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Vitamin D, Calcium, and Phosphorus in Patients with Chronic Kidney Disease
In a large, unselected population that serum 1,25 OH2 D3 levels decline early in CKD before significant elevations in PTH are observed. Hypocalcemia and hyperphosphatemia, when and if they occur, are noted in the later stages of CKD. Future research should be directed toward attempting to further describe the relationship between vitamin D levels, eGFR and other factors related to clinically meaningful outcomes, by testing the impact of early interventions with activated vitamin D therapy.
We describe here, in the largest observational study of an unselected cohort of patients with varying levels of kidney dysfunction, the prevalence of abnormalities of vitamin D metabolites, iPTH, and Ca and P. This study demonstrates a number of key findings, some of which corroborate previous work, and some of which are novel. Within this cohort, we attempted to better define 1,25 OH2 D3 deficiency, or more specifically, low values of 1,25 OH2 D3. Thus we describe a high prevalence of low values of 1,25 OH2 D3 within this population, even at higher levels of eGFR than usually expected or has not been reported previously. Note that the low values are congruent with the low range of values as reported by the laboratory reference range. We also describe the prevalence of elevated iPTH levels, which increased significantly at eGFR values below 50 ml/min/1.73 m2. Importantly, neither of these changes was associated with demonstrable changes in serum Ca, P, or major differences in values of 25(OH)D3. The dissociation of HPTH from any significant changes in serum Ca and P in patients with a lower eGFR, whereas physiologically expected, underscores the need to assess this hormone level irrespective of these mineral metabolites. The late occurrence of hyperphosphatemia was not present in enough of the population to explain the high prevalence of HPTH in stage 4 disease.
The univariate predictors of low 1,25 OH2 D3 levels differed by eGFR values, but most interestingly, in the multivariate analysis, we demonstrated that DM, elevated UACR, and eGFR were independently associated with low levels of 1,25 OH2 D3. There also seemed to be a strong association between low 1,25 OH2 D3 levels and the prevalence of HPTH. Although the Kidney Disease Outcomes Quality Initiative guidelines recommend iPTH testing in CKD patients at eGFR levels below 60 ml/min/1.73 m2, in general, such testing only occurs in a small number of patients, and these findings provide further support for those testing guidelines. Although PTH testing is clearly more practical at present, these findings also have implications for 1,25 OH2 D3 testing of individuals, given the biological relevance of that deficiency to HPTH, and the demonstration here that low levels of 1,25 OH2 D3 occur earlier in the course of eGFR decline than does elevations in iPTH levels. However, in the absence of longitudinal or outcome data that would provide clinical relevance, the use of 1,25 OH2 D3 levels as a surrogate for the development of HPTH is premature, as this cross-sectional analysis of baseline data cannot and does not address this question. Prospective descriptive and then, interventional clinical trials where 1,25 OH2 D3 is repleted, with subsequent measurement of clinically meaningful outcomes related to this treatment are required to address this question.
Low serum 1,25 OH2 D3 occurs for a variety of reasons, and has been recently described as being more prevalent than previously thought in western populations. Although decreased renal 1-α hydroxylase in CKD is largely responsible for reduced circulating levels of 1,25 OH2 D3, other potential factors may exist, which also suppress this hydroxylating enzyme. In addition, low levels of the 25(OH)D3 substrate may contribute to decreased levels of 1,25 OH2 D3 production, particularly in CKD patients with nephrotic range proteinuria. One recent survey noted that 86% CKD patients (n=43) had inadequate 25(OH)D3 levels (<30 ng/ml), which has been previously defined by others.[13,14] In our study, we also found that although many subjects had inadequate 25(OH)D3 levels, only 12% were frankly deficient in 25(OH)D3 deficient (<15 ng/ml). In addition, our large sample allowed us to determine that the relationship between 25(OH)D3 and 1,25 OH2 D3 was not significant (R2=0.3666, P=0.3433 at eGFR<60 ml/min), which is consistent with Ishimura's observation; and while statistically significantly different among the eGFR groups, the values were of questionable clinical significance (4--5 ng/ml). In this analysis, the relationship between serum 25(OH)D3 with elevated iPTH and decreased GFR levels was less relevant than that of 1,25 OH2 D3. This finding may have therapeutic ramifications as recent Kidney Disease Outcomes Quality Initiative guidelines currently suggest the use of ergocalciferol (vitamin D2) as the initial treatment for HPTH in CKD stage 3 and 4. However, the findings herein of an early low levels of 1,25 OH2 D3 and some preliminary data that show that this treatment regimen may not effectively suppress PTH, may require that those recommendations are revisited.
This study had several limitations. The patient ages were weighted to older individuals (71% of the sample was over 65 years old) and although a large proportion of CKD patients fall within this age range, these data may not be generalizable to patients between 40 and 65 despite their inclusion in the sample. The results are cross-sectional analyses, thus causal relationships between dependent variables (kidney function) and independent variables (vitamin D metabolites, iPTH, Ca, and P) cannot be defined. No longitudinal data has been reported here, thus relationships between the variables and different eGFR levels may change over time in different individuals. In addition, kidney disease was defined by a single creatinine measure used to estimate the eGFR. In fact 22% of the cohort changed 'classification' within the time period of screening and enrollment into the study, further underscoring the problems with defining populations based on single values without accompanying urine tests or clinical data. Nonetheless, the majority (78%) of the population did have persistent decreases in their kidney function, within relatively stable categories. The population appears representative of the general US population, but because the entry criteria included the presence of a serum creatinine in the patient record, this population, by default, may have less healthy well being, as indicated by the underlying need to order the test. Finally, the findings of this study represent associations. Interventional studies are needed to define the serum levels of 1,25 OH2 D3 that would provide adequate suppression of iPTH and subsequent potential untoward effects of mineral imbalances.
Despite these limitations, the study expands our knowledge on the prevalence of abnormalities of key hormones at different levels of eGFR, and raises questions regarding the relative importance of 25(OH)D3 and 1,25 OH2 D3 in the biology of abnormalities of PTH. Although we cannot separate the potential effects of these derangements on cardiovascular disease, we can speculate that 1,25 OH2 D3 and PTH may have independent roles in promoting vascular calcification and cardiac events. For example, it has been known for sometime that low 1,25 OH2 D3 is associated with coronary artery calcifications in non-CKD populations. It is also known that 1,25-dihyroxyvitamin D levels are indirectly associated with serum renin levels in hypertensive subjects, a finding that was recently corroborated in vitamin D receptor knockout mice. Elevated PTH is known to cause cardiomyocyte damage in animals with CKD and parathyroidectomy in dialysis patients is associated with reductions in left ventricular hypertrophy and in cardiovascular mortality. Thus, taken together we may speculate that low 1,25 OH2 D3 and elevated iPTH levels in CKD stage 3 and 4 may contribute to the high prevalence of cardiovascular and advanced renal disease seen in these populations. In addition, the independent association between low 1,25 OH2 D3 and high UACR may support the observed anti-proteinuric effect of active vitamin D in CKD patients. Further long term data relating the levels to outcomes, and ulitmately a randomized controlled trial examining the impact of activated vitamin D on cardiovascular outcomes should be undertaken.
In summary, we found, in a large, unselected population that serum 1,25 OH2 D3 levels decline early in CKD before significant elevations in PTH are observed. Hypocalcemia and hyperphosphatemia, when and if they occur, are noted in the later stages of CKD. Future research should be directed toward attempting to further describe the relationship between vitamin D levels, eGFR and other factors related to clinically meaningful outcomes, by testing the impact of early interventions with activated vitamin D therapy.
Authors and Disclosures
A. Levin,1 G. L. Bakris,2 M. Molitch,3 M. Smulders,4 J. Tian,5 L. A. Williams,5 D. L. Andress 6
1Department of Nephrology, University of British Columbia, Vancouver, BC, Canada
2Rush Hypertension/Clinical Research Center, Rush University Medical Center, Chicago, Illinois, USA
3Division of Endocrinology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
4Quintiles Strategic Research Services, Falls Church, Virginia, USA
5Renal Global Project Team, Abbott Laboratories, Abbott Park, Illinois, USA
6Division of Nephrology, University of Washington School of Medicine, Seattle, Washington, USA