Division of Nephrology, University of California at San Francisco, San Francisco, CA 94143, USA
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Abstract |
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Methods. We analysed the Third National Health and Nutrition Examination Survey (NHANES III; 19881994) data for 14722 adults aged 17 years with measurements of serum creatinine and all electrolytes including ionized calcium. General linear models were used to determine the relationship between mean concentrations of electrolytes and different levels of CockcroftGault creatinine clearance (CrCl). Sample weights were used to produce weighted regression parameters.
Results. Changes in mean serum phosphorus and potassium concentration were evident at relatively modest reductions in CrCl (around 50 to 60 ml/min). Changes in the anion gap and mean levels of ionized calcium and bicarbonate were not apparent until CRI was advanced (CrCl 20 ml/min). For example, compared with women with CrCl >80 ml/min, those with CrCl 6050, 5040, 4030, 3020 and
20 ml/min had mean serum phosphorus concentrations that were higher by 0.1, 0.1, 0.2, 0.3 and 0.8 mg/dl (all P<0.05), and mean serum potassium concentrations that were higher by 0.1, 0.1, 0.1, 0.2 and 0.4 mmol/l (all P<0.05), respectively. These changes were independent of dietary intake and the use of angiotensin converting enzyme (ACE) inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs).
Conclusions. Increases in serum phosphorus and potassium levels are apparent even among people with mild to moderate CRI. These findings should be broadly generalizable to the larger CRI population in the United States. Subtle elevations in serum phosphorus might contribute to the initiation and maintenance of secondary hyperparathyroidism, which is known to occur in mild to moderate CRI.
Keywords: chronic renal insufficiency; phosphorous; potassium
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Introduction |
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In addition to decreased haemoglobin, reduced renal function is associated with a variety of biochemical abnormalities reflected by changes in serum concentrations of calcium, phosphorus, bicarbonate and potassium. However, the extent of these changes and their magnitude in relation to renal function is not well defined, especially among persons with mild to moderate CRI. Currently, our knowledge is derived mostly from studies of relatively small numbers of individuals observed under carefully controlled conditions (such as in a clinical research centre) [4,5] or from CRI subjects recruited from outpatient nephrology practices [6,7]. To what extent these findings can be generalized to people with CRI in the general population is unclear.
Taking advantage of the nationally representative data collected in the Third National Health and Nutrition Examination Survey (NHANES III), we aimed to quantify the relationship between levels of renal function and serum concentrations of calcium, phosphorus, bicarbonate and potassium. We hypothesized that differences in one or more of these serum chemistries would be evident at different levels of renal function, even among individuals with mild to moderate CRI.
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Subjects and methods |
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Information on dietary intake was assessed in NHANES III through 24-h dietary recall and on medication usage through direct patient interview.
Assessment of renal function
Serum Cr was measured in NHANES III using the Hitachi 737 automated analyser (Boehringer Mannheim Diagnostics, Indianapolis, IN, USA) using a rate Jaffe reaction [10]. We assessed renal function as the creatinine clearance (CrCl; measured in ml/min) estimated from the CockcroftGault equation [11]:
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The CockcroftGault-estimated CrCl has been found to correlate well with measured CrCl in a wide variety of patient populations, including both adult men and women (correlation coefficients 0.8 to 0.9) [12]. For the small number of subjects without body weight data (0.2% of the sample), we assigned sex-specific median values.
Measurement of serum electrolytes
Besides serum Cr, the NHANES III serum biochemistry profile also included measurements of sodium, potassium, chloride, bicarbonate, albumin, total calcium and phosphorus using the Hitachi 737 automated analyser. In addition, ionized calcium was measured using a NOVA 7+7 electrolyte analyser (NOVA Biomedical, Waltham, MA, USA). The reported ionized calcium value was normalized for serum pH, i.e. adjusted to the ionized calcium value if the pH were 7.4 [10]. Between pH 7.2 and 7.6, the normalized calcium value was calculated with the equation:
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NHANES III examinees were asked to fast for at least 6 h before examination. However, laboratory test results and the duration of the fast were reported regardless of whether the fast was held or not.
Data management and statistical analysis
Data management and statistical analysis were conducted using SAS version 8.01 (Cary, NC, USA). NHANES III was not a simple random sample of the US population and not everyone had the same probability of selection. Appropriate sample weights were therefore used to obtain weighted regression estimates from the sampled population. The sample weights also adjusted for non-coverage and non-response [13,14]. It was thus possible to generalize the final results of the analysis to the US population (although the distribution of renal function in the study sample is not the same as the distribution of renal function in the whole US population).
We adopted the same analytical approach as in previous studies [3,15]. Individuals were divided a priori into eight categories of renal function by their CockcroftGault-calculated CrCl: >80 ml/min (reference), >70 to 80, >60 to
70, >50 to
60, >40 to
50, >30 to
40, >20 to
30 and
20 ml/min.
Serum chemistries of interest were examined as the dependent variable in a general linear model with age, race-ethnicity and categories of CrCl as independent variables. The value for age was that at the time of the screening interview. Race-ethnicity was predefined in NHANES III as non-Hispanic white (reference group), non-Hispanic black, Mexican-American, or other. The other category included all Hispanics who were not Mexican-American and all non-Hispanics from racial groups other than white or black. Analyses were stratified by gender. Ionized calcium (normalized) was the principal measure of serum calcium in our study. We also analysed total calcium and total calcium adjusted for albumin by a commonly used formula, where 0.8 mg/dl was added for every 1 g/dl depression in serum albumin below 4.0 g/dl [16].
To assess the impact of dietary intake on serum chemistry levels, we repeated the analyses, controlling for dietary intake, for various nutrients as well as the duration of fasting before phlebotomy. Dietary intake data were available in 14 233 of 14 722 participants (97%). To assess the impact of angiotensin converting enzyme (ACE) inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs) on serum potassium, we repeated this analysis after excluding subjects on ACE inhibitors or NSAIDs.
Finally, we determined the percentage of adults in the US in the different categories of CrCl who had a serum phosphorus level >4.5 mg/dl, the upper limit of the laboratory normal reference range.
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Results |
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Serum chemistries and renal function
We found a progressive increase in serum phosphorus concentration among subjects with decreased renal function that became evident as early as CrCl 5060 ml/min (Table 2). In contrast, the relationship between serum ionized calcium (normalized) and CrCl was weak and inconsistent (Table 3
). Only among those with CrCl
20 ml/min was there a trend towards lower mean serum ionized calcium. Serum total calcium or serum total calcium adjusted for albumin were not lower at lower levels of CrCl (data not shown).
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We found a significant decrease in mean serum bicarbonate only when CrCl was 20 ml/min (although this reached statistical significance only among women) (Table 4
). Since non-bicarbonate organic anions may accumulate with diminished renal function, we also measured the anion gap, defined as serum sodium-(serum chloride+serum bicarbonate). As with bicarbonate, we saw a significant change in the anion gap only when CrCl was
20 ml/min (Table 5
).
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Discussion |
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To the best of our knowledge, the analyses reported here are the first large-scale studies to quantify the relationship between the degree of CRI severity and its biochemical consequences using nationally representative data. Our results are therefore broadly generalizable. We found that different homeostatic abnormalities of CRI were apparent at different levels of renal function. Changes in mean serum phosphorus and potassium concentrations were evident at relatively modest reductions of CrCl (around 5060 ml/min). In contrast, changes in other biochemical parameters, e.g. the anion gap and ionized calcium and bicarbonate, were not apparent until CRI was advanced (CrCl 20 ml/min).
Our finding that serum phosphorus concentration is elevated in people with mild to moderate CRI differs from several previous studies [2026]. For example, Wilson et al. found in 12 CRI subjects (CrCl range 3878 ml/min) [26] and Llach et al. found in 13 CRI subjects (CrCl range 3493 ml/min/1.73 m2) [22] that serum phosphorus was lower than in controls. This has been used to argue that an elevated serum phosphorus level is unlikely to play an important role in the pathogenesis of secondary hyperparathyroidism in mild to moderate CRI [27,28]. Instead, the initiation and maintenance of hyperparathyroidism was ascribed to a deficiency in 1,25(OH)2 vitamin D [27,28].
However, the observation of low serum phosphorus in subjects with mild to moderate CRI has not been consistently documented [5,2933]. Studying 51 CRI subjects (CrCl range 591 ml/min/1.73 m2), Pitts et al. found a trend towards a higher serum phosphorus concentration among those with lower CrCl [29]. Our study confirms and extends the findings of Pitts et al. Indeed, the large sample size and accompanying statistical power allowed us to identify a specific range of CrCl at which changes may first be observed.
This subtle increase in mean phosphorus concentration in subjects with mild to moderate CRI suggests that elevations in serum phosphorus may contribute to the observed increases in parathyroid hormone at this level of renal function [29,34], even when mean serum phosphorus concentrations remain within the normal reference range. If so, since an early rise in serum phosphorus may not be accompanied by a corresponding decrease in calcium (as would be predicted by Bricker's trade-off hypothesis [35]), other mechanisms may be involved, such as a direct effect of phosphorus on the parathyroid gland [36]. The increased phosphorus concentration we observed with mild to moderate CRI was independent of dietary phosphorus intake or the duration of fasting prior to phlebotomy. Therefore, these data do not contradict the lack of postprandial rise in serum phosphorus that has been documented among eight children with GFR 2767 ml/min/1.73 m2 [24].
Our finding that decreased serum ionized calcium was not apparent until CrCl was 20 ml/min also agrees with the finding of Pitts et al. [29]. Llach et al. and Wilson et al. also found that serum calcium was similar among those with and without CRI [22,26]. Martinez et al. had speculated that abnormalities in the extracellular calcium sensor receptor might play a role in the pathogenesis of secondary hyperparathyroidism [33].
Our finding that changes in serum bicarbonate and the anion gap were not obvious until CrCl reached 20 ml/min is consistent with the literature showing that uraemic acidosis develops only in the later stages of renal insufficiency [37]. Our results differ from that of Frassetto et al. who found that serum bicarbonate level decreased with CrCl in the range of 80160 ml/min/70 kg [4]. Possible reasons for this discrepancy include the fact that Frassetto et al. analysed arterialized venous blood in 64 subjects who were in a steady state and on a controlled diet in a clinical research centre [4]. This method may be more sensitive than the one employed by NHANES III.
To the best of our knowledge, this is the first study that has shown statistically significant elevations in serum potassium in patients with mild to moderate CRI. These do not seem to be related to the use of drugs known to cause hyperkalaemia in susceptible subjects (e.g. ACE inhibitors and NSAIDs). The physiological significance of this subtle increase in mean serum potassium level (in the order of 0.10.2 mmol/l) is unclear. The associations between reduced renal function and increased levels of potassium and phosphorus are physiologically plausible. These trends are consistent across the genders and correlate with the severity of renal insufficiency (i.e. stepwise worsening of parameters with lower CrCl levels), and therefore probably reflect biological relationships.
It is notable that we were able to detect these changes despite the fact that various homeostatic, compensatory mechanisms may be in play throughout the course of CRI that serve to minimize changes in serum chemistries. Of great importance among these mechanisms are hormonal changes (e.g. aldosterone promoting urinary potassium excretion, or parathyroid hormone promoting urinary phosphorus excretion and calcium mobilization from bone). Our results suggest that these adaptations are unable to compensate completely for the decrease in GFR, as a subtle elevation in the mean serum potassium level can be detected in a study with sufficient power.
This study has several limitations that should be mentioned. Only calculated creatinine clearances were used; actual measurements of CrCl or GFR were not made. However, the use of estimated CrCl typically reduces misclassification of CRI severity compared with the use of serum Cr [6,7]. NHANES III data did not contain measurements of arterial blood gas, parathyroid hormone, 1,25(OH)2 vitamin D and other parameters that would have enriched our analysis. That NHANES III examinees with mild to moderate CRI have elevated serum parathyroid hormone levels can only be extrapolated from previous studies [29,34]. Serum pH was measured but not reported and ionized calcium was reported after normalization. Serum biochemistry profile was measured only once. The day-to-day and even hour-to-hour fluctuations in fasting serum parameters, which were probably random, reduced the power of the study and led to underestimation of the true clinical association. This study was well powered due to the large number of NHANES III examinees. Complete information on potential medical interventions to treat the biochemical abnormalities of CRI were not available, although it is very unlikely that subjects with mild to moderate CRI were treated except in cases of significant hyperkalaemia. Despite this possible bias, elevations in mean serum potassium levels were still detected (and appeared to be independent of any dietary manipulation). The exclusion of NHANES III participants who did not have measures of serum Cr and electrolytes led to slight biases in the survey weights, but this was unlikely to influence our results substantially. Finally, since this is a cross-sectional study, we did not have information on how different biochemical parameters changed over time in individuals with progressive renal insufficiency.
In summary, elevations in serum phosphorus and potassium were apparent even in persons with mild to moderate CRI. These changes were independent of dietary intake and the use of ACE inhibitors or NSAIDs. Acidosis was not apparent and serum ionized calcium was not reduced except among people with CrCl 20 ml/min. These findings should be broadly generalizable to the larger US CRI population. Subtle elevations in serum phosphorus might contribute to the initiation and maintenance of secondary hyperparathyroidism that is known to occur in mild to moderate CRI.
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Acknowledgments |
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Notes |
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References |
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