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Table of Content - Volume 9 Issue 2 - February 2019
Correlation of serum calcium, phosphorus and alkaline phosphatase levels with eGFR in newly diagnosed chronic kidney disease patients
M Manju1, Suryapriya Rajendran2*, Sasmita Mishra3, S Vithiavathi4
{1Associate Professor, 2Assistant Professor, 3Professor, Department of Biochemistry}{ 4Professor,4Department of General Medicine} Aarupadai Veedu Medical College and Hospital, Pondicherry,- 607403, INDIA. Email: suryapriyammc05@gmail.com
Abstract Background: Chronic kidney disease or chronic renal failure is a health problem affecting mainly the elderly population. Chronic kidney disease (CKD) leads to many serious and life threatening complications like dyslipidemia, cardiovascular disease anemia and bone related problems. Bone related problems like renal osteodystrophy is one among the long term dreaded complications of CKD. Recently, CKD-MBD (Chronic kidney disease Bone mineral disorder) is the term used to describe all the bone associated defects arising due to long term CKD. CKD-MBD is one of the major risk factors for cardiovascular mortality2. With this background we decided to estimate serum calcium, phosphorus and alkaline phosphatase (ALP) levels in various stages of newly diagnosed chronic kidney disease patients and to correlate the values with eGFR (severity) in newly diagnosed chronic kidney disease patients. Only newly diagnosed CKD patients were taken as cases to avoid the influence of treatment (like calcium supplementation) on the levels of blood calcium, phosphorus and alkaline phosphatase. Material and Method: It was a case control study with 79 controls (eGFR>60) and 93 newly diagnosed CKD cases (eGFR < 60 ml/min/1.73 m2). CKD patients again divided into 3 subgroups - 43 stage 5 (eGFR < 15ml/min/1.73 m2), 25 stage 4 (eGFR 15 -29 ml/min/1.73 m2) and 25 stage 3 (eGFR 30-60ml/min/1.73 m2) CKD patients Result: The mean values of calcium (8.65 + 1.1mg/dl), phosphorus (4.72 + 0.96mg/dl) and ALP (154.78 + 50.15U/L) in the study group are significantly different than the control group in which the mean levels are 9.85 + 1.4 mg/dl, 3.2 + 0.53mg/dl and 102.1 + 51.44U/L respectively. eGFR has a strong negative correlation with phosphorus and ALP and a strong positive correlation with calcium in both stage 4 and 5 CKD Conclusion: Our study shows that as the severity of CKD increases as evidenced by decrease in eGFR, more is the change in bone mineral levels and the severity of bone disease of CKD also increases. Key Word: ALP, calcium, chronic kidney disease, CKD-MBD, eGFR, Phosphorus
INTRODUCTION Chronic kidney disease (CKD) is a chronic disease affecting about 5- 10% of the world population1 and the incidence is expected to rise approximately 5-8% every year. Chronic kidney disease is defined as kidney damage as evidenced by a glomerular filtration rate (GFR) of less than 60 ml/min/1.73 m2 for 3 or more months by Kidney Disease Outcomes Quality Initiative of the National Kidney Foundation. The main causative factors of CKD are diabetes mellitus, hypertension, chronic interstitial nephritis, glomerulonephritis and polycystic kidneys. KDOQI classified chronic kidney disease into five stages based on GFR. In the earlier stages of chronic kidney disease (eGFR is between 60 and 90 ml/min/1.73 m2) patients do not have any symptoms. Clinical manifestations typically appear in the later stages like stages 3 to 52. Chronic kidney disease leads to many long-term complications in different organs like iron deficiency anemia, hypertension, pulmonary oedema due to fluid overload, electrolyte abnormalities, sexual dysfunction dyslipidemia, nutritional disorders, metabolic acidosis, bone disorders and cardiovascular disease (CVD). CKD increases the risk of CVD, which itself is one of the main reasons of mortality in CKD. These complications can gradually result in progressive decline in kidney function, cardiovascular disease and death. Among these complications, bone complications in the form of deregulated metabolism of bone minerals like calcium, phosphorus, magnesium and alteration in synthesis and secretion of bone ALP are very common. This renal osteodystrophy is attributed to be one of the main reasons for morbidity and decline in quality of life. Chronic Kidney Disease- Mineral Bone Disorder (CKD-MBD) is complication due to CKD characterized by abnormalities of bone turnover, bone minerals and vitamin D metabolism and calcification in blood vessels and other soft tissues.4 CKD-MBD is supposed to cause cardiovascular complications ultimately resulting in worse disease outcome in CKD patients. Proper diagnosis and adequate treatment for CKD people with one or more of complications is a real concern and requires long term treatment including hospitalisation and regular hospital visits which imposes a large financial burden for the patient as well as the health care system of a country3. There is a lot of data from previous studies revealing that these disorders in mineral and bone metabolism are associated with increased risk for cardiovascular and soft tissue calcification and renal osteodystrophy2 This shows the importance of early diagnosis and treatment, so as to avoid such complications3. There are many previous studies dealing with CKD-MBD in CKD patients undergoing various types of treatment like conservative mode of management and renal replacement therapy, mainly various forms of dialysis. Bone complications have been reported as early as reduction of eGFR by 50 percent than normal.3. Renal osteodystrophy results in great alterations in the appearance and physiological functions of bone in patients with CKD.4. It is one of the components of CKD–MBD. There will be a lot of changes in the regulatory mechanisms of calcium and phosphorus homeostasis early in the course of CKD. These changes have to be picked up and proper correct treatment measures have to be started in the early stage itself. Otherwise they can result in significant consequences not only in the bone but also in blood vasculature in the form of vascular calcification.5,6 With this background, we aimed to estimate blood calcium, phosphorus and alkaline phosphatase levels in various stages of newly diagnosed chronic kidney disease patients and to correlate blood calcium, phosphorus and total alkaline phosphatase levels with eGFR (severity) in newly diagnosed chronic kidney disease patients. Only newly diagnosed CKD patients were taken as cases to avoid the influence of treatment (like calcium supplementation) on the levels of blood calcium, phosphorus and alkaline phosphatase. MATERIALS AND METHODS It was a hospital based case control study carried out in the Department of Biochemistry in our institute. The approval from the scientific research Committee and ethical committee of the institute was sought before commencing the study. Age and sex matched 172 subjects were included in the study. They were divided into two groups- Group A which included 79 apparently healthy subjects and Group B which included 93 newly diagnosed chronic kidney disease patients (cases). These 93 CKD patients were grouped into 25 stage 3 CKD (30 -60 ml/min/1.73 m2), 25 stage 4 CKD (15-30 ml/min/1.73 m2) and 43 stage 5 CKD or ESRD (< 15ml/min/1.73 m2). The subjects were recruited from department of Medicine (both outpatients and inpatients) by random sampling method. Patients with liver diseases, any systemic illness that may affect bone (except CKD), chronic alcoholism and malignancies were excluded from the study. After explaining the aims and procedure of the study and obtaining a written informed consent from the study subjects, a detailed clinical history was collected from them through a pre-tested, semi-structured questionnaire. 5ml of blood was collected by venipuncture from all the study subjects. Serum levels of calcium, phosphorus, alkaline phosphatase and creatinine were assayed in the fully automated biochemistry analyzer (Mindray, BS 380). MDRD (Modification of Diet in Renal Disease study) equation was used to calculate eGFR. eGFR= 186.3× (plasma creatinine)-1.154× age-0.203 (×0.742 for women)
RESULTS The results were analyzed by using SPSS 16 software (IBM Corporation, NY, USA). Without making any assumption about the distribution of data, normality distribution testing of the continuous variables was performed using the non-parametric test, Kolmogorov-Smirnov test (KS-test). Data was first analyzed and was found to be of normal distribution and hence results are expressed as mean ± SD. Student’s t test was used to compare the parameter values between the controls and cases for statistical significance and is shown in table 1, figure 1 and fig 2. ANOVA followed by post-hoc analysis was used to compare between various stages of CKD and is shown in table 2. The differences were considered statistically significant for a p value < 0.05. The relationship between eGFR and parameters like calcium, phosphorus and alkaline phosphatase was analyzed by Spearmans linear regression analysis shown in table3. Scatter gram was plotted by taking dependent variables like calcium, phosphorus and ALP on y-axis and eGFR, which is the independent variable on x-axis shown in Figure 3 and Figure 4. The levels of phosphorus and alkaline phosphatase were significantly increased and serum calcium levels were decreased in CKD patients when compared to normals (p<0.001). While comparing between the stage 3, 4 and 5 of CKD, it was found that, there was a statistically significant increase in phosphorus and ALP levels in stage 5 or ESRD (end stage renal disease) as compared to both stage 3 and stage 4 CKD patients (p<0.001). Similarly calcium levels are significantly increased in stage 5 CKD as compared to both stage 3 and stage 4 CKD patients. (p<0.001).There was no significant change in calcium, phosphorus or ALP levels between stage 3 and stage 4 CKD cases. eGFR was found to be negatively correlated with phosphorus in stage 4 CKD (r= - 0.44) and stage 5 CKD (r= -0.48). Similar strong negative correlation was found between eGFR and ALP in stage 4 CKD (r= - 0.49) and stage 5 CKD (r= -0.55). There was a strong positive correlation between eGFR and calcium in stage 4 CKD (r= 0.43) and stage 5 CKD (r= 0.33).Table 1: Comparison of variables in controls and CKD subjects[values expressed as mean + SD]
Table 2: Comparison of variables in stage 3, 4 and 5 of CKD
p < 0.001 as compared to stage 3CKD; p < 0.001 as compared to stage 4 CKD. Data expressed as mean+SD
Table 3: Univariate analysis showing the correlation between eGFR and other variables in CKD patients and various stages of CKD.
Figure 1: Figure 2:
Figure 3: Figure 4: Figure 1: Calcium and phosphorus levels in controls and stage 3, 4 and 5 CKD; Figure 2: Alkaline phosphatase levels in controls and stage 3, 4 and 5 CKD; Figure 3: Correlation between eGFR and calcium and phosphorus in CKD cases; Figure 4: Correlation between eGFR and ALP in CKD cases. DISCUSSION Our study showed that CKD cases had hypocalcemia, hyperphosphatemia and raised alkaline phosphatase levels. Among the CKD cases, stage 5 CKD or end stage renal diseases (ESRD) had significantly low calcium, high phosphorus and high ALP levels as compared to stage 3 and 4 CKD cases. Our study results are in concordance with many other studies like Freethi et al2. In CKD, as glomerular filtration rate decreases, there is a decline in calcium and phosphorus homeostasis mechanisms, resulting in decreased calcium levels and increased phosphorus levels. Few studies have substantiated that levels of hormones like parathyroid hormone (PTH), various forms of Vitamin D like calcitriol, calcidiol, fibroblast growth factor-23 (FGF-23), and growth hormone showed major alterations in various stages of CKD. Calcium, phosphorus, ALP, PTH, vitamin D and FGF-23 play a major role in both bone modelling in childhood and bone remodelling in adulthood. As a result, bone abnormalities are found in patients with stage 5 CKD and other stages like CKD 3 and 4. The focus of importance has now changed to extra osseous (vascular) calcification that may result from the CKD-MBD and the therapies used to correct these abnormalities. The proposed causes for vascular calcification in CKD especially ESRD patients are complicated, including disturbance of mineral metabolism, calcium based therapies, and the active process of formation of bone in vascular smooth muscle cells. It is now postulated that hyperphosphatemia leads to calcification of blood vessels, accompanied with the secretion of alkaline phosphatase (ALP).7 Hypocalcemia was observed in CKD cases in our study. Several studies have reported similar results.2,8 The proposed reasons for hypocalcemia in CKD can be decreased levels of calcitriol. The study results by Ravani et al 9 revealed decreased levels of calcitriol in the late stages (stage 4 CKD and ESRD). Vitamin D deficiency is also being attributed to play a major role in causation and progression of CKD.10,11 Studies have shown that there is a relation between CKD and secondary hyperparathyroidism12. In CKD patients, Gromadzinski L et al. have shown that hypocalcemia causes cardiac dysfunction especially of the left ventricle. 13 Hyperphosphatemia was observed in CKD cases which is similar to few studies like Block et al and Naves Diaz et al.14,15 Phosphorus is one of the main requisites for mineralization and proper formation of bone. Hyperphosphatemia plays a major role in the causation of vascular calcification and cardiovascular events in CKD. Hyperphosphatemia in CKD occurs due to failure of phosphorus excretion by kidneys. Due to impaired and defective bone remodeling in CKD, phosphorus moves from the bones to the blood causing hyperphosphatemia. Studies have shown that in CKD, osteoclastic activity is more than osteoblastic activity resulting in bone resorption. In CKD, the formation of 1,25 dihydroxycholecalciferol (active form of Vitamin D) is impaired due to defective activity of 1 alpha hydroxylase enzyme in the kidney. This in turn decreases calbindin formation resulting in decreased absorption of calcium from intestine, hypocalcemia and stimulation of parathyroid hormone (PTH) secretion. The increase in PTH levels result in increased release of phosphate from bone into blood. The decrease in calcitriol synthesis causes decrease stimulation to the osteocytes and osteoblasts for the secretion of fibroblast growth factor 23 (FGF23) 16. PTH exerts its action on both renal tubules and bone. In the kidneys, it increases the excretion of phoshate. In the bone, PTH stimulates calcium release from the bone. But the fact that the net effect is increase in phosphate levels shows the predominant effect of bone. Another cause for increased phosphate excretion is the inhibition of the two transport proteins (for inorganic phosphate) in the proximal convoluted tubules of nephrons namely Na/Pi co-transporters, NaPi2a and NaPi2c by the inorganic phosphate ions themselves.17,18 Our study showed increased levels of alkaline phosphatase which is in support with many other studies like Jonathan et al 19. ALP is secreted from various organs like liver, biliary ducts, bone, and placenta. In chronic kidney disease patients, serum ALP level is found to be elevated in hyperparathyroidism and renal bone disease. Alkaline phosphatase will be high in blood in CKD patients with bone related complications. Many recent large population cohort studies have revealed an association between ALP levels and mortality risk in general population and CKD patients.20 Tissue-nonspecific alkaline phosphatase inactivates pyrophosphate, an active inhibitor of hydroxyapatite formation, resulting in calcification of major arteries21. In CKD, vascular cells undergo osteoblastic differentiation, and express several bone associated proteins. Alkaline phosphatase is one among them leading to mineralization of the endothelium, stiffening of arteries and vascular calcification resulting in the cardiovascular disease and mortality in CKD.22 High ALP levels are attributed as a reason for calcification in major arteries like coronary, carotid, aorta, and superficial femoral artery and therefore ALP has been considered as a marker for arterial stiffening.23 The limitations of our study are PTH and Vit D levels were not measured which would have given us a better and clear understanding on the mechanisms of alteration in bone mineral metabolism in CKD. Similar studies but with a large sample size would help to validate the findings of the study.
CONCLUSION This study emphasizes the fact that there is alteration in mineral metabolism in CKD, as evident from hyperphosphatemia, increased ALP and hypocalcemia. Severity of bone mineral disorder increases with decrease in eGFR. CKD patients with mineral and bone disorder are having higher chances of bone fractures and cardiovascular events. The study results highlight the importance of early detection of bone mineral disturbances in CKD (in the stage 3 CKD or before itself) for proper implementation of preventive measures for bone fractures and hence reducing the cardiovascular morbidity and mortality.
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