Elevations of serum phosphorus and potassium in mild to moderate chronic renal insufficiency

Chi-yuan Hsu and Glenn M. Chertow

Division of Nephrology, University of California at San Francisco, San Francisco, CA 94143, USA



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Reduced renal function is associated with a variety of biochemical abnormalities. However, the extent of these changes and their magnitude in relation to renal function is not well defined, especially among individuals with mild to moderate chronic renal insufficiency (CRI).

Methods. We analysed the Third National Health and Nutrition Examination Survey (NHANES III; 1988–1994) 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 Cockcroft–Gault 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 60–50, 50–40, 40–30, 30–20 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



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
There is increasing interest in understanding and treating the consequences of mild to moderate chronic renal insufficiency (CRI), defined by a reduced glomerular filtration rate (GFR) not requiring renal replacement therapy [1]. Given that 6.2 million Americans are estimated to have serum creatinine (Cr) >=1.5 mg/dl [2], the consequences of CRI may have important public health implications. We recently estimated that in the United States (US), 800 000 adults suffer from CRI-associated anaemia, defined by a haemoglobin concentration <11 g/dl [3].

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.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
NHANES III population
The design and operation of NHANES III has been described previously [2,8,9] (data downloaded from http://www.cdc.gov/nchs/about/major/nhanes/nh3data.htm#Data Files 1a). Briefly, NHANES III provides cross-sectional, nationally representative data on the health and nutritional status of the civilian, non-institutionalized US population. From 1988 to 1994, 39695 people were selected in a complex survey design and 31311 were examined. All NHANES III participants over the age of 12 years were eligible for measurement of a biochemistry profile that included serum chemistries and creatinine. Examinees reporting haemophilia or recent cancer chemotherapy treatment were excluded from the venipuncture. We included in this study only adults aged over 17 years who had a measurement of serum Cr as well as all electrolytes including sodium, potassium, chloride, bicarbonate, ionized calcium, phosphorus and albumin.

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 Cockcroft–Gault equation [11]:


where age is measured in years, weight in kg and serum Cr in mg/dl.

The Cockcroft–Gault-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:


(002)
where X was the measured pH of the sample, [Ca++]X was the ionized calcium concentration in the test solution, and [Ca++]7.4 was the normalized calcium concentration at pH 7.4. At pH 6.9–7.2 and 7.6–8.0, correction factors were employed by the microprocessor to predict normalized calcium values [10]. The coefficients of variation of these assays were all in the order of 1–2% [10].

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 Cockcroft–Gault-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.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
NHANES III population
Twenty thousand and fifty NHANES III participants, aged >=17 years, were examined. Among them, 14722 (73%) had complete measurements for biochemistry profile (including creatinine) and ionized calcium. The characteristics of these 7835 women and 6887 men are shown in Table 1Go. Since this study population is not a simple random sample of the US population, the prevalence of CRI shown here reflects not only the prevalence of CRI in the US population, but also the effects of sampling; older persons, Mexican-Americans and black persons were intentionally over-represented. These groups were subsequently weighted less in the regression analysis in order for the final results to be broadly generalizable.


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Table 1.  Characteristics of the NHANES III study population

 

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 50–60 ml/min (Table 2Go). In contrast, the relationship between serum ionized calcium (normalized) and CrCl was weak and inconsistent (Table 3Go). 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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Table 2.  Predicted change in mean serum phosphorus level by renal function

 

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Table 3.  Predicted change in mean serum ionized calcium (normalized) level by renal function

 
Despite a significant increase in mean serum phosphorus, 2% or fewer subjects with CrCl >40 ml/min had serum phosphorus concentrations above the laboratory normal reference range. In contrast, hyperphosphataemia was evident in 3% (95% confidence interval (CI) 1–6%), 7% (95% CI 1–12%) and 30% (95% CI 0–62%) of subjects with CrCl 40–30, 30–20 and <=20 ml/min, respectively.

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 4Go). 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 5Go).


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Table 4.  Predicted change in mean serum bicarbonate level by renal function

 

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Table 5.  Predicted change in mean serum anion gap by renal function

 
The relationship between serum potassium resembled that of serum phosphorus in that there was a stepwise increase in its mean level among subjects with decreased renal function, which first became evident at relatively modest reductions in renal function (CrCl 50–60 ml/min) (Table 6Go).


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Table 6.  Predicted change in mean serum potassium level by renal function

 
In general, the relationships between levels of CrCl and biochemical parameters were similar in men and women (P values for interaction >0.05). These relationships did not materially change after we adjusted for dietary intake of calcium, phosphorus, potassium or protein (as proxy for dietary acid load), or for the duration of fasting before phlebotomy (data not shown). The relationship between categories of CrCl and serum potassium persisted when we examined only those individuals not on ACE inhibitors or NSAIDs (13082 of 14722; data not shown).



   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Increasing attention is being paid to understanding and treating the consequences of CRI [1719]. We have recently demonstrated in a large cohort of ambulatory patients, and independently in NHANES III examinees, that a decrease in haemoglobin is apparent at more modest degrees of renal insufficiency than previously realized [3,15]. Specifically, we found that a statistically significant decrease in mean haemoglobin concentration was apparent among men starting at Cockcroft–Gault-estimated CrCl 60–70 ml/min and among women starting at CrCl 40–50 ml/min.

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 50–60 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 38–78 ml/min) [26] and Llach et al. found in 13 CRI subjects (CrCl range 34–93 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 5–91 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 27–67 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 80–160 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 0.1–0.2 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.



   Acknowledgments
 
C.-y.H. and G.M.C are supported by the U.S. National Institutes of Health (grant numbers DK58411 and DK61520). We would like to thank Drs Lynda Frassetto, Charles McCulloch, Anthony Portale and Anthony Sebastian for their thoughtful input.



   Notes
 
Correspondence and offprint requests to: Chi-yuan Hsu, Division of Nephrology, University of California, San Francisco, Room 672 HSE, 513 Parnassus Avenue, San Francisco, CA 94143-0532, USA. Email: hsuchi{at}medicine.ucsf.edu Back



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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 10. 1.02
Accepted in revised form: 3. 4.02