Assessment of renal function: selected developments

Tests commonly used to assess the glomerular filtration rate (GFR) and to detect renal tubular damage are critically reviewed. Creatinine clearance which is frequently used for assessment of the GFR is prone to several errors. The plasma creatinine can be used to provide a rough guide but for reliable measurement of the GFR, 51Cr-EDTA clearance is recommended. Measurements of the urinary excretion of low molecular weight proteins, enzymes and kidney tissue proteins have been used to detect tubular damage. Of the low molecular weight proteins excreted, beta-2-microglobulin is unstable and measurement of retinol-binding protein or alpha-1-microglobulin is recommended for the detection of chronic renal tubular malfunction. Of the many enzymes that have been studied, urinary N-acetyl-beta-D-glucosaminidase or alanine aminopeptidase are recommended as being the most useful for the early detection of acute renal tubular damage. Among renal tissue proteins that have been measured in urine adenosine-deaminase-binding protein, a tubular brush border antigen appears to have considerable potential for providing early warning of renal allograft rejection.     

The relationship between the renal clearance of creatinine and the apparent renal clearance of beta-2-microglobulin in patients with normal and impaired kidney function

The renal clearances of creatinine and beta 2-microglobulin of patients with either normal or impaired kidney function were measured. The renal clearance of beta 2-microglobulin depends on the urinary pH and must be considered as an apparent renal clearance because after tubular reabsorption the compound is metabolized in the kidney. Impaired kidney function reduces the percentage of tubular reabsorption of beta 2-microglobulin.     

Comparative nephrotoxicity of gentamicin and tobramycin: pharmacokinetic and clinical studies in 201 patients.

A total of 201 critically ill patients were studied during 267 courses of gentamicin or tobramycin treatment (139 gentamicin courses and 128 tobramycin courses). Of these 267 courses, pharmacokinetic and clinical data were obtained for 240 (120 gentamicin and 120 tobramycin). The data collected for pharmacokinetic analysis included measurements of serial blood and urine levels, urinary excretion of beta 2-microglobulin, protein levels, and granular casts. A two-compartment model was used to assess tissue accumulation, and in 89 courses the predicted accumulation was confirmed by cumulative urine collection or postmortem tissue analysis. As groups, the patients given gentamicin and tobramycin did not differ in age, weight, creatine clearance, total dose given, duration of treatment, initial aminoglycoside through serum levels, number of dosage adjustments, concurrent use of furosemide, or concurrent cephalosporins. Previous aminoglycoside treatment (usually gentamicin) had occurred more frequently in the tobramycin treated patients (P less than 0.01), and more males than females received tobramycin (P less than 0.05). Pharmacokinetic assessments of renal damage were based on both changes in glomerular filtration rate (serum creatinine levels, creatinine clearance) and renal tubular damage (beta 2-microglobin, casts), but only patients with elevated aminoglycoside tissue levels leading to renal tubular damage and subsequent creatinine clearance decreases were considered to have experienced aminoglycoside nephrotoxicity. In the pharmacokinetic analysis of nephrotoxicity, 29 gentamicin courses (24%) and 12 tobramycin courses (10%) were complicated by nephrotoxicity (P less than 0.01). The 201 study patients were also evaluated independently for clinical nephrotoxicity (defined as a serum creatinine level increase of 0.5 mg/dl or more). Clinical nephrotoxicity occurred at rates of 37% in the gentamicin-treated group and 22% in the tobramycin-treated group (P less than 0.02). In these similar groups of critically ill patients, tobramycin was less nephrotic than gentamicin.     

Urinary casts as an indicator of renal tubular damage in patients receiving aminoglycosides.

We assessed the value of quantitative cast excretion as an early marker of renal tubular damage in 154 seriously ill patients. One hundred twenty-four of these received aminoglycoside antibiotics, and 30 of the 124 experienced a rise in serum creatinine of 0.5 mg/dl or more during therapy. The remaining 30 of the 154 patients were treated with other antibiotics and served as controls. Casts were quantitated in random urines collected before morning diuretic doses. Cast counts in control patients averaged 44 +/- 51 casts during the intensive care unit admission. Patients given aminoglycosides without a significant rise in serum creatinine of 0.5 mg/dl or more excreted 153 +/- 196 casts, significantly more than controls. In comparison to both the control and nontoxic patients, the 30 nephrotoxic patients excreted significantly more casts (625 +/- 364) and were significantly higher as early as 9 days before serum creatinine first rose. Daily urinary cast counts are a rapid and inexpensive means of identifying early renal tubular damage in critically ill patients given aminoglycosides.     

Differentiation of glomerular, tubular, and normal proteinuria: determinations of urinary excretion of β2-microglobulin, albumin, and total protein

A low molecular weight beta(2)-globulin (beta(2)-microglobulin), albumin, and total protein were measured in concentrated 24-hr urine specimens from 20 healthy subjects and 30 patients with clinical proteinuria of glomerular or tubular type. Classification of proteinuria was made on the basis of clinical diagnosis and size distribution of urinary proteins after gel chromatography. The molecular radii (Stokes' radii) of beta(2)-microglobulin and albumin, estimated by gel chromatography, were 15 A and 35 A.The average 24-hr urinary excretion in healthy subjects was 0.12 mg for beta(2)-microglobulin, 10 mg for albumin, and 80 mg for total protein. The patients with renal glomerular disorders had normal or only somewhat increased excretion of beta(2)-microglobulin, despite considerably increased excretion of albumin and total protein. Most of the patients with tubular dysfunction excreted large amounts of beta(2)-microglobulin, although they excreted normal or only slightly increased amounts of albumin and only moderately increased quantities of total protein. Consequently, the ratio or urinary albumin/urinary beta(2)-microglobulin was high in glomerular proteinuria (1100: 14,200), intermediate in normal proteinuria (33: 163), and low in tubular proteinuria (1.0: 13.3). Determinations of urinary clearances of beta(2)-microglobulin and albumin in four healthy subjects and 11 patients indicated that increased excretions of the two proteins were associated with increased clearances. The results suggest that quantitative determinations of urinary beta(2)-microglobulin and urinary albumin may be useful for detecting disorders of the renal handling of plasma proteins. The findings also seem to suggest a selective tubular reabsorption of the two proteins.Estimates on sera revealed a close correlation between serum levels of beta(2)-microglobulin and creatinine and also a greatly raised serum concentration of beta(2)-microglobulin after bilateral nephrectomy.     

Renal glomerular and tubular impairment during strenuous exercise in young women

Creatinine, total protein, albumin and beta2-microglobulin were measured in the urine of fifteen healthy women before and after strenuous short-term exercise. The heavy intermittent load produced an increased urinary excretion of total protein, albumin and beta2-microglobulin, while creatinine was unaffected. The renal clearance of albumin and beta2-microglobulin showed very high values after stopping the exercise. However, 45 min after the end of exercise, total protein returned to initial values while albumin and beta2-microglobulin remained high. The urinary ratio between beta2-microglobulin and albumin is higher in urine collected after exercise than in normal proteinuria. This implies that post-exercise proteinuria is of glomerular and tubular origin.     

Urinary excretion of albumin in normal man: the effect of water loading

The urinary excretion of albumin and beta 2-microglobulin in response to two different types of oral water load was studied in 18 healthy subjects. Both acute water loading (1 litre of tap water given over 10 min) and chronic water loading (250 ml of water given every 20 min for the 4-h duration of the test) produced a short-lived but significant increase in the urinary excretion of albumin, but not in beta 2-microglobulin. Albumin excretion returned promptly to basal values in spite of high and sustained urine flow. The decrease in haematocrit, plasma osmolality, plasma sodium concentration and pulse rate and the increase in creatinine clearance suggest that the elevation in albumin excretion might be the result of a transient volume expansion associated with an increase in glomerular filtration rate and in filtration of albumin. However, a washout of proteins from the tubular lumen with preferential reabsorption of small molecular weight proteins (i.e. beta 2-microglobulin) during high tubular flow cannot be excluded. Studies investigating changes in urinary albumin excretion should be performed after baseline conditions of stable urinary excretion of albumin have been established.     

Population pharmacokinetic model of Vancomycin based on therapeutic drug monitoring data in critically ill septic patients

PurposeThe present study aimed to establish a population pharmacokinetic model of vancomycin, including adult critically ill septic patients, with normal and impaired renal function.Materials and methodsA prospective analysis of 146 concentrations from 73 adult critically ill septic patients treated with 1-h intravenous infusion of vancomycin were included in the study. A nonlinear mixed effects modeling (NONMEM) approach was applied for data analysis and evaluation of the final model. The influence of creatinine clearance calculated by the Cockcroft-Gault equation (CrCl), and other potential covariates on vancomycin clearance (CL) were evaluated.ResultsThe final one-compartment pharmacokinetic model includes the effect of CrCl on CL. Population pharmacokinetic values for a typical subject were estimated at 0.024 l/h for CL dependent on renal function (CLCrCl), 1.93 l/h for residual portion of CL (not dependent on renal function), and 0.511 l/kg for volume of distribution (V). According to the final model, for patients with CrCl = 120 ml/min, the median vancomycin total CL is 4.81 l/h, while CrCl-dependent fraction accounts for approximately 60% of CL.ConclusionsThe developed population vancomycin model may be used in estimating individual CL for adult critically ill septic patients, and could be applied for individualizing dosage regimens taking into account the continuous effect of CrCl.     

Renal handling of beta2-microglobulin in experimental renal disease.

Renal extraction and urinary excretion of 125I-labelled beta2-microglobulin was studied in rats. The effect of ischaemic renal injury, experimental pyelonephritis, and unilateral nephrectomy was investigated. The tubular secretion of o-iodohippurate (OIH) was measured for comparison. The urinary excretion was calculated as the ratio between the clearance of protein and the glomerular filtration rate. The glomerular filtration rate was estimated as clearance of polyethylene glycol (PEG 1000). The renal arteriovenous concentration difference was lower for beta2-microglobulin than for PEG 1000 IN ALL THE EXperimental groups. In unilateral renal disease the beta2-microglobulin excretion of the intact kidneys was similar to that of the diseased kidneys. A significant differences was noted only after ischaemic renal injury. The same was found for OIH. After removal of the intact kidneys the excretion of beta2-microglobulin increased about 10-fold in pyelonephritic animals and 2- to 30-fold in animals with ischaemic renal injury. One hour after unilateral nephrectomy in normal animals the ratio increased about 50 per cent. The tubular secretion of OIH did not change noticeably. It is concluded that the glomerular filtration is a main step in the intrarenal catabolism of beta2-microglobin and that its urinary excretion is considerably influenced by a reduction in the functioning kidney mass.     

Vancomycin dosing in critically ill patients: robust methods for improved continuous-infusion regimens

Despite the development of novel antibiotics active against Gram-positive bacteria, vancomycin generally remains the first treatment, although rapidly achieving concentrations associated with maximal efficacy provides an unresolved challenge. The objective of this study was to conduct a population pharmacokinetic analysis of vancomycin in a large population of critically ill patients. This was a retrospective data collection of 206 adult septic critically ill patients who were administered vancomycin as a loading dose followed by continuous infusion. The concentration-versus-time data for vancomycin in serum was analyzed by a nonlinear mixed-effects modeling approach using NONMEM. Monte Carlo simulations were performed using the final covariate model. We found that the best population pharmacokinetic model consisted of a one-compartment linear model with combined proportional and additive residual unknown variability. The volume of distribution of vancomycin (1.5 liters/kg) was described by total body weight and clearance (4.6 liters/h) by 24-hour urinary creatinine clearance (CrCl), normalized to body surface area. Simulation data showed that a 35-mg/kg loading dose was necessary to rapidly achieve vancomycin concentrations of 20 mg/liter. Daily vancomycin requirements were dependent on CrCl, such that a patient with a CrCl of 100 ml/min/1.73 m2 would require at least 35 mg/kg per day by continuous infusion to maintain target concentrations. In conclusion, we have found that higher-than-recommended loading and daily doses of vancomycin seem to be necessary to rapidly achieve therapeutic serum concentrations in these patients.     

Small and middle molecular weight solute clearance in nocturnal intermittent peritoneal dialysis.

OBJECTIVES: To determine the dialysate-to-plasma (D/P) concentration ratios and peritoneal dialytic clearance (CI(D)) of substances with a wide range of molecular weights in subjects receiving a simulated nocturnal intermittent peritoneal dialysis (NIPD) session. DESIGN: Open-label single-dose study. SUBJECTS: Six end-stage renal disease patients undergoing peritoneal dialysis (PD). SETTING: Clinical research center of a university-affiliated hospital. INTERVENTIONS: Subjects received intravenous gentamicin and vancomycin on the first day of the study. Subjects received no PD until their return on the following day, when subjects underwent a simulated NIPD session utilizing four 2- to 2.5-L peritoneal dialysate dwells of 2 hours. Blood and dialysate samples were collected immediately before the session and after each dialysate dwell for determination of urea, creatinine, gentamicin, vancomycin, and beta2-microglobulin (beta2M) concentrations. Each solute's D/P concentration ratio and peritoneal CI(D) were calculated. MEASUREMENTS AND MAIN RESULTS: The (mean +/- SD) 2-hour D/P concentration ratios were 0.78 +/- 0.05 (urea), 0.49 +/- 0.11 (creatinine), 0.38 +/- 0.08 (gentamicin), 0.11 +/- 0.06 (vancomycin), and 0.07 +/- 0.03 (beta2M). Peritoneal CI(D) values (mL/min of dialysis) were 19.0 +/- 2.8 (urea), 12.1 +/- 3.5 (creatinine), 8.4 +/- 2.8 (gentamicin), 2.7 +/- 1.5 (vancomycin), and 1.7 +/- 0.8 (beta2M).The D/P concentration ratios and peritoneal CI(D) values for urea, creatinine, and gentamicin were significantly different from vancomycin and beta2M (repeated measures ANOVA, p < 0.05). Beta2-microglobulin peritoneal CI(D) was strongly related to gentamicin peritoneal CI(D) (r = 0.96, p < 0.05). CONCLUSION: Small molecular weight solutes have significantly greater D/P and peritoneal CI(D) than middle molecular weight solutes in NIPD. In NIPD, daily peritoneal CI(D) of beta2M is lower than that reported in continuous ambulatory PD. NIPD also results in lower drug CI(D) than that reported in continuous ambulatory PD studies.     

Effect of renal insufficiency on the concentration of free retinol-binding protein in urine and serum

The concentration of retinol-binding protein (RBP) in urine was determined in 20 healthy individuals and 119 patients with various renal diseases involving tubular or glomerular dysfunction. The sera from 4 healthy individuals and 33 patients were chromatographed on Sephadex G-75 to measure the concentration of free (i.e. not prealbumin-bound) RBP. In healthy individuals, the mean concentration of free RBP in serum was 5.8 mg/l and represented 14% of total RBP; the renal clearance and the fractional tubular uptake of free RBP averaged 0.032 ml/min and 99.97%, respectively. In patients, the concentration of free RBP and the percentage of free RBP in serum were on logarithmic scales inversely correlated with the endogenous creatinine clearance (r = -0.80 and -0.76) and increased in parallel with the serum creatinine (r = 0.67 and 0.66) and beta 2-microglobulin concentrations (beta 2-m, r = 0.76 and 0.89). The semi-logarithmic plot of urine versus serum concentration of free RBP suggests a renal threshold for the tubular reabsorption of this protein at a concentration of about 25 mg/l in serum. The existence of this threshold is confirmed by the relationship between urinary RBP and serum beta 2-m showing that urinary excretion of RBP is invariably high when the serum level of beta 2-m exceeds 5 mg/l. The latter value corresponds precisely to the renal threshold for the tubular reabsorption of beta 2-m. The corresponding value for free RBP derived from the relationship between both proteins is 24 mg/l.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of cimetidine, ranitidine, and antacid on renal function

Serum creatinine and beta 2-microglobulin levels, endogenous creatinine clearance, the urinary beta 2-microglobulin excretion rate, and urinary protein levels were monitored serially in 29 patients with duodenal ulcers randomly allocated to receive eight weeks of treatment with cimetidine, ranitidine, or an antacid. A clinically insignificant increase in endogenous creatinine clearance was noted in patients given ranitidine. No adverse change in any of the variables measured was detected in any group of patients during the 12-week period of study.     

Prognostic value of tubular proteinuria and enzymuria in nonoliguric acute tubular necrosis

BACKGROUND: Acute tubular necrosis (ATN) has high mortality, especially in patients who require renal replacement therapy (RRT). We prospectively studied the diagnostic accuracy of the urinary excretion of low-molecular-weight proteins and enzymes as predictors of a need for RRT in ATN. METHODS: In 73 consecutive patients with initially nonoliguric ATN, we measured urinary excretion of alpha(1)- and beta(2)-microglobulin, cystatin C, retinol-binding protein, alpha-glutathione S-transferase, gamma-glutamyltransferase, lactate dehydrogenase, and N-acetyl-beta-D-glucosaminidase early in the course of ATN. RESULTS: Twenty-six patients (36%) required RRT a median of 4 (interquartile range, 2-6) days after detection of proteinuria and enzymuria. Patients who required RRT had higher urinary cystatin C and alpha(1)-microglobulin [median (interquartile range), 1.7 (1.2-4.1) and 34.5 (26.6-45.1) g/mol of creatinine] than patients who did not require RRT [0.1 (0.02-0.5) and 8.0 (5.0-17.5) g/mol of creatinine]. Urinary excretion of cystatin C and alpha(1)-microglobulin had the highest diagnostic accuracies in identifying patients requiring RRT as indicated by the largest areas under the ROC curves: 0.92 (95% confidence interval, 0.86-0.96) and 0.86 (0.78-0.92), respectively. Sensitivity and specificity were 92% (95% confidence interval, 83-96%) and 83% (73-90%), respectively, for urinary cystatin C >1 g/mol of creatinine, and 88% (78-93%) and 81% (70-88%) for urinary alpha(1)-microglobulin >20 g/mol of creatinine. CONCLUSION: In nonoliguric ATN, increased urinary excretion of cystatin C and alpha(1)-microglobulin may predict an unfavorable outcome, as reflected by the requirement for RRT.     

原发性高血压病对早期肾功能的影响

目的 探讨原发性高血压病对早期肾功能影响的临床意义.方法 通过肾动脉造影、内生肌酐清除率排除肾性高血压,检测入选的原发性高血压病患者的肾小球滤过功能指标和肾小管功能指标.结果 高血压1、2、3组尿β2-微球蛋白(β2-MG)/肌酐(Cr)均高于对照组(P＜0.05),尿N-乙酰β-D-氨基葡萄糖苷酶(NAG)/Cr在高血压2、3组明显增高(P＜0.01).高血压1、2、3组尿渗透压均低于对照组(P＜0.01).在3 h尿微量白蛋白检测中,高血压3组高于对照组(P＜0.01).结论 原发性高血压病在对早期肾功能的影响中,肾小管近端重吸收功能、远端浓缩功能较肾小球滤过功能更易受损.     

Safety and tolerability of multiple doses of imipenem/cilastatin

The safety and tolerability of 1 gm imipenem and cilastatin given together every 6 hours for 10 days was evaluated in a randomized, double-blind, placebo-controlled trial in normal subjects. Nausea was more common in the drug-treated group (five of six subjects) than in the control group (two of six subjects). No consistent changes in hepatic function indices were noted. Although beta 2-microglobulin excretion showed a significant trend of rising over time in the drug group, there were no differences between groups with regard to 24-hour urinary excretion of either N-acetyl-beta-glucosaminidase or beta 2-microglobulin. Urinalysis did not reveal any casts and serial creatinine clearance determinations showed no change in renal function in either the drug- or placebo-treated groups. Pure tone audiograms were performed before and after dosing in 11 of 12 subjects; no changes were noted. We conclude that the combination of imipenem and cilastatin was well tolerated and safe.     

Renal effects of cardiopulmonary bypass in the elderly

Cardiopulmonary bypass is widely believed to be injurious to renal function. The unknown consequences of renal dysfunction with modern techniques of bypass in the elderly caused us to examine creatinine clearance and the excretion of sensitive marker proteins in older adult patients undergoing CABG. Thirty male patients were divided into three groups: group I with an age up to 60 years, group II with an age between 61 and 70 years, inclusive and group III 71 years and over. Serum creatinine and urea, creatinine clearance, and alpha1-microglobulin (alpha1-MG), N-acetyl-beta-D-glucosaminidase (NAG), Tamm-Horsfall protein (TH) and immunoglobulin G (IgG) were all measured daily, pre- and postoperatively. Creatinine clearance remained lower in the older patients without significant differences. Raised excretion rates of alpha1-MG, and IgG were seen after CPB. The increase in alpha1-MG and NAG during the postoperative period revealed tubular damage in all elderly patients. Measurements of alpha1-MG, NAG and IgG represent useful supplements to standard clinical tests for recognizing early and differentiated changes in renal function.     

The effects of arginine, dextran and Haemaccel infusions on urinary albumin, beta 2-microglobulin and N-acetyl-beta-D-glucosaminidase

Male volunteers were infused with L-arginine dextran and Haemaccel. Arginine (0.5 g/kg body weight infused over 30 min) resulted in transient highly significant increases in urinary albumin (p less than 0.001), beta 2-microglobulin (p less than 0.001) and N-acetyl-beta-D-glucosaminidase [NAG] (p less than 0.001). These effects lasted less than 120 min. Dextran 40 and 70 (500 ml infused over 2 h) did not affect urinary albumin, beta 2-microglobulin or NAG excretion. Haemaccel (8 ml/kg body weight infused over 2 h) resulted in significant increases in urinary albumin (p less than 0.05) and beta 2-microglobulin (p less than 0.01) during the second hour of the infusion. It also caused a biphasic increase in urinary NAG excretion, the initial peak (p less than 0.05) coinciding with the peak of albumin and beta 2-microglobulin excretion. The second peak which was more defined (p less than 0.01) occurred 21-24 h after the beginning of the infusion. Neither arginine or Haemaccel have been reported to be nephrotoxic whereas dextran infusions are a well recognised cause of acute tubular necrosis. These data indicate that increases in urinary beta 2-microglobulin and NAG are not always reliable indicators of nephrotoxicity or renal tubular cell damage.     

Urinary excretion of complement C3d in patients with renal diseases

INTRODUCTION: Complement-mediated tubular injury may play an important role in the progression of renal diseases. C3d is a presumed marker of complement activation. Its precursor C3dg has been detected in the urine of patients with membranous nephropathy. However, little is known of the renal handling of C3d or its excretion in other renal diseases. METHODS: We measured the urinary excretion of albumin, IgG, beta2-microglobulin (beta2m), and of complement C3d in patients with tubulo-interstitial nephritis (TIN; n= 8), in patients with membranous nephropathy (n = 35) and in patients with nonmembranous glomerular diseases (23 nonproliferative and 21 proliferative). Fractional excretions (FE) were calculated using creatinine clearance as marker of GFR. RESULTS: C3d was not measurable in the urine of the healthy controls, but was detectable in seven out of eight of the TIN patients (median excretion 0.11 mU min-1, range 0.006-2.4 mU min-1). In these patients the urinary excretion of beta2m was clearly elevated (median 26.6 micro g min-1, range 1.0-103 micro g min-1). The FE of C3d correlated with the FE of beta2microglobulin (r = 0.83, P = 0.01), and their ratio amounted to 0.03 (range 0.003-0.06), a value in agreement with the expected sieving coefficient. Urine C3d was detectable in all but three of the patients with glomerular diseases (median excretion 0.36 mU min-1, range 0.004-7.9 mU min-1); C3d-excretion did not differ between the three subgroups of patients with glomerular diseases. FEC3d correlated with FEIgG (r = 0.88, P < 0.01). The ratio FEC3d/FEbeta2m was 0.78 (range 0.04-9.99). Selected patients with membranous nephropathy were re-analyzed after (partial) remission of proteinuria. Reduction of proteinuria resulted in a decrease of C3d excretion. CONCLUSION: Urinary excretion of C3d is elevated in patients with TIN, most likely as a mere consequence of decreased tubular reabsorption. In patients with glomerular diseases urinary excretion of C3d is increased and related to proteinuria, independent of the underlying glomerular disease. In these patients there is evidence of increased local formation of C3d.