Department of Medicine, Division of Nephrology, University Medical Center, Nijmegen, The Netherlands
Correspondence and offprint requests to: A. J. W. Branten, MD, Department of Medicine, Division of Nephrology 545, University Medical Center Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Email: a.branten{at}nier.umcn.nl
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Abstract |
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Methods. Inulin clearance (GFR) and creatinine clearance (ECC) have been simultaneously measured in a cohort of 42 patients with proteinuria and 45 healthy controls. The clearance of creatinine by tubular secretion (TScreat) can be estimated by ECCGFR. TScreat was calculated in both groups. Regression analysis was performed to identify factors that independently influence tubular creatinine secretion.
Results. The mean age (±SD) of the patients was 41±13 years, serum albumin 26±9 g/l, median (IQR) proteinuria 4.5 (3.68.2) g/10 mmol creatinine, serum creatinine 103 (84143) µmol/l, ECC 85 (69118) ml/min/1.73 m2, and GFR 54 (3683) ml/min/1.73 m2. Median TScreat amounted to 29 (2136) ml/min/1.73 m2. In the healthy controls serum creatinine was 75 (7081) µmol/l, ECC 118 (109125) ml/min/1.73 m2, GFR 106 (102115) ml/min/1.73 m2, and TScreat 11 (3.519) ml/min/1.73 m2. By regression analysis serum albumin was identified as an independent predictor of tubular creatinine secretion. We divided the patients in two subgroups based on serum albumin levels. TScreat was 24 (1429) ml/min/1.73 m2 in patients with serum albumin levels >25.8 g/l, and 36 (2854) ml/min/1.73 m2 in patients with serum albumin levels <25.8 g/l (P<0.01).
Conclusion. Serum albumin levels influence tubular creatinine secretion. As a result, the endogenous creatinine clearance as well as estimated GFR using a modified MDRD equation more pronouncedly overestimate glomerular filtration rate in nephrotic syndrome.
Keywords: creatinine clearance; nephrotic syndrome; renal function; tubular handling
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Introduction |
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Based on the data of the Modification of Diet in Renal Disease (MDRD) study prediction equations have been developed that allow a better estimate of GFR in patients with renal diseases [4]. Recently, a simplified MDRD equation was published, which used serum creatinine as the only serum assay, and which had similar predictive ability as the original MDRD equation [5,6]. This simplified equation has already been used in large studies [7]. However, the performance of this formula in patients with hypoalbuminemia is unknown.
In the present study we have examined the relationship between ECC and GFR in patients with proteinuria. Our data indicate that tubular handling of creatinine is dependent on serum albumin levels.
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Methods |
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Laboratory measurements
In blood and urine samples creatinine was determined according to a modified Jaffé method on a Hitachi 747 autoanalyser (Roche, Almere, The Netherlands). Inulin concentrations were determined in duplicate by a semi-automatic technique (centrifugal analysis, Multistat) using enzymatic degradation of inulin [9]. Albumin was measured in serum by immunonephelometry on a BNII nephelometer (Behring, Marburg, Germany) using antibodies whose specificity was checked by Ouchterlony double immunodiffusion and immunoelectrophoresis (Dako, Gloostrup, Denmark). Urinary protein was measured in 24 h urine samples using a turbidimetric method with trichloroacetic acid.
Calculations and statistics
The creatinine clearance was calculated according to the standard formula Ucr*V/Pcr in which Ucr is the creatinine concentration in the timed urine portion, V is the volume of the timed urine portion, and Pcr is the plasma concentration of creatinine measured in the same time period. The GFR was calculated with the same formula, but now using inulin concentrations instead of creatinine concentrations. The clearance of creatinine by tubular secretion (tubular clearance of creatinine; TScreat) was calculated from ECCGFR. The simplified MDRD equation was used as follows: estimated GFR = 186 * [Plasma creatinine]1.154 * [Age]0.203 * [0.742 if patient is female] (plasma creatinine in mg/dl). Because all patients were Caucasian the correction factor for black people in the formula was eliminated [5]. Since serum urea was not regularly measured in our patients we were not able to use the extensive MDRD equation [4]. Total proteinuria as measured in 24 h urine samples was expressed as grams per 10 mmol creatinine to correct for errors in urine collection.
Results are given as means (±SD) or medians (interquartile range; IQR) when appropriate. For comparisons of means and medians the Student T-test or the MannWhitney U-test were used respectively. The Spearman correlation test was used to identify individual factors that are related to the TScreat. Next, linear regression analysis was carried out, using a forward stepwise procedure, to determine which of these individual factors independently influenced the TScreat. To allow regression analysis non-parametic parameters were transformed. TScreat showed a normal distribution after square root transformation, serum creatinine and proteinuria after log transformation. The transformed TScreat was defined as the dependent variable and the identified factors as a result of the univariate analysis were introduced as possible predicting variables. A P-value <0.05 was considered significant. All statistics were performed using SPSS software, version 11 (SPSS, IL, Chicago, USA).
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Results |
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The relationship between the ECC and GFR for the two subgroups is depicted in Figure 2. It is evident that the regression lines are different. To illustrate the consequences of this difference for clinical practice, we calculated GFR for a typical patient with a measured ECC of 80 ml/min. In healthy controls an ECC of 80 ml/min/1.73 m2 represents a GFR of 60 ml/min/1.73 m2; in patients with proteinuria and a serum albumin level >25.8 g/l it represents a GFR of 57 ml/min/1.73 m2; in patients with a serum levels <25.8 g/l an ECC of 80 reflects a GFR of 42 ml/min/1.73 m2. As expected, we observed a similar difference between the patient groups when considering the relationship between calculated GFR using the simplified MDRD formula and true GFR (inulin clearance) (Figure 3).
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Discussion |
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It is well known that ECC overestimates GFR, due to fact that creatinine is not only filtered but also secreted by the renal proximal tubules. Under normal circumstances tubular secretion contributes approximately 1015% to renal creatinine clearance, the ratio of ECC/GFR amounting to 1.15 in healthy volunteers [1,10]. In patients with a decreased renal function the relative contribution of tubular secretion to renal creatinine clearance increases, which explains the widely recognized fact that ECC increasingly overestimates GFR at lower GFR [10].
Previous investigators have already pointed to the sometimes marked discrepancies between ECC and GFR in patients with a nephrotic syndrome, however, our study is the first to demonstrate the independent association between serum albumin levels and tubular creatinine handling resulting in a more pronounced overestimation of GFR. Berlyne et al. described four patients with a nephrotic syndrome and ECC/GFR ratios ranging from 1.24 to 2.37 [3]. However, the two patients with the highest ratio had markedly impaired GFR (inulin clearance). Carrie et al. studied 38 patients with a nephrotic syndrome [23]. The mean ECC/GFR ratio was 1.70±0.11. In these nephrotic patients inulin clearance was impaired. The impairment of renal function could not fully explain the increased ratio of ECC/GFR since a significantly lower ratio (1.22±0.14) was observed in patients with a comparable GFR. The latter group of "control" patients suffered form heart failure, and therefore it remained undetermined if tubular creatinine handling was altered in the nephrotic patients or in the patients with heart failure [2]. In a study in diabetic patients cimetidine, an inhibitor of creatinine transport, more pronouncedly reduced creatinine clearance in patients with macroproteinuria [11]; however, again GFR (inulin clearance) was lowest in patients with macroproteinuria. In contrast, Anderson et al. did not observe a difference in the ratio ECC/GFR between nephrotic and non-nephrotic subjects [12].
Our observations suggest that alterations in tubular creatinine handling take place as consequence of hypoalbuminaemia which can lead to major errors in the estimation of renal function in patients with a nephrotic syndrome. Our calculations indicate that in patients with a nephrotic syndrome roughly a 25% decrease of GFR may occur without any change in ECC or serum creatinine. This means that in such patients a fall in GFR will not be noticed, even by slight increases of serum creatinine.
Our study explains some discrepancies in the literature with respect to renal function parameters in patients with proteinuria. Experimental data have unequivocally shown that a reduction of albumin causes a decrease in the ultrafiltration coefficient Kf [13]. As a consequence GFR and filtration fraction are decreased when measured by precise techniques (inulin clearance or comparable methods) in patients with a nephrotic syndrome. In contrast, serum creatinine and creatinine clearance are reported as normal in most patients with minimal change nephropathy [14,15].
In recent years new equations have been developed for the estimation of GFR. Based on the MDRD data a new formula was developed, which has been validated in patients with renal failure [4]. In the MDRD formula parameters included were age, sex, race, serum creatinine, serum urea, and serum albumin. Levey et al. have subsequently published a simplified formula that included only serum creatinine as serum parameter [5]. Serum albumin and urea were excluded since these variables supposedly only contributed <1% to the observed variance of the calculations [6]. This simplified formula has been tested also in patients without renal diseases [6], and has been applied in recent studies [7]. It is clear from our study that the performance of this simplified formula is also dependent on serum albumin levels, overestimation of GFR being more prominent in patients with severe hypoalbuminaemia. Thus, a formula solely based on serum creatinine as the only serum marker should not be used in studies that include patients with severe proteinuria.
Unfortunately, serum urea levels were only available in 11 of our patients. Application of the original MDRD formula in this subgroup suggested a better performance of the original formula (data not shown). However, the paucity of data do not allow firm conclusions and larger studies are needed to validate the original MDRD formula particularly in patients with proteinuria.
It is difficult to speculate on the mechanism that may cause the altered tubular handling of creatinine in patients with low serum albumin levels. Apparently, tubular creatinine secretion is increased in patients with low serum albumin levels. Of note, serum albumin and not proteinuria was independently related to tubular creatinine handling. One mechanism could be that low serum albumin levels reflect lesser transport of albumin bound molecules that normally compete with creatinine for tubular transport.
We would like to point out an alternative explanation. We feel that our findings may be compatible with a decrease in creatinine reabsorption. In patients with a nephrotic syndrome and severe hypoalbuminemia proximal sodium reabsorption is reduced [16]. As such, creatinine reabsorption as a passive process will be influenced by changes in water and sodium reabsorption. The findings of Carrie et al. [2] with low ECC/GFR ratio in patients with heart failure also are compatible with such an idea, since in these patients creatinine reabsorption will be increased. Admittedly, creatinine reabsorption has only been demonstrated in some animal species [17]. There are data available in human studies suggesting the presence of tubular reabsorption of creatinine, particularly in patients with low rates of urine flow, however proof is lacking [1820]. Although studies in humans are difficult, we feel that such a process cannot be excluded.
In conclusion, the present data indicate that serum albumin levels influence tubular handling of creatinine. As a result GFR is more pronouncedly overestimated by ECC in patients with a nephrotic syndrome. In patients with a nephrotic syndrome a normal serum creatinine should not be regarded as evidence of a normal GFR.
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Acknowledgments |
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Conflict of interest statement. None declared.
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References |
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