The role of theophylline in contrast-induced nephropathy: a case-control study.

BACKGROUND: Various strategies for the prevention of contrast-induced nephropathy (CN) have been studied, with conflicting results. Adenosine may play an important role in the pathogenesis of CN. This study prospectively assessed the role of oral theophylline in the prevention of CN. METHODS: We randomized into two groups 70 patients with diabetes mellitus who were undergoing coronary angiography (CAG) with high-osmolar contrast media. Group I (n=35) underwent routine CAG, and group II (n=35) received oral theophylline 200 mg b.d. 24 h before and for 48 h after CAG. Serum Na(+), K(+), blood urea nitrogen (BUN), creatinine, osmolality, glomerular filtration rate (GFR) and urinalysis were performed before and after CAG. The (99m)Tc-DTPA-clearance method was used to assess GFR. RESULTS: Following angiography, patients in the control group showed a significant rise in serum creatinine (1.19+/-0.23 vs 1.44+/-0.32 mg/dl, P=0.003) and BUN (13.95+/-2.61 vs 17.55+/-3.9 mg/dl, P=0.01) along with a fall in GFR (85.4+/-14.7 vs 66.85+/-14.8 ml/min, P=0.008). The mean percentage fall in GFR was 35.8%. There was no significant change in serum creatinine (1.16+/-0.18 vs 1.24+/-0.21 mg/dl), BUN (12.8+/-3.36 vs 14.8+/-2.5 mg/dl) and GFR (86.8+/-15.8 vs 80.3+/-16.0 ml/min) in those receiving theophylline. No patient in the theophylline group had a >25% rise in serum creatinine, compared with 7/35 in the control group (P=0.017). In the control group, 11/35 (31%) developed CN, as demonstrated by a >/=25% fall in GFR, while only one patient in the theophylline group had a fall in GFR (P=0.004). None of the pre-angiographic variables could predict the development of CN. CONCLUSIONS: Following the use of high-osmolar contrast media for routine CAG, CN may develop in 31% of diabetic patients. Patients who received prophylactic oral theophylline had a significantly lower risk of CN than those who did not.     

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.     

Insulin-dependent diabetes and renal hypouricemia

We studied 14 patients (11 women and 3 men) from 18 to 33 years old, suffering from type I diabetes mellitus with normal renal function (creatinine clearance 106.91 +/- 28.73 ml/min) and serum uric acid below 2.5 mg/dl (2.34 +/- 0.11 mg/dl) as well as a high uric acid clearance (23.04 +/- 5.92 ml/min) and fractional urate excretion (21.4 +/- 2.6) versus urate clearance 9.82 ml/min and fractional urate excretion 8.80 +/- 1.3 in 14 normal control subjects. The study of the uricosuric mechanisms was conducted by the combination of probenecid (PB) test which inhibits the reabsorption of secreted urate, and pyrazinamide (PZA) test, which inhibits its tubular secretion. The results of studies indicate that the increase in urate clearance was accounted for by increased PZA-nonsuppressible urate suggesting a decreased reabsorption of filtered urate. Increased PZA-suppressible urate excretion combined with impaired response to a uricosuric drug is consistent with impaired reabsorption of secreted urate. According to our findings, increased urate excretion in diabetic patients may be attributed to the inhibition of both filtered and secreted reabsorption. This reabsorptive tubular abnormality is consistent with the view of an interference of tubular reabsorption of glucose with the tubular capacity for uric acid reabsorption.     

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.     

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.     

Effect of furosemide on the obstructed kidney

The effect of furosemide on the obstructed kidney was studied in dogs. In control kidneys (n = 4) the renal blood flow (RBF) was increased transiently after intravenous infusion of 20 mg of furosemide; from 12.9 +/- 1.2 to 14.8 +/- 1.4 ml/min/kg.B.W. No change in the renal pelvic pressure was observed. Urine flow increased from 0.47 +/- 0.12 to 4.98 +/- 1.15 ml/min at 20 minutes after furosemide administration. Increases in the fractional fluid excretion rate (V/GFR), the fractional sodium excretion rate (FENa) and the fractional potassium excretion rate (FEK) were observed and the maximum values were obtained at 20 minutes after furosemide administration. In two-week unilateral incompletely obstructed kidneys (incomplete UUO; n = 5), RBF was lower than that of the control kidney, whereas a tendency of transient increase was also noticed after furosemide administration; from 8.4 +/- 1.9 to 10.5 +/- 2.3 ml/min/kg.B.W. The renal pelvic pressure increased immediately and transiently after furosemide infusion. Increase in the urine flow was significant, but the value was lower than that of control, and the maximum value was marked at 20 minutes after furosemide administration. V/GFR, FENa and FEK were also increased in incomplete UUO, but the peak values were lower than those of control. In two-week unilateral completely obstructed kidneys (complete UUO; n = 5), RBF was markedly decreased (3.14 +/- 0.38 ml/min/kg.B.W.), and no significant increase was noticed after furosemide administration. The renal pelvic pressure was gradually and continuously increased after furosemide infusion. The fractional excretion rate of pelvic urine components was variable. In particular, V/GFR was significantly increased 60 minutes after furosemide administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fucoidin, an inhibitor of leukocyte adhesion, exacerbates acute ischemic renal failure and stimulates nitric oxide synthesis

OBJECTIVES: To lessen renal ischemic injury caused by fucoidin, a substance capable of reducing tissue infiltration by neutrophils, and to seek a possible interrelationship with the nitric oxide system which may also modulate leukocyte infiltration. MATERIAL AND METHODS: Acute ischemic renal failure was induced in rats by uninephrectomy followed by 60 min of clamping of the renal artery. The rats were injected with fucoidin (25 mg/kg) or fucoidin+nitroprusside (2.5 mg/kg) before reperfusion, and urine was collected for 24 h afterwards. Serum and urine were examined for creatinine sodium and protein; creatinine clearance and fractional excretion of sodium (FENa) were calculated. The renal tissue of the sacrificed animals was examined histologically for tissue damage and histochemically for myeloperoxidase, a marker of neutrophil infiltration. The nitric oxide system was evaluated by measuring urinary nitrates and inducible nitric oxide synthase messenger RNA (iNOs mRNA). RESULTS: Renal failure was more severe in the fucoidin group than the nitroprusside group (creatinine clearance 0.11+/-0.08 ml/min for ischemia+fucoidin versus 0.26+/-0.11 ml/min for ischemia only; p<0.002). Adding nitroprusside to fucoidin lessened the decline in creatinine clearance (0.13+/-0.13 ml/min; p=NS). Fucoidin was associated with greater tubular damage, as evidenced by increased FENa (7.2%+/-2.8% vs 1.51%+/-1.96% for ischemia only; p<0.001). Nitroprusside weakened this trend. Fucoidin caused an increase in the fractional excretion of nitrates, a response accompanied by increased iNOS mRNA. CONCLUSIONS: Fucoidin failed to protect the kidney from ischemic damage and was even nephrotoxic. It also stimulated the formation of iNOS RNA.     

Amino acids protects against renal ischemia-reperfusion injury and attenuates renal endothelin.1 disorder in rats

To investigate nephroprotective effects ofa mixture of 8 L-amino acids on renal ischemia-reperfusioninjury and its effects on renal endothelin-1 (ET-1).     

Effects of acute and chronic dosing of NSAIDs in patients with renal insufficiency

Administration of nonsteroidal anti-inflammatory drugs (NSAIDs) to patients with chronically impaired renal function has been reported to cause abrupt and sustained reductions in renal plasma flow (RPF), glomerular filtration rate (GFR), and solute and water excretion in association with decreased renal prostanoid production. However, the time course of these acute effects and whether they are sustained during chronic exposure to the NSAIDs are unknown. Accordingly, using standard clearance and balance techniques, we investigated the effects of acute (zero to four hours) and chronic (five days) oral administration of two different NSAIDs on renal function in patients with stable, mild to moderate chronic renal insufficiency (CRI) and in normal subjects. In patients, acute oral administration of ketoprofen (K) and indomethacin (I) resulted in significant decreases in GFR (K: from 36 +/- 3 to 20 +/- 4 ml/min, P = 0.001; I: from 37 +/- 6 to 30 +/- 7 ml/min, P = 0.032; in RPF (K: from 194 +/- 21 to 146 +/- 21 ml/min, P = 0.002; I: from 222 +/- 33 to 147 +/- 18 ml/min, P = 0.016); and in urinary PGE2 excretion (K: from 0.60 +/- 0.25 to 0.08 +/- 0.02 ng/min, P = 0.05; I: from 0.34 +/- 0.06 to 0.18 +/- 0.06 ng/min, P = 0.042). Fractional excretion of sodium chloride and fractional free water clearance (CH2O/CIn) also decreased significantly after both agents. In normal subjects, GFR and RPF were not significantly decreased after acute dosing, whereas urinary PGE2 and fractional excretions of NaCl and free water decreased significantly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Measurement of glomerular filtration rate in ICU patients using 99mTc-DTPA and inulin.

Improved and reliable methods for assessing glomerular filtration rate (GFR) in intensive care patients are needed in light of known deficiencies using creatinine clearance. We compared simultaneous two-hour clearances of inulin (CIn), creatinine (CCr), and 99mTc-diethylenetriaminepentaacetic acid (CDTPA) in 18 medical or surgical intensive care patients (range, 49 to 92 years old) with blood urea nitrogen (BUN) levels greater than 17.9 mmol/liter (0.5 mg/ml), serum creatinine levels greater than 150 mumol/liter (0.02 mg/ml), or estimated Cockcroft clearance less than 60 ml/min. Patients had severe renal dysfunction with average GFR of 35 ml/min (range, 2 to 69 ml/min). CDTPA and CCr correlated significantly with CIn, although CDTPA tended to provide a closer approximation. Cockcroft clearance (32 +/- 4 ml/min) was grossly similar to CDTPA and CIn and correlated significantly, especially when weight was calculated using actual as opposed to ideal body weight. In a subset of 13 patients with CIn less than 30 ml/min, only CDTPA was significantly correlated with CIn. In patients in the intensive care unit, CDTPA provides a rapid, accurate, and inexpensive clinical assessment of GFR, even at very low GFRs.     

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)     

Hypercholesterolaemia and treatment with statins do not alter L-arginine-induced changes of renal haemodynamics.

BACKGROUND: Hypercholesterolaemia has been found to impair endothelial function in the systemic and coronary circulations and lipid-lowering therapy with statins has been shown to improve this abnormality. METHODS: We examined the impact of hypercholesterolaemia on L-arginine-induced renal vascular relaxation by a cross-sectional study, and the effects of lipid-lowering therapy by a double-blind, randomized, placebo-controlled study. Using constant infusion input clearance technique (PAH and inulin respectively), changes of renal plasma flow (RPF) and glomerular filtration rate (GFR) in response to intravenous infusions of L-arginine (100 mg/kg/30 min and 500 mg/kg/30 min) were studied in 21 hypercholesterolaemic humans (age 57+/-9 years, LDL-cholesterol 211+/-35 mg/dl) and in 20 young healthy (age 26+/-2 years, LDL-cholesterol 90+/-27 mg/dl) and 20 older healthy age-matched control individuals (age 50+/-8 years, LDL-cholesterol 106+/-20 mg/dl). In addition, changes of blood pressure, heart rate, urinary excretion of sodium, and cyclic guanosine monophosphate were measured. Patients were analysed before and after 3 months treatment with either fluvastatin (40 mg twice daily, n=11) or placebo (n=10). RESULTS: In hypercholesterolaemic patients, L-arginine increased RPF and GFR (P<0.01) and urinary excretion of sodium (P<0.05) in a dose-dependent manner. Interestingly, changes were similar between the hypercholesterolaemic patients and the young and the age-matched control individuals (DeltaRPF 100 mg/kg/30 min, 40+/-51 ml/min vs 40+/-52 ml/min, P=NS; DeltaRPF 500 mg/kg/30 min, 114+/-85 ml/min vs 130+/-78 ml/min, P=NS). L-arginine significantly lowered systemic arterial pressure and increased heart rate in all groups. Despite significant reductions in LDL-cholesterol levels (291+/-35 mg/dl vs 213+/-30 mg/dl, P<0.001), treatment with fluvastatin did not alter the renal haemodynamic response pattern to L-arginine infusion when compared to baseline values and to those with placebo. CONCLUSION: In contrast to studies performed in the vasculature of the human forearm or the coronary circulation, our results suggest that hypercholesterolaemia is not associated with an impaired L-arginine-induced renal vascular relaxation.     

The inhibition of thromboxane synthesis has no influence on HgCl2-induced acute renal failure in the rat

Renal function parameters and urinary thromboxane B2-excretion were studied in the rat in HgCl2-induced acute renal failure. Studies were performed before and 3 h after the inhibition of thromboxane synthesis alone, after HgCl2 alone, or after the combination of HgCl2 and thromboxane-synthesis inhibition. Thromboxane-synthesis inhibition alone by indomethacin (5 mg/kg i.v.), imidazole (25 and 50 mumol/kg per min i.v.) and dazoxiben (5 mg/kg i.v.) had no effect on glomerular filtration rate (GFR) or para-aminohippuric acid clearance (CPAH), whereas urinary thromboxane excretion was suppressed. Only the administration of the selective blockers imidazole and dazoxiben resulted in a marked increase in urinary volume (V) and fractional sodium excretion (FENa). HgCl2 alone (2 mg/kg i.v.) caused a decrease in GFR and CPAH with -38% (P less than 0.01), and urinary thromboxane B2 excretion increased from 20.3 +/- 1.5 to 30.6 +/- 2.6 pg/min. (P less than 0.01). The administration of indomethacin, imidazole (50 mumol/kg per min) and dazoxiben prevented the increase in thromboxane B2 excretion 3 h after HgCl2 to values of 3.3 +/- 1.2, 6.9 +/- 0.6 and 13.0 +/- 1.6 pg/min respectively (P less than 0.01 versus control for all values). Despite this, the decrease in GFR and CPAH after HgCl2 could not be prevented. A decrease of GFR with -44, -54, -57 and -32% and of CPAH with -37, -49, -57 and -27% were observed for indomethacin, imidazole 25 and 50 mumol/kg per min and dazoxiben respectively. This evolution was not significantly different from what was observed with mercury alone. Selective thromboxane synthesis inhibition resulted in a decrease of serum free ionised calcium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal outcome after ciclosporin-induced nephrotoxicity.

BACKGROUND: Renal outcome after ciclosporin (CsA) is not clear in most studies involving patients with many renal comorbid conditions. We first report on renal function recovery after CsA in previously healthy kidney patients. METHODS: Uveitis patients, enroled in a unique single centre cohort follow-up study initiated in 1987, were prospectively evaluated for plasma creatinine and glomerular filtration rate (GFR) before, during (>2 years) and after (>6 months) CsA therapy. We hypothesized that CsA alters renal function progressively over time according to two additive exponential components (irreversible and reversible) and used a mixed linear model with exponential speed parameters maximizing the likelihood. RESULTS: Twenty-seven patients treated for 60+/-34 months (CsA 5.1+/-2.5 mg/kg/day) were followed up for 56+/-42 months after CsA withdrawal. Baseline creatinine was 0.92+/-0.15 mg/dl. The reversible effect of CsA was quantified as a 0.11+/-0.07 mg/dl increase in creatinine/100 mg CsA/day (P<0.001) and a 6.0+/-3.7 ml/min/1.73 m(2) decrease in GFR/100 mg CsA/day (P<0.0001). The irreversible effect was quantified as a 0.03+/-0.05 mg/dl increase in creatinine/100 g cumulative CsA received (P<0.007) and a decrease of 3.3+/-3.9 ml/min/1.73 m(2) GFR/100 g CsA. CONCLUSIONS: Although significant decrease in GFR is induced by low-dose CsA therapy in previously healthy kidney patients, renal function recovery is possible after CsA withdrawal and best predicted by CsA daily dosage. Irreversible loss in GFR is correlated to cumulated CsA exposure. The lowest CsA dosage and shortest exposure time effect as well as unlimited renal monitoring are required in order to provide the best long-term renal outcome.     

Beneficial effects of atrial natriuretic factor on cisplatin-induced acute renal failure in the rat

The organometal cisplatin has potent antitumor properties. However, its use is sometimes complicated by significant nephrotoxicity. This is characterized by tubular necrosis and impairment of the glomerular filtration rate (GFR). On the other hand, it has been demonstrated that atrial natriuretic factor (ANF) increases GFR in normal euvolemic rats. In the present study, we have therefore tested if this new potent natriuretic compound could restore some of the renal parameters affected by cisplatin. To investigate this issue, acute renal failure was induced in 9 rats by intraperitoneal injection of cisplatin 10 mg/kg body weight (b.w.). Renal function was studied 72 h later using the 3H-inulin clearance method and was compared with the renal function of 5 normal euvolemic rats. The cisplatin-treated rats showed high blood urea nitrogen levels, a 74% reduction of whole kidney GFR (0.308 +/- 0.047 vs. 1.17 +/- 0.08 ml/min/100 g b.w.) and a significant increase in the fractional excretion of urine, sodium and potassium. After 2 control clearances, synthetic ANF was administered intravenously as a prime (12 micrograms/kg b.w.) and then as a constant infusion (1 microgram/kg/min) to 6 cisplatin-treated rats. This promptly doubled the GFR (0.603 +/- 0.113 ml/min/100 g b.w.) and induced a significant increase in the excretion rate of urine, sodium and potassium. These results demonstrate that the administration of ANF has a beneficial effect on the experimental model of acute renal failure induced by cisplatin.     

Myoglobin release and renal function in polytraumatized patients in intensive care

The excessive release of myoglobin following extensive skeletal muscle trauma, burns, and myopathies may result in renal dysfunction. Due to its molecular size, myoglobin is filtered through the glomerulus and is in part reabsorbed by the tubular system. intraluminal deposition of myoglobin following renal hypoperfusion and the impact of endogenous mediators on cell function contribute to the pathogenesis of acute renal failure. The present study was aimed to investigate the relation between myoglobin and renal function in polytraumatized patients. Thirty-four patients with an Injury Severity Score (ISS) of 28 +/- 3.1 (SEM) and a mean age of 39.5 years (range 18-70) were studied prospectively. Myoglobin, sodium, and creatinine concentrations in plasma and urine were determined 8-hourly. Myoglobin excretion, fractional myoglobin excretion, myoglobin clearance, creatinine clearance, and fractional excretion of sodium were calculated. The mean concentration of plasma myoglobin on the 1st day post-trauma was 3087 ng/ml. A continuous decrease in plasma myoglobin concentration could be observed, with a mean value of 497 ng/ml on day 7. The myoglobin concentration in urine showed marked fluctuations: the mean values were 3.37-4.12 mg/ml on day 1 and 0.78-1.34 mg/ml on day 7. There was no correlation between plasma and urine myoglobin concentrations. The myoglobin concentration increased during the period of observation, but there was no correlation with the creatinine clearance. The fractional excretion of myoglobin was in the range of 1% to 14%. There was no correlation between the fractional excretions of myoglobin and sodium.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Creatinine clearance as a measure of GFR in screenees for the African-American Study of Kidney Disease and Hypertension pilot study

Serum creatinine and endogenous creatinine clearance (CrCl) are widely used measures of renal function. This study compares the precision, bias, and sources of error in using different CrCl measures to estimate the glomerular filtration rate (GFR) in 118 men and women screened for the African-American Study of Kidney Disease and Hypertension (AASK) pilot study. We measured serum creatinine, 24-hour CrCl, and CrCl during timed clearance periods conducted simultaneously with an 125I-iothalamate GFR study. Serum creatinine was measured using two different kinetic rate Jaffe methods (CX3 and Hitachi). After standardization for body surface area, the different measures of renal function available for each individual were compared with the 125I-iothalamate GFR simultaneous to the CrCl. In a subset of 50 participants, the CrCl measures were compared with a follow-up GFR (fGFR). The mean 125I-iothalamate GFR was 65.2 (SD, 26.4), with a range of 11 to 122 mL/min/1.73 m2. The mean +/- SD percentage differences from the GFR were -9%+/-22% for the Cockcroft-Gault estimated CrCl, 1%+/-29% for the 24-hour CrCl, and 8%+/-16% for the CX3 simultaneous CrCl. The Hitachi method overestimated serum creatinine and underestimated GFR. Compared with an fGFR, the mean +/- SD differences were 2%+/-19% for the first GFR, -6%+/-20% for the Cockcroft-Gault estimated CrCl, 10%+/-28% for the 24-hour CrCl, and 14%+/-29% for the CX3 simultaneous CrCl. Thus, the increased precision with which the timed CrCl predicted its simultaneous GFR did not extend to improved ability to predict a future GFR. The fractional excretion of creatinine, measured as the ratio of the CX3 simultaneous CrCl to 125I-iothalamate clearance, increased with decreasing GFR but was lower than expected (mean +/- SD of 1.21+/-0.16 for GFRs between 20 and 40 mL/min/1.73 m2). The lower fractional excretion explains why the 24-hour and Cockcroft-Gault CrCls did not overestimate GFR, but the reasons for this lower excretion are uncertain. Creatinine assay specificity and calibration are important sources of variability that must be examined in any CrCl measure of GFR. We conclude that despite requiring substantially more time and effort, neither the outpatient 24-hour urine nor the timed CrCl offered increased precision over a calculation based on serum creatinine, sex, age, and weight in predicting GFR.     

Effects of H2-receptor antagonists on renal function in cyclosporine-treated renal transplant patients

H2-receptor antagonists have been frequently avoided in cyclosporine-treated transplant patients because of concern regarding possible exacerbation of nephrotoxicity. To determine whether the reported increase of serum creatinine levels in cyclosporine-treated transplant patients receiving H2-receptor antagonists was due to a true decrease in glomerular filtration rate or was secondary to altered renal tubular handling of creatinine, simultaneous inulin and creatinine clearances were analyzed in 11 cyclosporine-treated renal transplant recipients before and after H2-receptor antagonist administration. Seven patients received one week of cimetidine 300 mg p.o. four times daily and eight received one week of ranitidine 150 mg p.o. two times daily. Prior to study, all patients had stable renal function and were maintained on prednisone (mean dose 0.2 +/- 0.01 mg/kg/day) and cyclosporine (mean dose 5 +/- 0.6 mg/kg/day). Four patients were also receiving azathioprine (2 mg/kg/day). Cimetidine administration resulted in a significant increase (P less than 0.05) in mean serum creatinine concentration from 2.0 +/- 0.3 mg/dl to 2.4 +/- 0.3 mg/dl and a significant reduction (P less than 0.05) in mean creatinine clearance remained unchanged during this same period. Serum creatinine levels returned to baseline values for all patients following discontinuation of the drug. Ranitidine administration had no consistent effect on serum creatinine concentration, creatinine clearance or inulin clearance. Cyclosporine trough levels and BUN were unchanged by either drug. These results confirm previous observations demonstrating an increase in serum creatinine and a reduction in creatinine clearance following administration of H2 receptor antagonists, especially cimetidine. Failure to document a simultaneous reduction in inulin clearance is consistent with the hypothesis that H2-receptor antagonists do not exacerbate cyclosporine nephrotoxicity and lower GFR, but rather compete with creatinine for tubular secretion.     

Influence of albumin infusion on the urinary excretion of beta2-microglobulin in patients with proteinuria

Most filtered proteins are reabsorbed by the renal proximal tubule by a mechanism that involves binding to the brush border membrane and endocytosis. Under normal conditions the low-molecular-weight protein beta2-microglobulin (beta2M), which is used to detect tubular injury, is reabsorbed almost completely. However, in proteinuric patients an increased urinary excretion of beta2M may not simply reflect tubular damage but might also result from a decreased tubular reabsorption due to competitive mechanisms. To examine the magnitude of such an effect we have studied the renal effects of albumin infusion (40 g in 2 h of a 20% solution) in 10 patients with a glomerular disease and proteinuria >3.5 g/24 h. Before, during and after albumin infusion the GFR (inulin clearance), RPF (PAH clearance), blood pressure and the urinary excretion of albumin, IgG, transferrin and beta2M were measured. Albumin infusion resulted in a slight decrease of the GFR (72 +/- 11 ml/min before and 67 +/- 10 ml/min after infusion), an increase of the RPF (379 +/- 66 ml/min before and 445 +/- 83 ml/min after), a decrease of the filtration fraction (0.20 before and 0.17 after), and hemodilution. After infusion the urinary excretion of albumin increased from 4.5 +/- 0.7 to 8.4 +/- 1.6 mg/min (p < 0.05). The urinary excretion of IgG and transferrin increased, probably reflecting a change in glomerular size-selectivity. In contrast, the urinary excretion of beta2M did not change significantly (baseline 12 +/- 5 microg/min, end 13 +/- 6 microg/min, percentage change 16.8 +/- 11%). To correct for changes in tubular load we calculated the fractional reabsorption of beta2M. The initial rise in albuminuria during infusion did not affect fractional tubular reabsorption (Delta%: 0. 72 +/- 0.52%, median 0.005%). In the period after infusion a slight decrease was noted (median -0.33%, p < 0.01). A decrease in the fractional reabsorption was particularly observed in patients with pre-existing tubular damage. In conclusion: infusion of albumin in proteinuric patients has no clinically relevant effect on the tubular reabsorption of beta2M. Therefore, beta2M is useful as a parameter to detect tubular injury and alterations in tubular handling of proteins in patients with proteinuria and glomerular diseases.