LIST OF TABLES
Table 4.1 Urea and Creatinine in PRE-D, 0-HAD, 1-HAD and controls 45
Table 4.2 Sodium, Chloride, Potassium and Bicarbonate In
PRE-D, 0-HAD, 1-HAD and controls 47
Table 4.3 Zinc, Copper, Selenium, Cobalt in PRE-D,
0-HAD, 1-HAD and controls 49
Table 4.4 Calcium, Phosphate, Parathyroid Hormone
in PRE-D, 0-HAD, 1-HAD and controls 51
Table 4.5 Parathyroid Hormone Levels in Both Haemodialysis
and controls 53
Table 4.6 Urea, Creatinine and Electrolytes Levels in Male and Female
Subjects in PRE-D group 55
Table 4.7 Zinc, Copper, Selenium, Cobalt in Male and Female
Subjects in PRE-D group 57
Table 4.8 Calcium, Phosphate, Parathyroid Hormone
in Male and Female Subjects in PRE-D group 59
Table 4.9 Urea, Creatinine and Electrolytes Levels in Male and Female
Subjects in 0-HAD Group 61
Table 4.10 Zinc, Copper, Selenium, Cobalt in Male and Female
Subjects in 0-HAD Group 63
Table 4.11 Calcium, Phosphate, Parathyroid Hormone
in Male and Female Subjects in 0-HAD Group 65
Table 4.12 Urea, Creatinine and Electrolytes Levels in Male and Female
Subjects in 1-HAD Group 67
Table 4.13 Zinc, Copper, Selenium, Cobalt in Male and Female
Subjects in 1-HAD Group 69
Table 4.14 Calcium, Phosphate, Parathyroid Hormone
in Male and Female Subjects in 1-HAD Group 71
6
ABBREVIATIONS
ROD Renal Osteodystrophy
CKD Chronic kidney disease
PTH Parathyroid hormone
Na+ Sodium
K+ Potassium
Cl- Chloride
HCO3- Bicarbonate
PO4
2- Phosphate
Ca2+ Calcium
Zn Zinc
Cu Copper
Se Selenium
Co Cobalt
OPG Osteoprotegerin
RANKL Receptor activator of NF-kappa B ligand
RANK Receptor for RANKL
PRE-D Predialysis
0-HAD 0-hour after dialysis
1-HAD 1-hour after dialysis
7
TABLE OF CONTENTS
CHAPTER ONE
1.0 Introduction 1
1.1 Justification 4
1.2 Aims 4
1.3 Objectives 4
CHAPTER TWO
2.0 Literature Review 5
2.1 The Kidney 5
2.2 Pathophysiology 6
2.3 Chronic Kidney Diseases 7
2.4 Signs and Symptoms of Chronic Kidney Disease 8
2.5 Causes of Chronic Kidney Disease 9
2.6 Stages in Chronic Kidney Disease 10
2.7 Prevalence of Chronic Kidney Disease 12
2.8 Dialysis 14
2.9 Haemodialysis 14
2.10 Trace Element 15
2.11 Trace Elements Status in Haemodialysis Patients 20
2.12 Renal Osteodystrophy 22
2.13 Parathyroid Hormone 23
2.14 Calcium 26
2.15 Phosphorous 27
2.16 Bone and Mineral Metabolism In Chronic Kidney Diseases 27
2.17 Sodium 29
2.18 Potassium 30
2.19 Bicarbonate 31
2.20 Chloride 32
CHAPTER THREE
3.0 Subjects, Material and Methods 34
8
3.1 Subjects 34
3.2 Materials 34
3.3 Methods of Analysis 35
Chapter Four
4.0 Results 45
CHAPTER FIVE
5.0 Discussion, Conclusion and Recommendations 73
5.1 Discussion 73
5.2 Conclusion 79
5.3 Recommendations 80
References 81
Appendix 89
9
ABSTRACT
Haemodialysis is the most common form of treatments for end stage renal
disease(ESRD), and is associated with considerable morbidity and mortality. This cross
sectional study was conducted to determine the biochemical changes in haemodialysis
patients by accessing their minerals and also to identify any biomarker that may lead to
renal osteodystrophy in these patients. A total of 100 participants were used for this
study. 50 haemodialysis subjects grouped into predialysis, 0-hour after dialysis and 1-
hour after and 50 apparently normal subjects. They were age matched into 21-30, 31-
40, 41-50, 51-60, 61-70. The minerals assayed were Na+, K+, Cl-, HCO3-, Ca2+, PO4
2-, Se,
Zn, Cu and Co. PTH was also analysed. Electrolytes were assayed by ion selective
electrode, trace elements by atomic absorption spectroscopy, Ca2+ by colorimetric
method, PO4
2+ by UV method and PTH by enzyme immunoassay method. The results
were subjected to statistical analysis (SPSS ver.17) and comparison made using student’s
t-test and ANOVA at P-value<0.05. The mean values of Na+, Cl-, HCO3- were significantly
lower in haemodialysis patients (Na+:127.92+6.24mmol/l, P=0.00; Cl-:
88.84+6.14mmol/l,P=0.00; HCO3-:16.46+2.97mmol/l,P=0.00) compared with the
controls (Na+: 141.28+2.51mmol/l; Cl- 100.32 + 2.28mmol/l;HCO3-24.64 +1.83mmol/l).
Also, the mean value of K+ was significantly higher in dialysis subjects (4.21±0.88mmol/l,
P=0.041) when compared with the control subjects (3.92±0.34mmol/l). Calcium level
was significantly low in dialysis subjects (8.41±0.72mg/dl, P=0.000) as compared with
the controls (9.65±0.50mg/dl). Phosphate on the other hand was significantly higher in
dialysis group (4.35±1.06mg/dl, P=0.00) when compared with the controls
(3.58±0.47mg/dl). However, the mean value of PTH in dialysis subjects was
(165.32±154.90ng/l) and it was significantly higher than the control (P=0.00)
(38.2±12.18ng/l). Zn and Se mean levels were significantly lower in dialysis subjects
(79.33±16.27μg/dl, P=0.02 and 6.67±1.43μg/dl, P=0.00) compared with the control
(88.97±9.77μg/dl and 9.00±2.48μg/dl) respectively. Cu showed a significantly high mean
value in the dialysis (117.54±14.69μg/dl, P=0.01) when compared with the control
subjects (108.50±15.49μg/dl). There was no significant difference in the mean level of
Co (0.03±0.01μg/dl, P=0.26) when compared with the controls (0.04±0.00). Comparison
of the mean levels of these minerals between male and female counterparts among the
different dialysis groups showed no significant differences. More so, no significant
difference was observed when the mean levels of these minerals were compared
between 1-hour after dialysis and immediately after dialysis group. In conclusion, this
study showed that there is a marked reduction in the zinc and selenium status in
haemodialysis patients. Also there appears to be prevalence of renal osteodystrophy
(ROD) in our institution probably because of inadequate monitoring of these patients.
Decrease in these minerals may be the cause of high risk of infection and oxidative stress
observed in these patients. The prevalence of ROD in these patients may result in
cardiovascular death. Therefore, I recommend that these minerals should be assessed
from time to time so as to monitor these biochemical changes observed in these patients.
10
CHAPTER ONE
1.0 INTRODUCTION
Haemodialysis is the most common form of treatment for end stage renal disease (ESRD),
and is associated with considerable morbidity and mortality due to accelerated
cardiovascular disease and infection. Despite the well documented burden of disease
much remains to be learned about how best to prevent these complications of
haemodialysis. Haemodialysis removes uremic toxins primarily allowing equilibration of
plasma and dialysate across a semi-permeable membrane. Dialysate is created by adding
carefully regulated quantities of biologically essential ions such as potassium, sodium,
bicarbonate and calcium to water that has been treated to reduce solutes to very low
levels. The dialysate concentration of other substances such as trace elements is not
routinely manipulated. Substances that have lower concentration in dialysate than in
blood tend to be removed by dialysis. Although this is appropriate in the case of uremic
toxins, it may lead to depletion of biologically essential substances. Besides the potential
for ongoing removal of trace elements by dialysis, haemodialysis patients are at risk for
low dietary intake of such substances due to uremia related anorexia and dietary
restriction. Haemodialysis patients are exposed to very high volumes (> 300 litres/week)
of dialysate therefore even minute levels of toxic substances in source water could lead to
tiny concentration gradients between blood and dialysate which in turn could lead to
clinically relevant toxicity. Substances present in dialysate but not in blood will tend to
accumulate in the patient and the lack of renal clearance in haemodialysis patients might
theoretically lead to toxicity of ingested trace elements even when they are not present in
dialysate. Thus haemodialysis patients are at theoretical risk for both deficiency and
accumulation of trace element depending on dietary intake removal by dialysis, the
11
composition of the source water used for haemodialysis, and residual kidney function (D’
Hease et al., 1996; Zima et al., 1999).
Deficiency of essential trace elements (such as Zinc or Selenium) and excess of potentially
harmful trace elements (such as lead or arsenic) are both known to have adverse
consequences in the general population (Prasad, 1988; Suadicana et al., 1992) It is
plausible that imbalance in the trace element (if present) would contribute to morbidity
and mortality among haemodialysis patients.
Renal osteodystrophy is a bone pathology characterized by bone mineralization deficiency
that is a direct consequence of the electrolyte and endocrine derangements, which
accompany chronic kidney disease (Bonomin et al., 1998; Svara, 2009). Disturbances in
mineral and bone metabolism are common in patients with chronic kidney disease (CKD).
Histological evidence of renal osteodystrophy (ROD) is apparent in patients with moderate
renal failure and progresses as renal failure advances. The overall incidence of ROD in
patients with advanced renal failure and those treated with maintenance haemodialysis
(HD) is 90 to 100%(Massry and Glassock, 2001) A large body of evidence indicates that
these metabolic derangements are associated with an increase in mortality and morbidity,
leading to the development of bone pain, fractures, bone deformity, myopathy, tendon
rupture and growth retardation in patients. In addition, these metabolic derangements
and/ or their therapies may have long term effects on soft tissue calcification (Eknoyan et
al., 1999; Block et al., 2004; Svara, 2009). Renal failure commonly causes
hyperphosphatemia and low serum 1,25(OH)2D3, and secondary hypocalcaemia. These
conditions result in secondary hyperparathyroidism and subsequent development of
hyperparathyroid bone disease. Because of decreased renal synthesis of 1, 25 (OH) 2D3,
may also set in (Burtis and Ashwood, 2003).Metabolic acidosis may be a feature of chronic
renal failure. An attempt at buffering the hydrogen ions by bone results in bone
12
demineralization (Slatopolsky et al., 1996). Various types of bone abnormality are seen in
patients with uraemia.
High turnover bone disease caused by excess parathyroid hormone(PTH) is a central
feature of renal osteodystrophy seen in chronic dialysis patients (Hruska and Teitelbaum,
1995; Stevens et al., 2004). This abnormality almost inevitably develops in uraemic
patients without appropriate therapeutic modalities. Decreased concentrations of ionized
calcium and 1,25 dihydroxy vitamin D3(1, 25(OH)2D3 or calcitriol due to phosphate
retention are the most important stimuli for parathyroid hormone secretion, which can be
corrected in most patients with appropriate therapy. However it is still difficult to suppress
PTH secretion in substantial numbers of patients. Some of these patients may only
respond to a supraphysiological concentration of calcitriol (Fukuda et al., 1993). These
observations suggest that the resistance of parathyroid cells to calcitriol may serve as
another stimulus for PTH secretion in chronic renal failure. Reduction of calcitriol receptor
density in parathyroid gland is currently considered the main mechanism responsible for
the observed resistance in chronic renal failure (Isah, 2007). The role of phosphate in the
pathogenesis of secondary hyperparathyroidism through the modulation of serum calcium
and calcitriol production has long been recognized as an indirect mechanism. In addition,
parathyroid tissue culture supports the direct effect of phosphate to stimulate PTH
secretion and synthesis (Slatopolsky et al., 1996).
13
1.1 JUSTIFICATION
Studies have shown that average blood concentration of biologically important trace
elements were substantially different in haemodialysis patients compared with healthy
controls. Since both deficiency and excess of trace elements are potentially amenable to
therapy, the hypothesis that trace elements status influence the risk of adverse clinical
outcomes appears worthy of investigation. It has also been shown that prevalence of
renal osteodystrophy in haemodialysis patients is high in our institution, possibly because
of inadequate patient monitoring and lack of insight into ROD among both patients and
physicians. The two most commonly encountered types of ROD are high turnover
hyperparathyroid and low turnover adynamic bone disease. Serum levels of PTH are
considered an adequate screening tool to separate these two diseases (Eknoyan et al.,
2003).
1.2 AIMS
To evaluate some minerals and biochemical parameters in patients undergoing
haemodialysis in Nnamdi Azikiwe University Teaching Hospital, Nnewi.
1.3 OBJECTIVES
1. To evaluate the biochemical changes in haemodialysis patients by determining the
levels of these trace elements; Cobalt, zinc, selenium and copper as compared with
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