|Year : 2019 | Volume
| Issue : 4 | Page : 191-195
Prevalence and pattern of chronic kidney disease-mineral bone disorders among hemodialysis patients in kano, northwest nigeria
Alhaji Abdu1, Aliyu Abdu2, Fatiu A Arogundade3
1 Department of Internal Medicine, Abubakar Tafawa Balewa University Teaching Hospital, Bauchi, Nigeria
2 Department of Internal Medicine, Bayero University/Aminu Kano Teaching Hospital, Kano, Nigeria
3 Department of Medicine, Obafemi Awolowo University Teaching Hospital Complex, Ile Ife, Osun, Nigeria
|Date of Web Publication||05-Dec-2019|
Dr. Alhaji Abdu
Department of Internal Medicine, Abubakar Tafawa Balewa University Teaching Hospital, P.M.B. 0117 Bauchi
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Introduction: Mineral and bone disorders (MBD) are among the important complications of chronic kidney disease (CKD) including end-stage renal disease. In addition to the higher rate of all-cause and cardiovascular-related mortality, MBD is also a cause of significant morbidity in CKD patients. Materials and Methods: This is a cross-sectional study of all consenting patients on hemodialysis at Aminu Kano Teaching Hospital, between December 2011 and June 2012. With the aid of an interviewer-administered questionnaire, the demographic profile and clinical features of the patients were obtained. After a general physical examination, blood sample was taken for the determination of calcium, phosphate, intact parathyroid hormone, 25 hydroxy (25[OH]) Vitamin D3, packed cell volume, serum creatinine, and potassium. Results: Forty-eight patients on maintenance hemodialysis were recruited for the study, 39 (81.3%) were male and 9 (18.8%) were female. The age range was 40–59 years, with a mean of 45.96 ± 13.7 years. Chronic glomerulonephritis was the predominant cause of CKD (25%). Hyperphosphatemia was noted in 19 (39.5%) of the patients, whereas 22 (46%) had hypocalcemia. In 26 (54.1%) of the patients, the calcium-phosphate product was >4.55 mmol2/L2. We found that 58% of the patients had CKD-MBD, of which 15 (31%) had secondary hyperparathyroidism, whereas 13 (27%) had features suggestive of adynamic bone disease. None of the patient had normal serum 25(OH) Vitamin D3(mean: 43.79 ± 21 ng/ml). Conclusion: CKD-MBD is common among patients on hemodialysis in our center. Screening for CKD-MBD and appropriate use of phosphate binder and Vitamin D when indicated are highly recommended.
| Abstract in French|| |
Introduction: Les maladies minérales et osseuses comptent parmi les complications importantes de la néphropathie chronique, notamment: phase terminale de la maladie rénale. Outre le taux plus élevé de mortalité toutes causes confondues et liée à la cardiopathie, la MBD est également une cause de morbidité chez les patients atteints d'IRC. Matériels et Méthodes: Ceci est une étude transversale de tous les patients consentants sous hémodialyse à Aminu Hôpital universitaire de Kano, entre décembre 2011 et juin 2012. À l'aide d'un questionnaire administré par un intervieweur, le le profil et les caractéristiques cliniques des patients ont été obtenus. Après un examen physique général, un échantillon de sang a été prélevé pour la determination de calcium, de phosphate, d'hormone parathyroïde intacte, de 25 hydroxy (25 [OH]) vitamine D3, de volume de globules rouges, de créatinine sérique et de potassium. Résultats: Quarante-huit patients sous hémodialyse d'entretien ont été recrutés pour l'étude, 39 (81,3%) étaient des hommes et 9 (18,8%) des femmes. La tranche d'âge était comprise entre 40 et 59 ans, avec une moyenne de 45,96 ± 13,7 ans. La glomérulonéphrite chronique était la principale cause de néphropathie chronique (25%). Une hyperphosphatémie a été notée chez 19 (39,5%) des patients, alors que 22 (46%) présentaient une hypocalcémie. Dans 26 (54,1%) des patients, le le produit de phosphate de calcium était> 4,55 mmol2 / L2. Nous avons constaté que 58% des patients étaient atteints de MRC, dont 15 (31%) avaient une atteinte secondaire. hyperparathyroïdie, alors que 13 (27%) présentaient des signes évocateurs d'une maladie osseuse adynamique. Aucun patient ne présentait un taux sérique normal de 25 (OH) Vitamine D3 (moyenne: 43,79 ± 21 ng / ml). Conclusion: La MPC est fréquente chez les patients hémodialysés de notre centre. Dépistage de CKD-MBD et l'utilisation appropriée du liant de phosphate et de la vitamine D lorsque cela est indiqué sont fortement recommandés.
Keywords: Biochemical markers, chronic kidney disease-mineral bone disorders, maintenance hemodialysis, Northwest Nigeria
|How to cite this article:|
Abdu A, Abdu A, Arogundade FA. Prevalence and pattern of chronic kidney disease-mineral bone disorders among hemodialysis patients in kano, northwest nigeria. Ann Afr Med 2019;18:191-5
|How to cite this URL:|
Abdu A, Abdu A, Arogundade FA. Prevalence and pattern of chronic kidney disease-mineral bone disorders among hemodialysis patients in kano, northwest nigeria. Ann Afr Med [serial online] 2019 [cited 2022 Aug 7];18:191-5. Available from: https://www.annalsafrmed.org/text.asp?2019/18/4/191/272400
| Introduction|| |
Chronic kidney disease-mineral bone disorder (CKD-MBD) is a systemic disorder of mineral and bone metabolism due to CKD manifesting with one or combinations of abnormalities of calcium, phosphorus, parathyroid hormone (PTH) or Vitamin D metabolism, abnormalities of bone turnover, mineralization, volume, linear growth or strength, and vascular or soft-tissue calcification. The major consequences of disordered mineral metabolism in CKD patients are secondary hyperparathyroidism (SHPTH), renal osteodystrophy, and vascular calcification in addition to increasing morbidity.,, Changes in mineral metabolism have also been associated with higher rates of both all-cause mortality and cardiovascular-related mortality.,,
Diagnosis of CKD-MBD using bone biopsy is invasive; in addition, facilities for histomorphometry are not universally available, particularly in a developing country such as Nigeria. Likewise, bone mineral density testing by dual-energy X-ray absorptiometry is not routinely available and affordable. Therefore, changes in serum calcium, phosphorus, PTH, and alkaline phosphatase are generally used to evaluate for CKD-MBD. In this study, changes in the serum PTH and Vitamin D3 are used to diagnose and classify CKD-MBD.
The aim of this study was to determine the prevalence of CKD-MBD and describe its pattern among patients on maintenance hemodialysis in Kano, Northwestern Nigeria.
| Materials and Methods|| |
This is a cross-sectional study of consecutive patients on maintenance hemodialysis at Aminu Kano Teaching Hospital (AKTH), a major referral facility in Northwestern Nigeria seen between December 2011 and June 2012. All patients signed written informed consent, and the study was approved by the Ethics and Research committee of the hospital. During the study period, there were fifty patients on maintenance hemodialysis, one refused consent and another was excluded on account of hepatitis B-related chronic liver disease. Therefore, 48 patients were evaluated in this study.
The exclusion criteria included refusal of consent, age <18 years, presence of thyroid or liver disease, and those with primary or metabolic bone disease or on hormone replacement therapy. With the aid of interviewer-administered questionnaires, information on sociodemographic data, possible cause of CKD, duration on dialysis, use of phosphate binders, and Vitamin D supplementation were obtained from the patients and recorded. All patients had complete physical examination, and blood sample was taken for determination of calcium, phosphorus, alkaline phosphatase, PTH, 25 hydroxy Vitamin D3 (25[OH]D3), packed cell volume, potassium, bicarbonate, creatinine, and albumin.
Diagnosis of chronic glomerulonephritis was based on history of progressive edema, hypertension, anemia, proteinuria, red cell casts, and bilaterally shrunken kidneys on ultrasound of younger persons. Hypertensive nephrosclerosis was diagnosed based on the history of long-standing hypertension and clinical features of long-standing hypertension such as hypertensive heart disease, thickened arterial wall, and locomotor brachialis. Diagnosis of diabetic nephropathy was entertained in a known diabetic (≥5 years), with microalbuminuria or proteinuria, hypertension, azotemia, and normal or enlarged kidneys on ultrasound. Obstructive uropathy was diagnosed on the basis of ultrasound features of hydronephrosis, clinical and biochemical features of kidney disease in a patient with history, and clinical evidence of urinary tract obstruction.
Intact PTH (iPTH) and 25(OH)D3 were analyzed by electrochemiluminescence immunoassay on a fully automated Cobas e 411 analyzer (Roche Diagnostics GmbH, Germany). Based on the serum level of iPTH, patients were classified into:
- SHPTH; iPTH >400 pg/ml
- Adynamic bone disease (ABD); iPTH <65 pg/ml
- Normal: iPH 65–400 pg/ml.
Data were analyzed using the Statistical Package for the Social Sciences Version 20 (SPSS Inc., Chicago, IL, USA). Quantitative variables were presented as mean and standard deviation. The Mann–Whitney U-test was used to compare mean of nonparametric variables; the Spearman's rank-order correlation was used to determine relationship between various groups. Multiple regression analysis was used to identify potential risk factors for CKD-MBD. P < 0.05 was considered statistically significant.
| Results|| |
The mean age of the participants was 45.96 ± 13.7 years with about 60% in the age group of 40–59 years, 39 (81.3%) were male and nine (18.7%) were female. [Table 1] shows the baseline characteristics of the participants. Thirty-four (70.4%) of the participants were the Hausa, whereas 16.6% and 10.4% were of the Igbo and Yoruba ethnic groups, respectively. Trading constitutes the highest occupation (30%), whereas civil servants and farmers formed 16.7% and 15% of the study participants, respectively.
|Table 1: Mean Blood Pressures and serum level of measured laboratory parameters in the study population|
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Chronic glomerulonephritis was the predominant cause of CKD (25%). Pruritus was the most common presenting symptom as depicted in [Table 2]. The median duration on dialysis was 19.3 ± 21.9 months, with 23 (47.9%) of the patients on three dialysis sessions per week, whereas 19 (39.6%) and 6 (12.5%) were on twice and once weekly hemodialysis, respectively. Twenty-three patients had mean Kt/V of <1.22, of which 56% had abnormal PTH level. The remaining 25 patients had mean Kt/V >1.22 and 72% had abnormal PTH level. There is a significant relation between Kt/V >1.22 and development of CKD-MBD (P = 0.001). Nineteen (39.5%) of the patients had hyperphosphatemia and 20 (41.6%) had normal phosphate level. Hypercalcemia was seen in 4 (8.3%) of the patients and 22 (46%) had hypocalcemia. In 26 (54.1%) of the patients, the calcium phosphate product was >4.55 mmol2 L −2. Alkaline phosphatase was raised in 9 (41.0%) of the patients.
|Table 2: Cause of chronic kidney disease and clinical features of the patients|
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Fifteen patients (31%) had iPTH >450Pg/ml (SHPTH) and 13 (27%) had iPTH values <65 pg/ml (ABD); therefore, the overall prevalence of CKD-MBD was 58%. None of the patients had normal 25 (OH) Vitamin D level, 43 (89.0%) had Vitamin D deficiency, whereas 5 (10.4%) had Vitamin D insufficiency [Table 3]. Serum 25 (OH) Vitamin had negative correlation with SHPTH (r = −3.3: P =0.023) and ABD (r = −3.1; P = 0.03). SHPTH was seen in 12 (80%) males and 3 (20%) females, and ABD was seen 12 (92.3%) and 1 (7.7%) of males and females, respectively. There is no statistically significant association between gender and CKD-MBD [Figure 1].
|Figure 1: Showing proportion patients with different forms of chronic kidney disease-MBD. SHPTH = Secondary hyperparathyroidism, ABD = Adynamic bone disease|
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SHPTH is statistically associated with high alkaline phosphatase (Z = −2.144; P = 0.032). There was no significant association between SHPTH and ABD with corrected serum calcium, phosphate, or alkaline phosphatase; however, packed cell volume was statistically associated with ABD [Table 4]. Thirty-three (68%) of the patients were on Vitamin D supplement in the form of oral calcitriol, whereas 21 (43.8%) were on calcium carbonate, and none of the patient on phosphate binder has hyperphosphatemia.
|Table 4: Relationship of forms of CKD–MBD with certain Biochemical parameters|
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On multiple regression analysis, age >65 years (odds ratio [OR] =2.5, 95% confidence interval [CI]: 1.58–3.2, P = 0.02), diabetes mellitus (OR = 1.9, 95% CI: 1.8–2.6, P = 0.03), acidosis (OR = 0.5, 95% CI: 0.24–2.90, P = 0.04), and < 2 hemodialysis sessions per week (OR = 4.25, 95% CI: 3.6–4.8, P = 0.02) as well as hypercalcemia (OR = 1.8, 95% CI: 0.8–3.2, P = 0.03) were found to be associated with the development of CKD-MBD [Table 5].
|Table 5: Multiple regression analysis to find potential risk factors for CKD-MBD|
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| Discussion|| |
Disturbances in mineral and bone metabolism are common among CKD patients. There are distinct differences between developing and developed countries, regarding the prevalence, pathogenesis, and the management of CKD-MBD. Such differences included ethno-racial factors, dialysis quality, types of dialysis membrane, dialysis water, aluminum and strontium toxicities as well as economic factors such as limiting use of effective newer phosphate binders, calcimimetics, and Vitamin D. This study elucidated the prevalence and pattern of CKD-MBD among patients on maintenance hemodialysis and factors associated with it.
This study corroborated earlier findings of relatively younger age of end-stage renal disease (ESRD) patients in Africa., This has been attributed to the high frequency of infectious causes of chronic glomerulonephritis. Diabetes mellitus which is the leading cause of CKD in Europe, USA, and Japan causes only 10% of CKD in this study.,,, We found the total prevalence of CKD-MBD to be 58%. This is higher than the prevalence of 24% reported by Sanusi et al. in Ile Ife. This could be explained by the small number of patients who had serum PTH analyzed in their study. However, the prevalence compares well with Okoye et al. in Enugu, who found 85% of their predialysis patients had abnormal PTH level. The prevalence is also similar to what Sidy et al. and Buargub et al. obtained in Senegal and Libya, respectively.,
However, the prevalence rate was lower than what Santoso et al. in Indonesia and Ziólkowska et al. reported., Santoso et al. studied 48 Indonesian hemodialysis patients with iPTH and found a prevalence of 72%. Similarly, Ziólkowska et al. found the prevalence of CKD-MBD in Polish children on hemodialysis of 63%. In the study, iPTH value of >200 pg/ml was used to subclassify the patients and this may be the reason for the higher prevalence. In a systematic review of the literature between 1985 and 2007, Samina and Mohammed found the overall prevalence of CKD-MBD of 79%; most of the studies included in the meta-analysis performed bone biopsy which could explained the higher prevalence.
Our study found the predominant from of CKD-MBD to be SHPTH, this is also in agreement with a study in Senegal, in which SHPTH was found in 57 of 118 (48%) patients on hemodialysis. However, the pattern was different from North America in mid-1980s. Monier-Faugere and Malluche while assessing the trends in renal osteodystrophy among 2248 dialysis patients from 1983 to 1995 found increasingly higher prevalence of ABD. Interestingly, 61% of the patients were on aluminum-containing phosphate binders which could affect the evolution of CKD-MBD.
Perhaps, race is another important determinant of CKD-MBD, because in the general population, Africans have higher parathyroid glands mass and circulating PTH level than Caucasians. This could predispose blacks to more severe parathyroid disease when CKD develops. In a study of 1270 hemodialysis patients comprising 61% blacks, Gupta et al. were able to show a significant difference in serum calcium and phosphate between blacks and whites. Moreover, maximum PTH levels were significantly high in blacks, and after adjustment, PTH level remained higher than in whites (641.7 pg/ml vs. 346 pg/ml P < 0.0001). In another study of 76 hemodialysis patients of which 31% were blacks, Sawaya et al. found high PTH levels in blacks than whites.
Interpretation of PTH levels in blacks may be different from Caucasians as illustrated by many studies.,, Diagnosis of ABD in blacks is also poised with difficulties as it can present with normal PTH level. In developing country such as Nigeria, treatment of SHPTH using newer agents such as sevelamer, lanthanum carbonate, and calcimimetics is not feasible due to nonavailability and high cost. Therefore, cheaper drugs such as oral calcium carbonate and Vitamin D should be routinely prescribed to all ESRD patients on maintenance hemodialysis, who have abnormal serum biochemistry. Although the number of patients on calcium carbonate is low, it is noteworthy that all the patients have normal serum phosphorus.
This study highlighted the significance of available therapeutic agents for the treatment and prevention of CKD-MBD. While more than half of the patients were on Vitamin D supplement, none of the patients were found to have normal serum 25 hydroxy Vitamin D. This suggests that either the dose or quality of the oral calcitriol needs to be determined.
| Conclusion|| |
The prevalence of CKD-MBD among ESRD patients on maintenance hemodialysis is high, and despite the widespread use of phosphate binders and oral Vitamin D supplementation, the prevalence of hyperphosphatemia, Vitamin D deficiency/insufficient, and subsequent SHPTH is high.
This study uses serum iPTH to subclassifies and determines the prevalence of CKD-MBD. Our inability to do bone biopsy, serum fibroblast growth factor 23, osteocalcin as well as radiological markers suggest that the result of our study should be interpreted with caution.
The authors would like to thank Head and all staffs of Department of Medicine, AKTH, Kano, Nigeria.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone Disorder (CKD-MBD). Kidney Int Suppl (2011) 2017;7:1-59.
Goodkin DA, Bragg-Gresham JL, Koenig KG, Wolfe RA, Akiba T, Andreucci VE, et al.
Association of comorbid conditions and mortality in hemodialysis patients in Europe, Japan, and the United States: The dialysis outcomes and practice patterns study (DOPPS). J Am Soc Nephrol 2003;14:3270-7.
Raggi P, Boulay A, Chasan-Taber S, Amin N, Dillon M, Burke SK, et al.
Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease? J Am Coll Cardiol 2002;39:695-701.
Reddy YN, Abraham G, Reddy YN, Nagarajan P, Matthew M, Jayaseelan T, et al.
Mineral bone disease in maintenance hemodialysis patients: Association with morbidity and mortality. Indian J Nephrol 2014;24:302-7.
] [Full text]
Floege J, Kim J, Ireland E, Chazot C, Drueke T, de Francisco A, et al.
Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population. Nephrol Dial Transplant 2011;26:1948-55.
Tentori F, Blayney MJ, Albert JM, Gillespie BW, Kerr PG, Bommer J, et al.
Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: The dialysis outcomes and practice patterns study (DOPPS). Am J Kidney Dis 2008;52:519-30.
Wald R, Sarnak MJ, Tighiouart H, Cheung AK, Levey AS, Eknoyan G, et al.
Disordered mineral metabolism in hemodialysis patients: An analysis of cumulative effects in the hemodialysis (HEMO) study. Am J Kidney Dis 2008;52:531-40.
Salako BL, Ayodele OE, Kadiri S, Arije A. Prevalence of hepatitis B and C viruses in pre-dialysis patients with chronic renal failure. Afr J Med Med Sci 2002;31:311-4.
Qi Q, Monier-Faugere MC, Geng Z, Malluche HH. Predictive value of serum parathyroid hormone levels for bone turnover in patients on chronic maintenance dialysis. Am J Kidney Dis 1995;26:622-31.
Seck SM, Dahaba M, Ka EF, Cisse MM, Gueye S, Tal AO, et al.
Mineral and bone disease in black African hemodialysis patients: A report from Senegal. Nephrourol Mon 2012;4:613-6.
Okoye JU, Arodiwe EB, Ulasi II, Ijoma CK, Onodugo OD. Prevalence of CKD-MBD in pre-dialysis patients using biochemical markers in Enugu, South-East Nigeria. Afr Health Sci 2015;15:941-8.
Bryne C, Caskey F, Castledine C, Davenport A, Dawnay A, Fraser S, et al
annual report UK renal registry. Nephron 2018;138:151-64.
Annual Data Report 2017; United States Renal Data System. Minneapolis: United States Renal Data System Minnesota; 2018. Available from: http//www.usrds.org/atlas
. [Last accessed on 2018 Sep 25].
Ucido A. Differential diagnosis of chronic kidney disease (CKD): By primary diseases. Jpn Med Assoc 2011;54:22-6.
Travers K, Martin A, Khankhel Z, Boye KS, Lee LJ. Burden and management of chronic kidney disease in Japan: Systematic review of the literature. Int J Nephrol Renovasc Dis 2013;6:1-3.
Sanusi AA, Arogundade FA, Oladigbo M, Ogini LM, Akinsola A. Prevalence and pattern of renal bone disease in end stage renal disease patients in Ile-Ife, Nigeria. West Afr J Med 2010;29:75-80.
Buargub MA, Nabulsi MF, Shafeh TA. Prevalence and pattern of renal osteodystrophy in chronic hemodialysis patients: A cross sectional study of 103 patients. Saudi J Kidney Dis Transpl 2006;17:401-7.
] [Full text]
Santoso D, Yogiantoro M, Tomino Y. Osteodystrophy in Indonesian haemodialysis patients. Nephrology (Carlton) 2003;8:261-5.
Ziólkowska H, Pańiczyk-Tomaszewska M, Debiński A, Polowiec Z, Sawicki A, Sieniawska M. Bone biopsy results and serum bone turnover parameters in uremic children. Acta Paediatr 2000;89:666-71.
Samina SK, Mohammed RI. Diagnosis of renal osteodystrophy among CKD patients. Nephrol Dial Transpl 2009;38:45-59.
Harris SS, Soteriades E, Dawson-Hughes B; Framingham Heart Study, Boston Low-Income Elderly Osteoporosis Study. Secondary hyperparathyroidism and bone turnover in elderly blacks and whites. J Clin Endocrinol Metab 2001;86:3801-4.
Monier-Faugere MC, Malluche HH. Trends in renal osteodystrophy: A survey from 1983 to 1995 in a total of 2248 patients. Nephrol Dial Transplant 1996;11 Suppl 3:111-20.
Gupta A, Kallenbach LR, Zasuwa G, Divine GW. Race is a major determinant of secondary hyperparathyroidism in uremic patients. J Am Soc Nephrol 2000;11:330-4.
Sawaya BP, Butros R, Naqvi S, Geng Z, Mawad H, Friedler R, et al.
Differences in bone turnover and intact PTH levels between African American and Caucasian patients with end-stage renal disease. Kidney Int 2003;64:737-42.
Gupta A. Renal bone disease in black dialysis patients: Are algorithms developed for white dialysis patients valid? Nephrol Dial Transplant 2001;16:1518-9.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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