| Abstract|| |
We aim to evaluate the disturbances in mineral metabolism, abnormalities in bone mineral density (BMD), and extraskeletal calcification in newly detected, untreated predialysis stage 4 and 5 chronic kidney disease (CKD) patients at a tertiary care hospital in North India. This is cross-sectional observational study. A total of 95 (68 males, 27 females) newly detected patients underwent clinical evaluation, biochemical assessment [serum calcium, phosphorus, alkaline phosphatase (ALP), albumin, creatinine, intact parathyroid hormone (iPTH), 25- hydroxyvitamin D (25(OH)D)], BMD measurement (at spine, hip, and forearm) by dual-energy X-ray absorptiometry (DXA), lateral abdominal radiograph [for abdominal aortic calcification (AAC)], skeletal survey (to look for any abnormality including fractures), and echocardiography [for any cardiac valvular calcification (CVC)]. Symptoms related to CKD-mineral bone disorder were seen in 33.6% of the study patients. Prevalence of hypocalcemia, hyperphosphatemia, hyperparathyroidism, and hypovitaminosis D was 64.2%, 81.1%, 49.5%, and 89.5%, respectively. CVC was seen in 22.1% of patients on echocardiography, mostly involving the mitral valve. Patients with CVC were more likely to be males and smokers. There was no significant difference in iPTH levels between patients with or without CVC. AAC was seen in 10.5% of patients on lateral abdominal X-ray. Patients with AAC had higher levels of iPTH, phosphorus, and ALP and lower levels of calcium compared to patients without AAC. BMD by DXA showed a low bone mass in 41.05% of our patients and was more prevalent in CKD stage 5. Most of the study patients had hyperparathyroidism and low 25(OH)D levels. Our study shows that newly detected, naïve Indian CKD patients have a high prevalence of disturbances of mineral metabolism including hyperparathyroidism, Vitamin D deficiency, abnormal BMD, and valvular and vascular calcification, even before initiating dialysis.
|How to cite this article:|
Etta PK, Sharma R K, Gupta A. Study of chronic kidney disease-mineral bone disorders in newly detected advanced renal failure patients: A Hospital-based cross-sectional study. Saudi J Kidney Dis Transpl 2017;28:874-85
|How to cite this URL:|
Etta PK, Sharma R K, Gupta A. Study of chronic kidney disease-mineral bone disorders in newly detected advanced renal failure patients: A Hospital-based cross-sectional study. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2020 Sep 24];28:874-85. Available from: http://www.sjkdt.org/text.asp?2017/28/4/874/211327
| Introduction|| |
Chronic kidney disease (CKD) is associated with significant perturbations in bone and mineral metabolism, leading to altered serum concentrations of calcium, phosphorus, parathyroid hormone (PTH), and Vitamin D with abnormalities in bone remodeling, renal osteodystrophy (ROD), and extraskeletal calcification. These changes can be detected as early as when the estimated glomerular filtration rate (eGFR) falls to ≤60 mL/min/1.73 m2 body surface area. Early detection and management of CKD-associated mineral bone disorder (CKD-MBD) is important as it is associated with increased cardiovascular mortality due to associated increased risk of soft tissue, vascular, and cardiac valvular calcification. Spectrum of CKD-MBD has been poorly studied in Indian CKD patients, especially in the pre-dialysis stage. Therefore, we conducted a cross-sectional study of biochemical features, skeletal abnormalities, and extraskeletal calcification in newly detected, predialysis CKD stage 4 and stage 5 patients at our tertiary care center in North India.
| Subjects and Methods|| |
Ninety-five consecutive newly detected, untreated, predialysis stable CKD stage 4 and 5 patients (KDIGO CKD staging) attending the nephrology outpatient clinic between August 2013 and September 2014 were included in the study. The following patients were excluded:
- Age <20 years,
- Patients who were receiving calcium supplements, Vitamin D analogs, phosphate binders (PBs), steroids, anticonvulsants, anticoagulants, and calcineurin inhibitors for more than three months duration
- Patients who were treated with calcimimetics, bisphosphonates, and other drugs, which can affect bone mineral density (BMD)
- Patients with a history of cardiovascular disease such as coronary heart disease, cerebrovascular accident and peripheral vascular disease, and rheumatic heart disease
- Postmenopausal and pregnant females
- Patients with liver disease, thyroid illness, primary hyperparathyroidism, rheumatologic diseases, and malignancy (both hematological and solid organ origin).
Written informed consent was obtained from all study participants. The study protocol was approved by the Ethics Committee of our institute. All patients underwent detailed clinical evaluation. Demographic characteristics, history of current smoking and alcohol intake, fractures, diabetes mellitus (DM), hypertension (HTN), and etiology of CKD if known were noted. Physical examination included anthropometric measurements [height, weight, and body mass index (BMI)], blood pressure, bony tenderness, spine tenderness, bone deformity, and proximal muscle weakness assessment. Socioeconomic status was assessed based on a classification which included education level, occupation, and family income per month.
Fasting blood samples were tested for serum calcium (Ca), phosphorous (P), albumin, creatinine, alkaline phosphatase (ALP), glucose, alanine aminotransferase, aspartate aminotransferase, 25-hydroxy Vitamin D [25(OH)D], and intact PTH (iPTH). Samples for biochemistry were tested on the same day with an autoanalyzer (RX imola, Randox Labs, UK) using commercial kits. eGFR was calculated using abbreviated MDRD equation. Serum samples for estimation of iPTH and 25(OH)D were stored at −70°C till the assay. Serum 25(OH)D was measured by radioimmunoassay (RIA, Diasorin, Stillwater, Minnesota, USA). The sensitivity of the assay, interassay, and intra-assay coefficient of variation (CV) was 1.5 ng/mL, 9.4%, and 11.4%, respectively. Vitamin D [25(OH)D] deficiency, insufficiency, and sufficiency were defined as ≥20 ng/mL, >20 to 30 ng/mL, and >30 ng/mL, respectively. Serum iPTH was measured by immunoradiometric assay (IRMA, Diasorin, Stillwater, Minnesota, USA). The sensitivity, intra- and inter-assay CV of the iPTH assay was 1.5 pg/mL, 3.6%, and 3.4%, respectively. PTH level >300 pg/mL was labeled as hyperparathyroidism. Normal values of serum calcium and phosphorous were defined as 8.5–10.5 mg/dL and 2.5–4.5 mg/dL, respectively.
Bone mineral density
BMD was measured by dual-energy X-ray absorptiometry (DXA, Hologic QDR 4500, Bedford, USA) at the lumbar spine (antero-posterior, L1–L4), total hip, femoral neck, and nondominant forearm (l/3rd radius). The mean CV for lumbar spine was 0.239%. The BMD at various sites was analyzed using Caucasian database as per manufacturer. BMD was expressed as T-score and Z-scores. Calculated Z-score of ≤-2.0 was defined as below the expected range for age as per International Society for Clinical Densitometry Position statement (2007). World Health Organization’s (WHO) diagnostic criteria were applied to define osteoporosis (T-score ≤-2.5 either at the femoral neck, lumbar spine (L1–L4), or total hip) or osteopenia (T-score between −1 and −2.5 at above sites).
Lateral abdominal radiographs
Lateral lumbar X-ray was performed in a standing position using the standard radiographic equipment. A minimum of 8 cm of tissues anterior to the lumbar spine, which would include abdominal aorta, had to be visible. Abdominal aortic calcification (AAC) was assessed using a previously validated 24-point scale as described by Kauppila et al in a subgroup of participants of the Framingham Heart study.
For the 24-point score, calcified deposits along the anterior and posterior longitudinal walls of the abdominal aorta adjacent to each lumbar vertebra from L1–L4 were assessed using the midpoint of the intervertebral space above and below the vertebrae as the boundaries. Calcifications were graded as follows:
- 0 - no aortic calcific deposits
- 1 - small scattered calcific deposits less than one-third of the corresponding length of the vertebral level
- 2 - medium quantity of calcific deposits about one-third or more but less than two-thirds of the corresponding vertebral length
- 3 - severe calcification of two-thirds or more of the corresponding vertebral lengths.
The scores, obtained separately for the anterior and posterior walls, result in a range from 0 to 6 for each vertebral level and 0 to 24 for the total score.
Radiological survey of bones was performed with X-rays of skull – lateral view, dorsolumbar spine – anteroposterior (AP) and lateral view, pelvis – AP view, and both wrists including hands. We looked specifically for changes of hyperparathyroidism, osteomalacia, osteoporosis, lytic lesions, and fractures.
Echocardiography was carried out with patient in the left lateral decubitus position, in parasternal long and short axis views, to detect any calcification of cardiac valves, subvalvular apparatus, and aortic root and examined for any restriction of movement of valvular leaflets.
| Statistical Analysis|| |
Continuous variables were expressed as a mean ± standard deviation and discrete variables as frequencies/percentages. Distribution of variables was checked for normality with Kolmogorov–Smirnov test. Independent sample t-test was used for variables in normal distribution and Mann–Whitney U-test for those showing nonparametric distribution. Chi-square test was used for categorical variables. Statistical Package for the Social Sciences (SPSS) software version 16.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. P <0.05 was considered statistically significant.
| Results|| |
The study population consisted of 95 patients with a mean age of 37.0 ± 7.3 years and male to female ratio of 2.5:1. All of them were adults with newly detected CKD and were in pre-dialysis stage 4 and 5. DM and HTN were seen in 18.9% and 73.7%, respectively. Few patients had received calcium supplements (53.7%) and Vitamin D analogs (22.1%) for a short duration. The most common native kidney diseases were chronic glomerulonephritis (22.1%), chronic interstitial nephritis (23.2%), and diabetic nephropathy (18.9%). There were no significant differences in baseline characteristics between CKD stage 4 and 5 patients, except for usage of PBs (longer use in CKD-5) and BMI (higher in CKD-4) [Table 1].
Symptoms related to CKD-MBD were seen in 33.6% of patients (30.9% in CKD-4 and 37.5% in CKD-5). Most commonly reported symptoms were bone pains and myalgias. One patient had fracture of the dorsal spine; he also had abnormal PTH and Vitamin D levels and low bone mass on DXA. There were no significant differences in symptoms between CKD stages 4 and 5.
Overall, 64.2% were hypocalcemic, 81.1% were hyperphosphatemic, 81.1% had high alkaline phosphatase levels, 89.5% had 25 (OH)D levels ≤30 ng/mL, and 49.5% had PTH >300 pg/mL. Hyperparathyroidism, hypocalcemia, and Vitamin D deficiency were more prevalent in CKD stage 5 than stage 4 [Table 2].
Various clinical and biochemical variables affecting serum PTH and 25(OH)D were assessed. Patients with hyperparathyroidism (iPTH >300 pg/mL) were more likely to have lower eGFR, hypocalcemia, hyperphosphatemia, high ALP levels, and low 25(OH)D levels. Significantly more number of diabetics were seen in patients who had hyperparathyroidism. Patients with low Vitamin D levels (≤30 ng/mL) were more likely to have lower eGFR.
Cardiac valvular calcification
Overall, cardiac valvular calcification (CVC) was present in 22.1% of patients. It was present in 21.8% and 22.5% of CKD stage 4 and 5 patients, respectively. Patients with CVC were more likely to be males and smokers. There was no significant difference in iPTH levels between patients with or without CVC. Paradoxically, higher levels of HDL were observed in patients with CVC [Table 3] and [Table 4].
Abdominal aortic calcification
AAC was seen in 10.5% of the total patients. It affected 9.1% and 12.5% of CKD 4 and 5 patients, respectively. Most of the affected patients (90%) had less severe AAC (score <7). Patients with AAC had higher levels of iPTH, phosphorus, ALP, and low levels of calcium compared to patients without AAC. There was a nonsignificant trend towards higher prevalence of DM in patients with AAC [Table 3] and [Table 5].
The most common abnormality visible on X-rays was low bone density (osteoporosis/osteopenia). Osteomalacia with Looser’s zones was found in five and evidence of secondary hyperparathyroidism in three patients. Fracture of dorsal spine was found in one patient, who also had low bone mass (Z-score ≤ -2) on DXA, hyperparathyroidism, and Vitamin D deficiency.
Bone mineral density
Low Z-score of ≤-2 was found in 3.2% of patients at lumbar spine, 22.1% at hip, 8.4% at neck of femur, and 22.1% at the forearm. Females had a lower BMD at all sites in comparison to males except at forearm, but it was not statistically significant. Details regarding the Z-scores in various categories of patients are shown in [Table 6].
Clinical and laboratory characteristics were compared between two groups of patients with Z-scores of ≤-2 and >-2 at any of these four sites, i.e., lumbar spine (L1-L4), total hip, femoral neck, and nondominant forearm. Patients with low BMD were more likely to have hyperparathyroidism, high ALP levels, low 25(OH)D levels, and less likely to be obese. They also had lower eGFR [Table 7].
Using the WHO criteria for the classification of BMD (on basis of T-scores), osteoporosis and osteopenia were seen at lumbar spine in 4.2% and 49.5% patients, respectively. Similarly, the figures for femur neck were 5.3%, 55.8%, for the total hip 11.6%, 56.8%, and for forearm, it was 45.3%, 47.4%, respectively.
| Discussion|| |
We found a high prevalence of hypocalcemia (64.2%), hyperphosphatemia (81.1%), hyperparathyroidism (49.5%), and low Vitamin D levels (89.5%) in newly detected advanced renal failure patients, even before initiation of dialysis; the prevalence was higher in patients with CKD stage 5 than CKD stage 4. Low bone mass on DXA and CVC and AAC calcifications were identified in a significant number of patients.
Several other studies have also observed similar findings in Indian CKD patients. Agarwal described hypocalcemia in 29.9% and 49.6%; hyperphosphatemia in 45% and 41.8%; and hyperparathyroidism in 57.8% and 39.4% in CKD stage 4 and 5, respectively. He defined hyperparathyroidism as iPTH >110 pg/mL in stage 4 and iPTH >300 pg/mL in stage 5 CKD, according to the K/DOQI guidelines. Jabbar et al observed a prevalence of hyperparathyroidism of 60% in their patients with CKD stage
4 and 5, taking a cutoff of iPTH >300 pg/mL for both stages. In the same study, more than 90% of patients and in another study by Ghosh et al, 83.1% of patients with CKD stage 4 and
5 had Vitamin D level less than 30 ng/mL., Ghosh et al also observed a high prevalence of diabetes in patients with iPTH below the target range; they opined that this could be due to underlying adynamic bone disease, which has been described to be more prevalent in diabetic patients, especially in the elderly or those on peritoneal dialysis. In our study, we observed a high prevalence of diabetes in patients with iPTH level >300 pg/mL in CKD stages 4 and 5; this may be due to treatment naïve status in most of the patients.
A semi-quantitative echocardiographic scoring of CVC was described by Pressman et al, but this has not been validated in CKD patients. In our study, we qualitatively reported the presence of CVC, but it was not graded. CVC was noted in 22.1% of all patients, and mitral ± aortic valve involvement was most common. In a study by Valson et al, CVC was identified in 96% of predialysis CKD stages-4 and -5 patients. In another study on Caucasian pre-dialysis CKD patients, CVC was detected in 31% of patients. In contrast, the prevalence of mitral and aortic VC in healthy elderly Indian participants aged 60–64 years is only 2% and 28%, respectively. AAC on lateral abdominal X-ray was noted in 10.5% of all patients. In the study by Valson et al, AAC was identified in only 6.8% of predialysis CKD stages 4 and 5 patients. Shantha et al found a prevalence of AAC of 76.9% in predialysis CKD stage 5 patients, most of whom were on calcium-based phosphate binders. Good correlation between AAC and coronary artery calcification has been shown in some studies and is associated with increased all-cause and cardiovascular mortality. One European cross-sectional study, the CORD (Calcification Outcome in Renal Disease), reporting on 933 dialysis patients, showed the presence of AAC on lateral lumbar X-rays in 81% of the participants. In our study, patients with AAC had higher levels of iPTH, phosphorus, and alkaline phosphatase and low levels of calcium compared to patients without AAC. There is inconsistency in the literature regarding this relationship. Some observational studies have reported a positive correlation between phosphate, PTH, calcium, and vascular calcification;,, however, some others have not reported this association and reasons for these inconsistencies are unclear. There was no association between AAC and VC in our study.
In patients with CKD stages 4–5, BMD of the hip and radius is generally lower than that in the general population; lumbar spine BMD is similar to that in the general population. In the general population, a low BMD predicts fracture and mortality. The ability of BMD to predict fractures or other clinical outcomes in patients with CKD stages 4–5 is weak and inconsistent. The reasons for the poor performance of DXA in patients with CKD are not defined. Partially, this is because the measurements may overestimate BMD due to arthritic conditions, scoliosis, and aortic calcifications. Patients with CKD, especially those with a high serum PTH, have increased cancellous bone volume but decreased cortical thickness.
DXA cannot differentiate between cortical and trabecular bone. Quantitative computed tomography (CT) scan, which separately measures cortical and trabecular bone as it is a three-dimensional technique, can be a better tool. Different sites contain different percentages of trabecular bone (by weight). This is important to remember because bone remodeling in patients with CKD-MBD is different in trabecular bone compared with cortical bone.
Spine BMD measurements can be misleading if there are preexisting anatomic abnormalities in the bone, while hip measurements also can have positioning errors. Although forearm measurements provide the least ability to predict fractures in older persons without CKD, a meta-analysis by Jamal et al found that the forearm was the most sensitive site in patients with CKD stage 5. In our study also, we found a high prevalence of abnormal BMD at the forearm, in comparison to that of lumbar spine.
As per the KDIGO guidelines, in patients with CKD stages 3–5 with evidence of CKD-MBD, BMD testing need not be performed routinely because BMD does not predict fracture risk as it does in the general population, and BMD does not predict the type of renal osteodystrophy. Jamal et al found that low BMD at the spine and distal radius was associated with fracture status. Several other cross-sectional studies have also shown that BMD on DXA predicted fracture status in patients with CKD.,,, A number of randomized controlled trials of antiresorptive therapy have shown that BMD predicted fracture risk in the subset of patients with CKD stages 3–4.,,, BMD in patients with CKD stages 3–5 does not distinguish different types of ROD, as seen on bone histology. Few pilot studies found similar BMD in different types of ROD., In a study on 62 patients, Gerakis et al found that BMD by DXA was lower in osteitis fibrosa than in adynamic bone, but there were wide ranges in both types.
The BMD by DXA was lower in those with severe osteitis fibrosa in the study by Fletcher et al on 73 patients, particularly at the proximal forearm. In a study by Jabbar et al, about 37.5% and 12% of the patients showed osteopenia and osteoporosis, respectively, in Indian stage 4–5 CKD patients; most of them had hyperparathyroidism with high turnover bone disease. Nickolas et al, in a study on CKD patients, found a significant cortical loss that is related to hyperparathyroidism. In our study, there was a trend toward high prevalence of hyperparathyroidism in those with low BMD, indicating that high turnover could contribute to the development of osteoporosis.
We observed the high prevalence of low bone mass (Z-score ≤-2) in 41.05% of our patients. They were more likely to have hyperparathyroidism with high ALP levels, low 25(OH) D levels, and less likely to be obese. Based on WHO criteria, T-scoring of BMD, osteoporosis, and osteopenia were more commonly found at the forearm, probably due to the effect of secondary hyperparathyroidism.
| Limitations|| |
This is a hospital-based study in a referral center; hence data may not reflect true community-based CKD patients. The sample size was small. Bone histomorphometry, bone markers including fibroblast growth factor and bone-specific ALP, CT scan to accurately assess BMD and vascular calcification were not performed. Echocardiographic scoring for valvular calcification was not performed. Higher mean BMI in CKD 4 might have affected our BMD results.
| Conclusions|| |
Newly detected, treatment naïve Indian CKD patients have a high prevalence of disturbances of mineral metabolism including hyperparathyroidism, Vitamin D deficiency, abnormal BMD, and valvular and vascular calcification, even before initiating dialysis. A low prevalence of fractures was observed in our study.
Conflict of interest: None declared.
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Praveen Kumar Etta
Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]