24-hour Ccr) were chosen. All patients received IT including a low-protein diet, antihypertensive drugs including enalapril, erythropoietin and others to prevent and manage uremic states until the initiation of RRT. Clinical findings at the initiation of RRT and the outcomes after the start of RRT were examined. RESULTS: RRT was initiated 23.6 +/- 16.9 months after IT without any complication in all patients when mild uremic symptoms appeared. Uremic symptoms, blood pressure, serum albumin, potassium, calcium and urinary Cr excretion were well controlled except inorganic phosphate, hemoglobin and cardiac size. 24-hour Ccr and s-Cr were 3.4 +/- 0.7 ml/min and 17.4 +/- 3.8 mg/dl at initiation of RRT. The outcomes of all the patients were all well during chronic RRT. CONCLUSION: Intensive treatment prior to the start of RRT can diminish uremic symptoms and complications so that RRT might be initiated safely and with fewer problems, even in the face of lower 24-hour Ccr and markedly higher s-Cr.     

Evaluation of kidney function in renal transplant patients receiving long-term cyclosporine

We prospectively assessed renal function in a group of 29 renal transplant patients receiving cyclosporine (CsA) in order to determine the course of their renal function over time and the relationship between different markers of glomerular function. We measured serum creatinine, DPTA, and creatinine clearances, and urinary albumin excretion. The clinical course of 24 patients (83%) permitted repeat studies over a period of 32 +/- 1 (SEM) months, and in these patients DTPA clearance, creatinine clearance, and the serum creatinine concentration did not vary with time. Five of the patients (17%) lost their grafts and returned to dialysis. On initial evaluation patients who lost their grafts had a lower DPTA clearance than those whose function was maintained (29 +/- 3 v 46 +/- 2 mL/min/1.73 m2 body surface area [BSA], respectively, P less than 0.005) and all of them had a DTPA clearance of less than 40 mL/min/1.73 m2 BSA. There was an inverse correlation between the log of the urinary albumin excretion and the DTPA clearance (n = 33, r = -0.59, P less than 0.001), a direct correlation with the serum creatinine concentration (N = 33, r = 0.89, P less than 0.0001), but no correlation with time after transplantation. Thus, despite the continued use of CsA, renal function over time was stable in patients who underwent repeated studies, as was the relationship between the DTPA clearance and the clinically used markers of transplant function, the serum creatinine concentration, and the creatinine clearance.     

Mild renal dysfunction and cardiovascular risk in hypertensive patients

Mild renal dysfunction, defined as GFR <60 to 70 ml/min and/or the presence of increased urinary albumin excretion, is associated with higher cardiovascular morbidity and mortality in primary hypertension. The aim of the present study was to investigate the relationship between renal dysfunction and target organ damage (TOD), namely left ventricular hypertrophy (LVH), retinal vascular changes, and carotid atherosclerosis, in a large cohort of unselected middle-aged hypertensive patients with normal serum creatinine. A group of 934 untreated patients with primary hypertension (543 men, 391 women; mean age 50 +/- 11 yr) was studied. Renal function was estimated by the creatinine clearance using the Cockcroft-Gault formula and by the presence of albuminuria, measured as the albumin to creatinine ratio (A/C) in first morning urine samples. LVH was determined according to electrocardiographic criteria, and retinal vascular changes were evaluated by direct ophthalmoscopy in all patients. In a subgroup of patients (n = 340; 208 men, 132 women; mean age 47 +/- 9), the presence and extent of cardiac and vascular organ damage was also assessed by ultrasound techniques. Creatinine clearance was on the average 82 +/- 20 ml/min. The overall prevalence of ECG-detected LVH and retinopathy was 12 and 49%, respectively. Creatinine clearance was inversely related to duration of disease, systolic BP, serum glucose, total cholesterol, LDL cholesterol, and early signs of TOD, namely retinal vascular changes and LVH. Patients in the bottom quintile of creatinine clearance showed higher prevalence of both ECG-determined LVH (P = 0.04) and retinal vascular changes (P = 0.02). In the subgroup of patients who underwent ultrasound evaluation of cardiovascular structures, the prevalence of mild renal dysfunction was 18%, whereas the prevalence of LVH and carotid plaque was 49 and 26%, respectively. Patients with mild renal dysfunction showed higher left ventricular mass and increased intima-media thickness (P < 0.0001), as well as higher prevalence of LVH and carotid plaque as compared with those with normal renal function. Controlling for duration of hypertension and mean BP, the risk of TOD in our cohort increased by 20% for each 10 ml/min decrease in creatinine clearance and by 30% for each 0.2 mg/mmol increase in Log A/C. In conclusion, mild renal dysfunction is associated with preclinical end-organ damage in patients with primary hypertension. These data may help to explain the observed increase in cardiovascular mortality reported in these patients. The evaluation of creatinine clearance and urinary albumin excretion could be useful for identifying patients who are at higher cardiovascular risk.     

Impaired fibrinolytic activity in type II diabetes: correlation with urinary albumin excretion and progression of renal disease

Progression of renal disease and cardiovascular complications in type II diabetes mellitus have been shown to correlate with control of blood glucose, lipids, blood pressure, and smoking. These factors, however, do not appear to totally explain these diabetic complications. Renal disease and cardiovascular complications in type II diabetes are associated with vascular abnormalities and fibrosis, both of which may occur with impaired fibrinolysis. A cross-sectional study was therefore performed in 107 type II diabetic patients recruited from the Denver Metropolitan Area to examine the effect of impaired fibrinolysis, as assessed by the ratio of plasminogen activator inhibitor (PAI-1) to tissue-type plasminogen activator (t-PA). With urinary albumin excretion (UAE) as a risk factor for both renal disease progression and cardiovascular complications, the patients were analyzed with respect to UAE less than and greater than 1 gm/day. The age, blood glucose, hemoglobin A1C, duration of diabetes, lipids, body mass index, and smoking were no different between the groups. As expected, the group with greater UAE had worse renal function, the serum creatinine (1.98 +/- 0.24 vs 1.21 +/- 0.05 mg/dl, P < 0.001) and creatinine clearance (55.5 +/- 6.0 vs 76.8 +/- 2.7 ml/min, P < 0.001) were significantly different. The type II diabetic patients with greater UAE exhibited significantly higher PAI-1/t-PA (2.43 +/- 0.26 vs 1.85 +/- 0.07, P < 0.03). The past history of cardiac complications was also higher (87.5 vs 72.3%, P < 0.07) in the diabetic patients with more impaired fibrinolysis and greater UAE. Thus a prospective, randomized clinical trial in type II diabetes with PAI-1 inhibitors is needed.     

Microalbuminuria and deterioration of renal function after elective repair of infrarenal abdominal aortic aneurysm

AIMS: Renal dysfunction affects the prognosis of patients after aortic surgery. However, the factors associated with the postoperative deterioration of renal function has not been clarified precisely. METHOD: We prospectively examined renal function in 80 patients (age: 73 +/- 7 years, 66 males) who required the elective repair of infrarenal abdominal aortic aneurysm (AAA). Serum creatinine (Scr) was measured. 24-h-creatinine clearance (Ccr) and urinary albumin excretion (UAE) were determined. Renal volume and mean renal length were calculated using the data obtained by ultrasonography. 48 patients showed normal UAE (< 30 mg/day), and 24 had microalbuminuria (30-300 mg/day) and 8 had overt proteinuria (> 300 mg/day). Scr were 0.9 +/- 0.4, 1.0 +/- 0.3 and 2.1 +/- 1.3 mg/dl, respectively. RESULTS: On Day 5 after surgery, 12 patients (15%) showed deterioration of renal function as defined either by an increase in Scr (> or = 0.5 mg/dl) or by a decrease in Ccr > or =20%). The acute deterioration of renal function was related to mean renal volume, mean renal length, duration of operation and the use of antibiotics. At Month 12 after surgery, Scr increased in the overt proteinuria group. The deterioration of renal function at Month 12 was found in 8 patients (10%) with microalbuminuria or overt proteinuria, and related to preoperative Ccr, UAE, mean renal volume, mean renal length, smoking status and blood pressure. CONCLUSION: We conclude that the deterioration of renal function occurred in considerable number of patients with AAA after elective operation on acute and chronic phase, although the development of end-stage renal failure is rare. Factors related to the acute and late deterioration appears to be different. UAE and renal size should be measured, even if Scr is in normal range at preoperative observation.     

Effects of ciclosporin on plasma renin activity, catecholamines and prostaglandins in patients with idiopathic uveitis

Animals and humans undergoing treatment with ciclosporin (CS) show a reversible increase in renal vascular resistance and a decrease in glomerular filtration rate. The causes of these abnormalities have not yet been established. We evaluated the effects of a 1-week treatment with CS on creatinine clearance, renal arachidonic acid metabolites, plasma renin activity (PRA), plasma aldosterone levels, urinary excretion and plasma levels of catecholamines in 7 patients with idiopathic uveitis. We show that CS treatment induces a significant (p less than 0.05) decrease in creatinine clearance (from 132 +/- 0.5 to 108 +/- 8 ml/min); urinary 6-keto-PGF1 excretion (from 17.8 +/- 4.9 to 10.9 +/- 3.3 ng/mmol creatinine), urinary thromboxane B2 excretion (from 7.0 +/- 1.0 to 3.6 +/- 0.9 ng/mmol creatinine), upright PRA (from 4.2 +/- 0.9 to 2.3 +/- 0.8) and supine PRA (from 2.0 +/- 0.5 to 1.1 +/- 0.3). We found no change in plasma aldosterone levels and plasma levels and urinary excretion of catecholamines. We suggest that the reversible renal vasoconstriction observed in patients treated with CS may be induced by inhibition of renal prostacyclin synthesis. In this setting inhibition of PRA and angiotensin II formation may impair autoregulation of effective filtration pressure and therefore glomerular filtration rate.     

Long-term treatment of chronic renal insufficiency with Ibopamine (SB 7505), a new orally active dopamine-related drug

When administered orally Ibopamine, the diisobutyric ester of N-methyldopamine, has pharmacological properties similar to intravenous dopamine: in particular, both renal blood flow and the urinary excretion of sodium and water increase. The drug also enhances creatinine clearance, both in normal subjects and in patients with impaired renal function. Twenty-eight patients affected with chronic renal insufficiency were treated with oral Ibopamine (100 mg/day) for 4-56 weeks. They were divided into 2 groups according to whether the creatinine clearance was more or less than 15 ml/min: Group 1 contained 21 patients (mean clearance 29.09 ml/min) and Group 2 7 patients (mean clearance 8.42 ml/min). Ibopamine treatment was ineffective in Group 2, while in Group 1 patients there was a statistically significant increase in creatinine clearance (+23% after 3 months, +31% after 6 months). Drug tolerance was excellent from both clinical and laboratory points of view.     

Urinary excretion of endothelin-1 in normal subjects and patients with renal disease

To elucidate the pathophysiological significance of urinary endothelin-1 (ET-1), we measured urinary excretion of ET-1-like immunoreactivity (L1) in 17 patients with renal disease and 9 normal subjects. Twenty-four hour urinary ET-1-L1 excretion in patients with renal disease (358 +/- 68 ng, mean +/- SE) was significantly (P less than 0.005) greater than that of normal subjects (77 +/- 5 ng). In patients with renal disease. ET-1-L1 clearance (CET) exceeded creatinine clearance (CCR); CET/CCR (305 +/- 81%) was significantly (P less than 0.005) greater than that of normal subjects (43 +/- 13%). The 24-hour urinary excretion of ET-1-L1 in patients with renal disease showed significant correlation with that of N-acetyl-beta-D-glucosaminidase (r = 0.587, P less than 0.05), beta 2-microglobulin (r = 0.614, P less than 0.01) and albumin (r = 0.484, P less than 0.05). Intravenous infusion of saline (500 ml) in seven normal subjects did not affect urinary ET-1 excretion rate. These data suggest that urinary excretion of ET-1 derives mainly from renal tubular secretion at least in patients with renal disease, and that degradation and/or reabsorption of ET-1 at the tubular site may also contribute to the renal handling of ET-1. Therefore, urinary excretion of ET-1 should serve as a potential marker for renal injury.     

Renal 25-hydroxyvitamin D3-1-hydroxylase in patients with renal disease

Renal 25-hydroxyvitamin D3-1-hydroxylase (1-hydroxylase) activity has been measured in 20 patients with renal disease using the remaining portion of needle renal biopsy specimens taken for diagnostic purposes and in five patients using kidney tissue removed during transplantation. The 1-hydroxylase activity of 12 patients with asymptomatic proteinuria and/or hematuria (group A) measured 83.2 +/- 37.7 pg/mg tissue/20 min. Since these 12 patients did not show impaired mineral metabolism or pathological changes in the renal tubules, we have presumed that these results indicate normal activity in man. We also measured the 1-hydroxylase activity in four patients treated with prednisolone (group B). The 1-hydroxylase activity (81.1 +/- 27.1 pg/mg tissue/20 min) of group B did not differ from that of group A. However, the urinary excretion of calcium (ratio of calcium/creatinine) was increased (0.18 +/- 0.07 vs. 0.07 +/- 0.03, P less than 0.01) by prednisolone therapy. These data suggest that glucocorticoid-induced changes in urinary calcium excretion are not the result of a direct effect of glucocorticoid on renal 1-hydroxylase. In the three patients with mild renal insufficiency (group C), the 1-hydroxylase activity (75.4 +/- 22.4 pg/mg tissue/20 min) did not differ from that of group A. However, in five patients with severe renal insufficiency (group D), the 1-hydroxylase activity (8.5 +/- 3.7 pg/mg tissue/20 min) was significantly decreased (P less than 0.01).     

Safety and efficacy of fluvastatin in hyperlipidemic patients with chronic renal disease

BACKGROUND: There are few reports on the safety and efficacy of long-term treatment with statins in patients with chronic renal disease and hyperlipidemia. We evaluated these subjects treated with fluvastatin. METHODS: After a 4-week run-in period, a total of 80 patients with diabetic nephropathy or chronic glomerulonephritis were randomly allocated to receive dietary therapy and fluvastatin 20 mg/day (n=39), or dietary therapy alone (n=41) for a period of 48 weeks. Lipid parameters, rhabdomyolysis-related indicators, 24-hour urinary albumin excretion and creatinine clearance were measured. The pharmacokinetics of fluvastatin was examined in 8 patients. RESULTS: Creatinine clearance and 24-hour urinary albumin excretion did not differ between the two groups. The peak serum fluvastatin concentration (Cmax) was 141+/-67 microg/L and the mean AUC0-6 h was 341+/-149 microgh/L. Fluvastatin treatment significantly lowered serum total cholesterol, low-density lipoprotein (LDL) cholesterol and apo-lipoprotein B concentrations by 16%, 25%, and 22%, respectively, compared with patients receiving dietary therapy alone. There were no significant differences in serum triglyceride and high-density lipoprotein (HDL) cholesterol concentrations between the two treatment groups. Serum creatine kinase and aldolase concentrations did not change throughout treatment in both groups. CONCLUSIONS: Fluvastatin treatment significantly improved lipid parameters in patients with chronic renal disease. Fluvastatin was well tolerated, with no adverse effects on renal function and no muscular toxicity. However, the drug showed no direct renoprotective effects.     

Glomerular structure in IDDM women with low glomerular filtration rate and normal urinary albumin excretion.

Eight women with insulin-dependent diabetes mellitus (IDDM) with low creatinine clearance rate (CCR) and normal urinary albumin excretion (UAE) were compared with three other groups of diabetic women: 19 with normal creatinine clearance rate (CCR) and UAE, 7 with normal CCR and microalbuminuria, and 7 with low CCR and microalbuminuria. The four groups were similar in age, duration of diabetes, HbA1, incidence of urinary tract infection, prevalence of bladder neuropathy, and urinary urea nitrogen excretion rate. The prevalence of hypertension was similar among the groups, although mean arterial pressure was higher in the low CCR and microalbuminuria group. Renal area index was lower in the low CCR and normal UAE groups than in the other groups of diabetic patients, but was not different from normal. Morphometric measures of mesangial expansion and estimates of arteriolar hyalinosis and global glomerulosclerosis were increased to a similar degree in the low CCR and normal UAE, normal CCR and microalbuminuria, and low CCR and microalbuminuria groups compared with the group without abnormalities of renal function. Therefore, it is likely that diabetic glomerulopathy is, at least in part, responsible for the loss of glomerular filtration rate seen in the low CCR and normal UAE patients. Thus, the definition of incipient nephropathy may have to be expanded beyond the concept of microalbuminuria if longitudinal study of such patients reveals an increased risk of the subsequent development of overt nephropathy. Finally, screening for diabetic kidney disease among IDDM patients should include determination of glomerular filtration rate and measurement of UAE and blood pressure, especially among women.