Abstract
Secondary hyperparathyroidism is a common complication of renal failure. The exact prevalence in chronic hemodialysis patients in not known. We evaluated 122 patients who were receiving maintenance hemodialysis for at least 12 months in 2 dialysis centers in mid Michigan. Seventy-eight percent of the patients had iPTH above 200 pg/mL (mean 481 pg/mL), 19% had iPTH within the accepted normal range (mean 155 pg/mL), while 3% had level below 100 (mean 53 pg/mL). Phosphate, calcium, calcium phosphate product, age and time on dialysis are the important factors correlating with elevated iPTH. There was no significant difference in iPTH between diabetic and nondiabetic patients with mean iPTH of 403 pg/mL and 407 pg/mL respectively. Black patients had a statistically significant elevated iPTH compared with white patients with a mean iPTH of 438 pg/mL and 283 pg/mL respectively (p ≤ 0.004). Factors that predict the response to vitamin D therapy need to be evaluated to help reduce the high prevalence of secondary hyperparathyroidism. The patterns of bone disease in black patients need to be evaluated to further define the accepted normal iPTH range for this population.
Introduction
Secondary Hyperparathyroidism is a universal complication in patients with renal failure.Citation[[1]] The major mechanisms involved include decreased level of calcitriol and ionized calcium in early renal failure and, as the disease progress, a decrease in the number of vitamin D receptors and calcium receptors rendering the gland more resistant to calcitriol and calcium.Citation[[1]], Citation[[2]] Phosphate induces hyperplasia of the parathyroid gland and increase parathyroid hormone (PTH) synthesis and secretion independent of calcium and calcitriol.Citation[[1]], Citation[[2]], Citation[[3]]
A degree of secondary hyperparathyroidism must exist as a trade off to maintain normal bone modeling,Citation[[2]], Citation[[4]] however there is no consensus on the optimal intact parathyroid hormone (iPTH) level that will maintain normal bone turnover.Citation[[5]]
The treatment of secondary hyperparathyroidism includes the use of calcium supplement, phosphate binders, calcitriol, and dietary manipulation.Citation[[1]], Citation[[6]] Despite these measures, the prevalence of this disorder remains high with rates of 50% in hemodialysisCitation[[7]] and of 47% in peritoneal dialysis patients.Citation[[8]] However, there is no data on the prevalence in chronic hemodialysis patients.
Race is found to be a major determinant factor of secondary hyperparathyroidism in uremic patients.Citation[[9]] Black patients with ESRF have a high PTH and they have a greater bone mineral density compared to white patients.Citation[[10]]
The aim of this study is to assess the prevalence of secondary hyperparathyroidism in chronic hemodialysis patients and to assess the impact of race on prevalence.
Patients and Methods
We analyzed the records of chronic maintenance hemodialysis patients who were on hemodialysis for at least 12 months in 2 centers in Mid Michigan.
Patients who had parathyroidectomy or those on steroids, phenytoin, phenobarbitone or other factors that affect the bone biochemical parameters were excluded. One hundred and twenty-two patients satisfied these criteria and were all included in the study. All patients were receiving dialysis thrice-weekly using cuprophan dialyzers with standard dialysate calcium of 2.5 mEq/L.
The average of 2 iPTH assays that were 3 months apart were analyzed together with the average of 2 concomitantly drawn calcium, phosphate, albumin, bicarbonate, alkaline phosphate, and pre and post-dialysis urea for urea reduction ratio (URR) determination. Calcium was corrected for the concomitantly drawn albumin. The iPTH was determined by a commercial kit (reference range 12–64 pg/mL) and the other parameters were determined by a standard autoanalyzer. Patients were receiving their medicine as prescribed by their practicing nephrologist with the aim of maintaining normocalcemia (corrected calcium of 9–10.5 mg/dL), phosphate less than 5 mg/dL, calcium phosphate product (Ca X P) less than 55, and iPTH range of 100–200 pg/mL.
Intravenous calcitriol 1–2 µg commensurate with the iPTH was given at the end of dialysis after control of hyperphosphatemia and the dose was titrated depending on the iPTH level. Paricalcitol was given in a similar way and both were temporarily stopped if calcium exceeds 10.5 mg/dL or if the calcium phosphate product exceeds 70.
Statistics
Results are expressed as mean ± S.D. Unpaired student t test was used to analyze the difference between means. Pearson correlation coefficient was used to analyze the correlation of measured variables with iPTH. Probability values of <0.05 were considered significant. SPSS statistical package (SPSS inc.) computer software was used.
Results
The demographic data of the study population (n = 122) is shown in Tables and . The mean age was 58 ± 14. There was 61% male and 39% female. The race distribution comprised 80% blacks and 17% white. Hypertension was the cause of end stage renal failure (ESRF) in 50% of the patients and diabetes in 37% of the patients as is shown in .
Table 1. Demographic data (n = 122)
Table 2. Dialysis characteristics
The chemical data is shown in . The mean iPTH was 405 ± 216 pg/mL, phosphate 6.2 ± 1.8 mg/dL, corrected calcium 9.4 ± 0.7 mg/dL and the calcium phosphate product was 58 ± 17.
Table 3. Bone biochemical factors
We found that 19% of the patients had iPTH levels within the accepted normal range, 3% had levels below 100 pg/mL and 78% had iPTH above 200 pg/mL. The mean iPTH for these groups were 155, 53, and 481 pg/mL respectively (). Using Pearson correlation coefficient, the iPTH had a significant positive correlation with phosphate, calcium phosphate product, and time on dialysis. Age has a significant negative correlation. In those with iPTH above 200 pg/mL, phosphate and the calcium phosphate products continued to have a significant positive correlation as is the calcium, time on dialysis, and the dose of erythropoietin (). In those with iPTH level above 450 pg/mL the only significant correlation was with erythropoietin in a positive relation.
Table 4. Mean iPTH (pg/mL) in different groups (n = 122)
Table 5. Variables correlating with iPTH
Black patients had a higher iPTH compared to white with levels of 438 ± 208 pg/mL and 283 ± 223 pg/mL (p ≤ 0.004) respectively despite similar level of calcium, phosphate, URR, and time on dialysis ().
Table 6. Biochemical and dialysis variables in black and white patients
There was no difference in iPTH between diabetics and nondiabetics with levels of 403 ± 249 pg/mL and 407 ± 189 pg/mL respectively despite the fact that diabetics had a statistically significant shorter duration on dialysis and are older in age, factors that correlate with lower level of iPTH as shown in . There was also no difference in iPTH between diabetics and nondiabetics at cut-off value of iPTH above 200 pg/mL and 450 pg/mL.
Table 7. Biochemical and dialysis variables in diabetic and nondiabetic patients
Discussion
There is no consensus on the optimal level of PTH that will maintain bone turn over and generally this level is believed to be in the range of 100–200 pg/mL.Citation[[5]] Qi et al.Citation[[11]] found levels of more than150 pg/mL to have a positive predictive value (PPV) of 85% and levels of more than 250 pg/mL to have a PPV of 86% in hemodialysis patients. Hutchison et al.Citation[[12]] found levels above 200 pg/mL to have a PPV of 88% in CAPD patients. At a cutoff of 200 pg/mL we found the prevalence of secondary hyperparathyroidism in hemodialysis patients to be 78%, which is higher than the prevalence rate of 50% that was found by SalemCitation[[7]] using the same cutoff level of iPTH. This difference can be explained by the difference in time on dialysis (dialysis vintage) that was underestimated by Salem when he included all patients on hemodialysis. Neff et al. found duration of dialysis to be a major factor that determines parathyroid bone diseaseCitation[[13]]; recently Chertow found dialysis vintage to be a significant predictor of PTH in univariate and multivariate linear regression.Citation[[14]] Similarly Tokuyama found a linear relation between duration of dialysis and probability of parathyroidectomy.Citation[[15]] In our study we included patients who have been on dialysis for at least 12 months to allow for this effect. Our finding is in keeping with these studies and explains the high prevalence of hyperparathyroidism in our patients. To avoid overestimation, we have excluded patients with factors that are known to increase the PTH level.
Earlier studiesCitation[[16]], Citation[[17]] found a low prevalence of secondary hyperparathyroidism in diabetic patients. Vincenti et al. found this to be due to shorter time on dialysis and low rates of bone turn over.Citation[[16]] Andress et al. related this to low bone turn over due to accelerated rates of aluminum accumulation in diabetics.Citation[[18]] In our study we did not find a statistically significant difference in the prevalence of secondary hyperparathyroidism between diabetic and nondiabetic patients. The difference can be explained by the lack of use of aluminum in our patients. Our results is in agreement with Cundy et al.Citation[[19]] who suggested that diabetics, on long-term hemodialysis, are not uniquely protected against renal bone disease.
Gupta et al.Citation[[9]] found race to be a major determinant of hyperparathyroidism. In his study he found a mean iPTH of 641.7 pg/mL in blacks compared to 346 pg/mL in white. Similar finding were recently found by Stehman-Breen et al.Citation[[10]] Our study confirms this finding by showing a statistically significant difference in PTH based on race. The elevated PTH in blacks could overestimate the presence of hyperparathyroidism as it has been shown that in normal blacks the bone turn over is diminished,Citation[[20]] which may explain the elevated PTH. However, there are no studies in dialysis patients that have defined the normal PTH range for blacks and further studies are needed to define the correlation between PTH level and the pattern of bone disease in this population.
We conclude that the prevalence of secondary hyperparathyroidism in chronic hemodialysis patients is high and factors that predict the response to vitamin D such as MIBI scanCitation[[21]] and gland volumeCitation[[22]], Citation[[23]] need to be evaluated further to reduce this high prevalence. The optimal PTH level in blacks need to be well defined to allow for proper interpretation of PTH values in this large group and to avoid an unnecessary and costly treatment.
Acknowledgment
The authors would like to thank Mrs. Nancy Goeff for helping with data collection and Miss Jenny Duff for the statistical analysis.
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