Enalapril attenuates glomerular hyperfiltration following a meat meal

It has been shown that the glomerular filtration rate increases after a meat meal. We examined in humans whether enalapril, which has been shown to decrease glomerular capillary pressure in rats with chronic renal failure, could attenuate the renal response to a meat meal. Twelve healthy volunteers were studied after an oral protein load, 1.5 g/kg body weight, as lean cooked beef meat, and on a separate day, after eating the same meal with prior oral intake of enalapril. On the control day, creatinine clearance increased from 114.3 +/- 4.7 before the meal to 137.1 +/- 4.7 ml/min/1.73 m2 after the meal (p less than 0.001). On the enalapril intake day, creatinine clearance increased from 113.7 +/- 5.6 before the meal to 128.3 +/- 5.8 ml/min/1.73 m2 after the meal (p less than 0.01). However, the mean increase in creatinine clearance was lower on the enalapril intake than on the control day (14.0 +/- 4.3 vs. 21.0 +/- 4.1%, p less than 0.05). Mean arterial pressure before the meal was lower on the enalapril intake day than on the control day (76.2 +/- 3.5 vs. 84.2 +/- 3.6, p less than 0.01). Likewise, postprandial mean arterial pressure was lower on the enalapril day compared with the control day (69.9 +/- 2.8 vs. 78.5 +/- 3.7, p less than 0.01). We conclude that enalapril blunts the hyperfiltration which follows a meat meal.     

Protein-induced glomerular hyperfiltration: role of hormonal factors

High protein diets acutely elevate the glomerular filtration rate. To characterize this response we administered 1 g of protein/kg body weight as a beef steak meal to nine, healthy male subjects and measured glomerular filtration rate (inulin clearance), renal plasma flow (p-amino hippurate clearance), plasma renin activity, aldosterone and plasma and urinary catecholamines. The subjects ingested the meal on three separate days and were pretreated with either placebo, 50 mg indomethacin (to inhibit renal prostaglandin synthesis), or 10 mg enalapril (to inhibit angiotensin II synthesis). Following placebo treatment protein feeding significantly increased the glomerular filtration rate, from a pre-meal level of 101 +/- 7 ml/min/1.73 m2 to a post-meal level of 130 +/- 6 ml/min/1.73 m2, P less than 0.005. A parallel rise in renal plasma flow and a fall in renal vascular resistance were noted. Indomethacin pretreatment attenuated the increase in glomerular filtration rate following the protein meal, 105 +/- 6 ml/min/1.73 m2 pre-meal level to 118 +/- 4 ml/min/1.73 m2 post-meal, P greater than 0.1. Enalapril pretreatment had no significant effect on protein-induced glomerular hyperfiltration. Protein feeding following placebo increased plasma aldosterone concentration while the concentrations were unchanged in the studies where enalapril or indomethacin was administered. Protein feeding following placebo or indomethacin did not alter plasma renin activity while plasma renin activity rose following enalapril administration. Urinary norepinephrine excretion rose while plasma norepinephrine concentration was unchanged in all three study groups. A decrease in urinary dopamine excretion was also noted four hours after the protein meal was ingested.(ABSTRACT TRUNCATED AT 250 WORDS)     

Angiotensin converting enzyme inhibition improves glomerular size-selectivity in IgA nephropathy.

Clearances of uncharged dextrans of broad size distribution were used to evaluate the effects of a 30 day course of enalapril on glomerular barrier function in 10 patients with IgA nephropathy and proteinuria (from 1.4 to 5.6 g/day). Dextran clearance experiments were repeated three times: before enalapril therapy, after 30 days of enalapril and again 30 days after enalapril withdrawal. GFR, but not RPF, was significantly reduced by enalapril (basal 38.3 +/- 11.9, enalapril 30.2 +/- 12.6 ml/min/1.73 m2) and returned to basal values after enalapril withdrawal. Urinary protein excretion and fractional clearance of albumin were both significantly reduced by enalapril (basal 2.3 +/- 1.1 g/day and 102 +/- 90 x 10(-5), enalapril 1.2 +/- 0.6 g/day and 51 +/- 23 x 10(-5), respectively) and returned to basal values after enalapril withdrawal. Transglomerular passage of large dextrans (radii 54 to 62 A), but not of lower size (26 to 42 A) were significantly lowered by enalapril. When enalapril was withdrawn the dextran-sieving profile returned comparable to the baseline levels. A theoretical analysis of dextran-sieving profiles indicated that enalapril lowered the radius of largest membrane pores. This effect was independent from glomerular hemodynamic changes. We conclude that angiotensin converting enzyme inhibitors (CEI) in humans with IgA nephropathy reduces urinary protein excretion by a primary action on the intrinsic glomerular membrane properties enhancing barrier size-selective function. The hypofiltration associated with enalapril therapy in these patients, which was eliminated by its withdrawal, has to be taken into account as a possible undesired effect of CEI in long-term treatment.     

Angiotensin-converting enzyme inhibition ameliorates the defect in glomerular size selectivity in hyponatremic hypertensive syndrome

The glomerular size-selective properties in a patient with "hyponatremic hypertensive syndrome" were investigated before and after administration of the angiotensin-converting enzyme inhibitor enalapril. Hyponatremic hypertensive syndrome is a rare condition of renovascular hypertension characterized by electrolyte abnormalities (hyponatremia, hypokalemia), polyuria, and high renin activity. In this patient a marked increase in urinary protein excretion was observed. Treatment with enalapril normalized BP, corrected electrolyte abnormalities, and reduced proteinuria. Glomerular filtration rate (GFR), renal plasma flow (RPF), and the clearance of neutral dextrans of graded sizes were measured before and after 6 months of enalapril (20 mg/d) administration. Theoretical analysis of dextran and inulin clearance data with a model of glomerular size selectivity were adopted to separate effects of hemodynamic changes on macromolecule filtration from changes of intrinsic membrane selective properties. After enalapril urinary protein excretion decreased, GFR was unchanged and RPF almost doubled. Fractional clearance values of dextran molecules were markedly elevated in comparison with the corresponding values measured in a group of normal controls and were normalized by enalapril. Theoretical calculation of membrane pore characteristics showed that enalapril treatment reduced the radius of all membrane pores by approximately 1 nm. Altogether these results indicate that enalapril normalized glomerular filtration of neutral macromolecules and circulating proteins in a human condition of angiotensin II-induced proteinuria. Enalapril effectively restored glomerular size-selective function, reducing dimensions of membrane pores, independently of its effect on renal hemodynamics.     

Renal hemodynamics and reduction of proteinuria by a vasodilating beta blocker versus an ACE inhibitor.

The effects of a nonselective beta-adrenergic blocking drug with beta-2 agonist activity (dilevalol 200 mg) on proteinuria and renal hemodynamics were evaluated in a double-blind crossover study versus an ACE inhibitor (enalapril 5 mg) in eight patients with glomerulonephritis, moderate renal function impairment and proteinuria greater than 1 g/24 hr. Patients were studied after a one week placebo phase while off all other medications, except steroids in a few cases, and after three weeks of treatment. A 10-day placebo washout perod was included between the various drug treatments. During each period renal hemodynamics were measured by clearance techniques, and urinary protein excretion as well as fractional clearance of albumin and IgG were determined. Both drugs reduced mean arterial pressure and proteinuria to a similar extent [mean arterial pressure: placebo 108 +/- 13 mm Hg; dilevalol 103 +/- 11 mm Hg (P less than 0.05); enalapril 103 +/- 12 mm Hg (P less than 0.05); protein excretion: placebo 5.1 +/- 4.2 g/day; dilevalol 3.3 +/- 3.0 g/day (P less than 0.05); enalapril 2.8 +/- 2.8 g/day (P less than 0.05)]. The antiproteinuric effect was greater with enalapril than dilevalol. Dilevalol reduced GFR [baseline inulin clearance: 73.3 +/- 38 ml/min/1.73 m2; after dilevalol: 63.3 +/- 28 ml/min/1.73 m2 (P less than 0.05)] and the decrease of proteinuria correlated positively with the reduction of GFR. Enalapril did not significantly lower the GFR (inulin clearance during enalapril 66.8 +/- 23 ml/min/1.73 m2) and the reduction of proteinuria did not correlate with the lowering of the GFR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oxygen therapy improves renal function in patients with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) may cause edema independently of cardiac function. This study assessed the effects of oxygen therapy in renal hemodynamics and excretion of sodium and water in COPD patients. Twelve COPD patients without cor pulmonale (PaO2 < or = 60 mmHg), aged 66 +/- 9 years, were studied before and after 72 h of O2 therapy. Oxygen increased PaO2 from 56 +/- 4 to 85 +/- 22 mmHg (p < 0.0001), whereas PaCO2 did not change significantly. Oxygen induced significant increments in glomerular filtration rate (90 +/- 21 to 111 +/- 36 mL/min/1.73 m2, p = 0.03), sodium filtered load (10 +/- 3 to 12 +/- 5 mEq/min, p = 0.004), sodium excreted load (79 +/- 67 to 194 +/- 106 mEq/day, p = 0.0006), fractional excretion of sodium (0.51 +/- 0.49 to 1.30 +/- 1.32%, p = 0.015) diuresis (1048 +/- 548 to 1893 +/- 440 mL/day, p = 0.002), osmolar clearance (1.43 +/- 0.7 to 2.08 +/- 0.6 mOsm/min, p = 0.008) and decreased hematocrit (48 +/- 4 to 44 +/- 3%, p = 0.0038). Renal plasma flow and filtration fraction did not change after oxygen. In summary, use of oxygen caused increases of 36% in GFR, 35% in filtered load of sodium, 118% in diuresis, 258% in excreted load of sodium, and 178% in fractional excretion of sodium. These data suggest that oxygen-induced natriuresis and diuresis were likely more dependent of changes in the tubular manipulation of sodium than in glomerular hemodynamics. These changes occurred with a mild increase in PCO2, showing that oxygen therapy caused renal improvement independently of amelioration of hypercapnia.     

Renal response to a protein meal in children with single kidneys

The renal response of healthy adults to an oral protein load results in a significant increase of renal plasma flow (RPF) and glomerular filtration rate (GFR) 100 to 150 min after the meal. The renal response to protein loading of single kidney adults is unclear and it has not been evaluated yet in children. Therefore, we studied 8 children 10.2 +/- 1.1 years old, 6.7 +/- 1.41 years after nephrectomy (SK) and 4 healthy children (C). RPF was estimated by para-amino-hippurate clearance (Cpah) and GFR by inulin clearance (Cin) before and after an oral protein load of 1.5 g protein/kg body wt and expressed in ml/min/1.73 m2 BSA. Mean baseline Cin were similar in SK and in C (90 +/- 8 vs 103 +/- 12) while baseline Cpah was lower in SK (339 +/- 19 vs 481 +/- 36, p less than 0.005). After the meal GFR and RPF increased significantly in C (155 +/- 18 and 783 +/- 68, p less than 0.005 and p less than 0.05 vs baseline values, respectively) whereas no significant GFR and RPF changes were seen in SK (81 +/- 9 and 350 +/- 42, respectively). However, the 3 SK children with lower protein intake showed a mild vasodilating response. We conclude that in single kidney children hyperfiltration occurs at baseline conditions and the renal response to acute protein loading is partially or completely blunted, being modulated by protein intake.     

Effects of enalapril and eprosartan on the renal vascular nitric oxide system in human essential hypertension

BACKGROUND: Experimental data in humans on the contribution of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers to the nitric oxide system of the renal vasculature are inconsistent. Enalapril and eprosartan, alone and in combination, were used to determine their short-term effects on the renal nitric oxide system and renal hemodynamics of human subjects with essential hypertension. METHODS: Twenty male, white patients (27 +/- 1 years) with mild essential hypertension (143 +/- 11/95 +/- 6 mm Hg) were included in a double-blind, randomized, placebo-controlled, fourfold cross-over study with placebo, enalapril (20 mg/day), eprosartan (600 mg/day), or combination of both drugs (10 and 300 mg/day, respectively) each over a one week period followed by a two-week washout phase. After each study phase the glomerular filtration rate (GFR) and renal plasma flow (RPF) were determined. Basal nitric oxide synthesis of the renal vasculature was assessed by the decrease in RPF after inhibition of nitric oxide synthase with NG-monomethyl-L-arginine (L-NMMA; 4.25 mg/kg). RESULTS: After one week of therapy, the combination therapy decreased casual blood pressure by 5 +/- 2/3 +/- 1 mm Hg versus placebo (P < 0.01). Neither enalapril alone (-2 +/- 2/1 +/- 2 mm Hg, NS vs. placebo) nor eprosartan alone (-1 +/- 1/0 +/- 2 mm Hg, NS vs. placebo) had a clear-cut significant effect on casual blood pressure. In the combination phase, RPF increased by 123 +/- 36 mL/min (P < 0.01). Neither enalapril alone (+59 +/- 46 mL/min, P = 0.21) nor eprosartan alone (+113 +/- 51 mL/min, P = 0.06) had a clear-cut significant effect on RPF. Changes of RPF induced by treatment correlated with the L-NMMA induced decrease in RPF in the combination (r = 0.70, P < 0.01) and eprosartan phase (r = 0.86, P < 0.001), but not in the enalapril phase (r = -0.44, P = 0.10). Renal vascular resistance was reduced by each active treatment with the most prominent reduction in the combination phase. GFR was unaffected by any treatment. CONCLUSIONS: In contrast to the effects of either substance alone, a combination of half the dose of eprosartan with half the dose of enalapril had a prominent effect on renal perfusion. The effects of eprosartan on RPF are mediated, at least in part, by an increased bioavailability of nitric oxide in the renal vasculature.     

Evidence for renal vasodilation in pre-dialysis patients during correction of anemia by erythropoietin.

Results from animal experiments have suggested that treatment with recombinant human erythropoietin (rHuEPO) causes changes in renal hemodynamics which are detrimental to renal function. Therefore, the effects of correction of the anemia by rHuEPO on glomerular filtration rate (GFR; inulin clearance) and effective renal plasma flow (ERPF; PAH clearance) were studied in eight pre-dialysis patients. The studies were done before (Hct 0.24 +/- 0.05 liter/liter) and at 89 +/- 19 days after the start of rHuEPO therapy (Hct 0.39 +/- 0.03 liter/liter). To further evaluate the effects of ACE inhibition, 25 mg of captopril was given orally after baseline values had been obtained. Baseline GFR, renal blood flow (RBF) and filtration fraction (FF) did not change during rHuEPO therapy. At low hematocrit (Hct) captopril induced a significant increase in ERPF and RBF, and a decrease in MAP. After correction of the hematocrit the blood pressure lowering effect of captopril remained unchanged. However, captopril no longer induced changes in ERPF and RBF. We conclude that the increase in hematocrit had no adverse effects on GFR. The results suggest that changes in hematocrit may influence the effects of ACE inhibition on efferent vascular resistance. Therefore, the hematocrit should be taken into account when evaluating studies on the effects of ACE inhibition in the progression of chronic renal failure.     

Effects of Nva2-cyclosporine on glomerular filtration rate and renal blood flow in the rat

The effects of Nva2-cyclosporine on glomerular filtration and renal blood flow in rats were studied and compared with those of cyclosporine. An infusion of Nva2-cyclosporine (20 mg/kg) caused a 53% fall in glomerular filtration rate (1.0 +/- 0.08 to 0.47 +/- 0.09; P less than 0.001) and renal plasma flow (3.2 +/- 0.4 to 1.6 +/- 0.4; P less than 0.005). Nva2-cyclosporine when infused in a dose of 10 mg/kg caused a nearly identical fall in inulin clearance and renal plasma flow. By comparison an infusion of cyclosporine (20 mg/kg) caused a 50% decrease in inulin clearance and a fall in renal plasma flow from 2.6 +/- 0.3 to 0.9 +/- 0.3. Nva2-cyclosporine or cyclosporine was given chronically in a dose of 20 mg/kg intraperitoneally for seven days. Cyclosporine produced a 27% fall in creatinine clearance, whereas Nva2-cyclosporine produced a 19% decrease in creatinine clearance (NS). These studies suggest that Nva2-cyclosporine has adverse effects on renal blood flow and glomerular filtration rate similar to those seen with cyclosporine.     

The effect of acute and chronic protein loading on urinary pepsinogen A excretion

In 8 healthy male volunteers, urinary excretion (UE) and fractional clearance (FC) of pepsinogen A (PGA), beta 2-microglobulin (beta 2-m) and albumin were measured after 6 days high protein diet (HPD; 2.0 g/kg/day) and compared to values obtained after 6 days low protein diet (LPD; 0.5 g/kg/day). In addition, the effect of an acute protein load (APL; 500 g beef) on these variables were measured. Both chronic and acute protein loading induced a rise in glomerular filtration rate (GFR) of about 10% together with a parallel rise in effective renal plasma flow. UE PGA and FC PGA increased both after HPD (UE PGA 1,707 +/- 1,106 ng/min; FC PGA 23 +/- 12%) as compared to LPD (UE PGA 1,200 +/- 987 ng/min, p less than 0.01; FC PGA 18 +/- 12%, p less than 0.05), and after APL (UE PGA 2,276 +/- 1,389 ng/min; FC PGA 26 +/- 16%) as compared to baseline (UE PGA 1,418 +/- 965 ng/min, p less than 0.02; FC PGA 21 +/- 12%, p less than 0.05). UE and FC of beta 2-m and albumin were not affected by protein loading. As PGA is nearly freely filtered, it is concluded that the increase in fractional PGA clearance reflects a decrease in fractional tubular PGA reabsorption. Our results suggest that an increase in fractional protein clearance after protein loading is not necessarily due to an impaired glomerular permselectivity but represents a decreased fractional tubular reabsorption as a result of a GFR-mediated increase in filtered load without a concomitant increase in tubular reabsorption.     

Allopurinol and enalapril failed to conserve urinary NOx and sodium in ischemic acute renal failure in spontaneously hypertensive rats

BACKGROUND: Ischemia-reperfusion-induced acute renal failure (ARF) is associated with a high mortality in patients with hypertension and with an unfavorable outcome of kidney transplants from marginal donors. AIM: The influence of allopurinol and enalapril on urinary nitrate/nitrite (UNOx), glomerular filtration rate, plasma and urinary sodium, and hemodynamic parameters was examined in spontaneously hypertensive rats (SHR) with ARF. METHODS: ARF was induced by right-kidney removal and clamping the left renal artery for 40 min in 50 male 26-week-old SHR weighing 300 +/- 23 g. The rats were randomly allocated to five groups: (1) sham operated; (2) ARF; (3) ARF after pretreatment with 40 mg/kg allopurinol; (4) ARF after pretreatment with 40 mg/kg enalapril, and (5) ARF after pretreatment with 40 mg/kg allopurinol and 40 mg/kg enalapril. Creatinine clearance, UNOx (Griess reaction), cardiac output (dye dilution technique), mean arterial blood pressure, and renal blood flow were measured 24 h after reperfusion. Total vascular resistance and renal vascular resistance were calculated and compared between the groups. RESULTS: A nonsignificant decrease was found in both daily UNOx excretion and creatinine clearance when pretreated ARF groups and the ARF group without pretreatment were compared (p > 0.05). Significantly lower plasma sodium values (139.5 +/- 4.86 mmol/l) in the allopurinol-pretreated ARF group were found than in the ARF group without pretreatment, in the ARF group pretreated with enalapril, and in the sham SHR group (p = 0.029). The urinary sodium loss was greater in the enalapril-pretreated than in the allopurinol-pretreated ARF group (p = 0.047). Allopurinol and/or enalapril pretreatment decreased total vascular resistance (p = 0.003) in comparison with the sham SHR group. CONCLUSION: Neither allopurinol nor enalapril nor both were protective against ischemia-reperfusion injury in SHR, nor altered glomerular filtration rate and UNOx in a favorable direction.     

Isotopic renal function studies in severe hypothyroidism and after thyroid hormone replacement therapy

AIM: To investigate the possible changes in the renal tubular function in severe short-term hypothyroidism using (99m)Tc-MAG(3) renography. METHODS: 27 consecutive thyroidectomized patients (7 males and 20 females) aged 19-79 (mean 53) years were included in the present study. (99m)Tc-MAG(3) renography was performed in all patients before and after thyroid hormone replacement therapy. In addition, (51)Cr-EDTA clearance and serum creatinine concentrations were determined. RESULTS: The serum creatinine concentrations were significantly increased in hypothyroidism as compared with the concentrations after thyroxine substitution (1.30 +/- 0.44 vs. 1.04 +/- 0.32 mg/dl, p < 0.05). According to the (51)Cr-EDTA clearance, the glomerular filtration rate was significantly lower in hypothyroidism than after treatment (61 +/- 18 vs. 75 +/- 23 ml/min). In contrast, we did not find any significant change in the renographic parameters for (99m)Tc-MAG(3) before and after treatment (total excreted activity 20 min after administration 51 +/- 12 vs. 54 +/- 14%; T(max) left:right 4.2 +/- 1.77 : 3.91 +/- 1.06 min vs. 4.1 +/- 1.66 : 4.4 +/- 1.96 min). CONCLUSIONS: We did not find any influence of thyroid hormones on the outcome of (99m )Tc-MAG(3) renography. As (99m)Tc-MAG(3) reflects the tubular function, it seems that the renal hemodynamic changes in severe hypothyroidism mainly affect the glomerular function. In general, the glomerular filtration rate reduction seems to be reversible after hormone substitution therapy; however, care has to be taken in patients with renal insufficiency.     

Preservation of renal reserve in chronic renal disease

Protein-induced increases in glomerular filtration rate (GFR), termed renal reserve, is said to be abrogated with the onset of renal disease. However, this notion is inconsistent with the results from animal studies which suggest that alterations in protein intake modulate the glomerular hemodynamics in experimental renal disease. Accordingly, 12 normal subjects and 15 patients with renal disease received a protein meal providing 1 g/kg body weight protein. The subjects were pretreated with either placebo or an angiotensin I converting enzyme inhibitor, enalapril. A significant (P less than 0.05) increase in inulin and para-aminohippurate (PAH) clearance was noted in normal subjects as well as in patients with renal disease. The increase in GFR over basal values in normal subjects (28 +/- 9%), patients with moderate renal failure (20 +/- 13%), and advanced renal failure (21 +/- 14%) was not different. Plasma renin activity was unchanged following protein meal in the placebo studies although it increased following enalapril administration. Enalapril pretreatment did not alter the glomerular vasodilation and hyperfiltration following protein meal. We conclude that protein meal induces glomerular hyperfiltration in renal disease and that this protein-induced hyperfiltration is not mediated by angiotensin II. Because glomerular hyperfiltration is implicated in the progression of renal disease, these data suggest that even in patients who have advanced renal failure, high-protein diets may exert a detrimental effect on the kidney.     

Long-term preservation of renal function in hypertensive heart transplant recipients treated with enalapril and a diuretic.

Hypertension and progressive deterioration in renal function are commonly seen in heart transplant recipients treated for the long term with cyclosporine. Because angiotensin converting enzyme inhibitors have been associated with amelioration of renal dysfunction in some patients with hypertension and preexisting mild-moderate kidney failure, we treated nine hypertensive recipients of orthotopic heart transplants with enalapril (11 +/- 2 mg/day) and furosemide (62 +/- 15 mg/day) for 23 +/- 4 months. Most of the enalapril dose was given at bedtime, which minimized nocturnal and early morning hypertension. In addition to controlling blood pressure (154 +/- 6/100 +/- 2 mm Hg before enalapril vs 120 +/- 5/81 +/- 2 mm Hg currently; p less than 0.001 for both systolic and diastolic blood pressures by paired t test), there has been no increase in serum creatinine level over 684 +/- 102 days of follow-up (1.88 +/- 0.20 mg/dl before enalapril vs 1.81 +/- 0.17 mg/dl currently; p greater than 0.70). This is unlikely to be caused by the reduction in daily cyclosporine dose (492 +/- 60 mg/day before enalapril to 305 +/- 47 mg/day currently) because there were no significant changes in mean blood cyclosporine level (which has been maintained between 100 and 500 ng/ml). Treatment of hypertension with enalapril and a diuretic after heart transplantation may help prevent or delay the impairment of renal function often seen during prolonged cyclosporine therapy.     

Effects of methylprednisolone pulse therapy on progressive IgA nephropathy]

In order to estimate the effects of methylprednisolone pulse therapy on progressive IgA nephropathy, clinical parameters in eight patients with the disease were compared between before and after the therapy. In this study progressive IgA nephropathy was defined as follows; 24 hour urinary protein excretion was (++) or more and renal biopsy carried out just before the therapy revealed crescents, inevitably including cellular crescents, in 10% or more glomeruli observed. Methylprednisolone 1000 mg a day was intravenously administered for three consecutive days and the therapy was repeated with an interval of 4 days. The additional third course was given in two patients, in whom significant decrease in urinary protein had not been obtained after the original two courses of the therapy. Oral prednisolone 20 mg a day started simultaneously was tapered one month later to maintenance daily doses of 5-10 mg. After the pulse therapy urinary protein excretion was significantly decreased in every patient with a mean decrease from 2.3 +/- 0.5 (0.8-5.5)g to 1.1 +/- 0.3 (0-2.8)g (p less than 0.05). Glomerular filtration rate (GFR) was increased from 83 +/- 11 (31-115) ml/min to 96 +/- 10 (44-130) ml/min (p less than 0.05). In the initial biopsy crescents were observed in 25 +/- 7 (19-57)% of glomeruli observed and 20-100% of these were composed of cellular crescents. Complete loss of cellular crescents in 6 patients and a marked decrease from 73% to 33% in another were demonstrated by the second biopsies performed after the pulse therapy. These results suggested that the methylprednisolone pulse therapy significantly reduced urinary protein excretion and improved renal function through suppression of new crescent formation as well as transformation of cellular crescents to fibrocellular or fibrous crescents.     

The effect of ACE inhibitor and angiotensin II receptor antagonist therapy on serum uric acid levels and potassium homeostasis in hypertensive renal transplant recipients treated with CsA.

BACKGROUND: The angiotensin II (AT II) type I receptor antagonist losartan has been reported to increase urinary uric acid and potassium excretion. These effects might be beneficial in cyclosporin (CsA)-treated renal transplant recipients, who frequently suffer from hyperuricaemia and hyperkalaemia. METHODS: In this prospective, open, randomized, two-way cross-over study we included 13 hypertensive CsA-treated patients after renal transplantation and administered either the angiotensin-converting enzyme (ACE) inhibitors enalapril or losartan. Laboratory parameters, 24-h urinary protein excretion, and mean 24-h arterial blood pressure (MAP) were checked after 3 weeks treatment with enalapril, after a wash-out period of 2 weeks, and before and after a 3-week treatment course with losartan. RESULTS: Both drugs slightly reduced MAP (losartan from 97+/-6 to 94+/-9 and enalapril to 93+/-8 mmHg). Serum potassium levels significantly increased during enalapril therapy (from 4.3+/-0.5 to 4.8+/-0.4 mmol/l, P<0.05), as did, although not significantly, uric acid concentrations (from 7.8+/-1.9 to 8.2+/-1.8 mg/dl, P=0.5). Losartan, on the contrary, only mildly affected serum potassium (4.3+/-0.5 vs 4.5+/-0.5 mmol/l, P=0.25) and serum uric acid decreased (from 7.8+/-2.4 to 7.3+/-1.8 mg/dl, P=0.6). Serum aldosterone and urinary aldosterone excretion were significantly reduced only during ACE inhibitor treatment, which might explain the variable effects on potassium homeostasis. CONCLUSION: Losartan may be a useful agent to reduce blood pressure and serum uric acid levels in renal transplant recipients treated with CSA: Furthermore, in this high-risk population, the effects on serum potassium levels are less marked with losartan than with enalapril.     

Urinary prostaglandin E and kallikrein activity in glomerular hyperfiltration induced by a meat meal in man

Because renal vasodilator systems may be involved in the physiologic response to a protein meal, we studied the relationship of prostaglandin E (PGE) and kallikrein (KE) activity to the renal hemodynamic changes induced by a meat meal. Ten normal subjects on a maintenance diet providing 1 g protein per kg and 100 mmol Na daily were studied before and after a meal of 86 g of meat protein, once without medication, and again after treatment with indomethacin (150 mg daily for 3 days before and 50 mg the morning of the test). A carbohydrate meal of similar caloric, Na and K content was used in control studies. Glomerular filtration rate (GFR, inulin clearance), renal blood flow (RBF, para-aminohippurate [PAH] clearance), PGE and kallikrein urinary excretion were determined. All studies were performed during water diuresis to avoid bladder catheterization. The protein load induced an increase in GFR (ml/min, mean +/- s.e.m.: baseline 107.2 +/- 6.05, peak postmeal 146.4 +/- 6.79, p less than 0.01) and RBF (baseline 529.7 +/- 42.9, postmeal 678.9 +/- 61.9, p less than 0.05). Renal hemodynamic changes were unrelated to changes in urinary PGE and KE excretion. Indomethacin treatment inhibited PGE excretion by 73% during the test meal but did not modify the protein-induced hyperfiltration. Our results suggest that these renal vasodilator systems are not primarily responsible for the hyperfiltration response. In addition, the data show that inhibition of prostaglandin synthesis is not a practical approach to prevent glomerular hyperfiltration in clinical practice.     

Initial effect of enalapril on kidney function in patients with moderate to severe chronic nephropathy

Angiotensin converting enzyme (ACE) inhibitors has been suggested to halt the progression of chronic renal failure. As the initial step of a controlled trial of this hypothesis, it was investigated whether start of enalapril in patients with severe chronic nephropathy might cause a critical fall in their renal function. Thirty-one patients were studied, 26 on chronic antihypertensive treatment with drugs other than ACE inhibitors and 5 untreated normotensive. 51Cr-EDTA plasma clearance and renal technetium-99m dimercaptosuccinic acid (99mTc-DMSA) scintigraphy were made before and 24 h after start of enalapril, mean dose 9 mg. Blood pressure fell from median 148/88 to 119/78 mmHg (p less than 0.01). Glomerular filtration rate (GFR) fell from median 14 to 12 ml/min/1.73 m2 (p less than 0.01). The median change in GFR was -14% (range -44% to +10%). The split renal function was unchanged and the scintigrams showed no intrarenal activity defects. In conclusion, enalapril caused a fall in GFR, which was clinically acceptable in most of the patients.     

Restrictions on use of creatinine clearance for measurement of renal functional reserve

The increase of glomerular filtration rate after a 90-gram oral protein load was determined in 9 healthy individuals by simultaneous measurements of both creatinine (Ccr) and inulin (Cin) clearances, performed before and every 30 min during 4 h after the meat meal. This protein load resulted in a short 26% increase of Cin at 90 min, and a sustained 29% increase of Ccr from 90 to 240 min after load. Individual peak values of Ccr occurred later than those of Cin (Ccr: 189 +/- 19 vs. Cin: 127 +/- 19 min; p = 0.023). These discrepancies were related to an increase of serum creatinine, and a subsequent increase of the net tubular excretion of creatinine which accounted for up to 15% of the urinary creatinine. The creatinine content of red meat could lead to overestimation of renal functional reserve when measured by creatinine clearance only.