44
The mean GFR ± SD were higher in both male and female subjects with SCD compared with sex-matched controls. The differences between the mean values for both sexes were statistically significant for the male group (p=0.009) and for the female group (p=0.019), respectively. Figure 4
Figure 4. Compare the mean GFR of study population based on gender correlation
Fourty three (72%) of the SCD and 57(95%) of control children had GFRs that were within normal range, 8(13%) and 9(15%) of the subjects with SCD had GFRs that were below and above the normal range respectively. Table VI compares number of SCD children with GFR above and below the normal range with those of control children. Although the SCD cohort had more children with GFR outside the normal range, the difference was not significant.
0 20 40 60 80 100 120 140
Males Females
Comparism of mean GFR of study groups
45
Table VI: Comparison between Number of SCD and Control Children with GFR above & below the normal Range.
Normal Number of subjects
GFR with GFR outside Fisher`s Exact Test P Rangea normal range
SCD Controls
Below 8(47) 3(100) Above 9(53) 0(0) 0.218 Total 17(100) 3(100)
a86 to 162ml/minute/1.73m2 (3 – 14 years). Figures in brackets represent percentages.
Of the 60 SCD subjects studied, 49 (82%) had history of previous episode(s) of VOC out of whom 33 (67%) had GFRs within normal range, 7 (14%) had GFRs below normal and 9 (19%) had values above normal range. Out of the 11 (18%) SCD subjects with no previous episode of VOC, 10 (91%) had GFR within normal range, 1 (9%) had GFR below the normal range and none had GFR above normal. The comparison of GFR category and previous episode of VOC did not yield any significant difference; (Phi & Cramer`s = 0.22, P= 0.235) table VII.
46
TableVII: Comparison of previous episode(s) of VOC and GFR of Sickle Cell Disease Subjects.
Previous History GFR of VOC
With Hx of VOC No Hx of VOC Phi & Cramer`s P
Within Range 33 10
Below Range 7 1 0.22 0.235 Above Range 9 0
Out of the 60 SCD subjects studied, 28 (47%) had previous history of blood transfusion within the last 2 years to 3 months before enrolment in to the study. Eighteen (64%) of these had GFRs that were within normal range, 4(14%) below the normal range and 6 (22%) above normal.
Of the 32 (53%) SCD subjects with no previous history of blood transfusion, 25 (78%) had GFRs within normal range, 4 (13%) below normal range and 3 (9%) above. The comparison of GFR category of those with previous history of blood transfusion with those that had no history of transfusion yielded no statistical significant difference; (Phi & Cramer`s = 0.177, P= 0.39) table VIII.
Table VIII: Comparison of Previous Blood Transfusion and GFR of Sickle Cell Disease Subjects.
Previous History
GFR of Blood Transfusion
Blood Transfusion No Transfusion Phi & Cramer`s P
47 Within Range 18 25
Below Range 4 4 0.177 0.39 Above Range 6 3
DISCUSSION
This hospital-based cross-sectional case-control study conducted among steady state SCD children aged three to fourteen years at the UMTH, in North-East Nigeria, was partly based on the fact that the chronic anaemia and recurrent episodes of vaso-occlusive crisis in SCD have effects on function of the kidney. The study showed that crises-free children in Maiduguri with
48
SCD have normal GFR. The study also indicated that normal children with HbAA have GFR within normal range. However, the study indicated that there was significant difference in GFR between SCD children in steady state and the age and sex matched Haemoglobin AA controls even though both groups have GFR that were within normal range. Similarly, study also indicated that crises-free children with SCD have normal GFR that is hardly influenced by previous episodes of vaso-occlusive or anaemic crises.
A prominent finding in this study is the documentation of GFR that is within normal range among children with SCD, this finding is consistent with findings of Okoro and
Onwuameze21 and the assertion that SCD patients under the age of 30 years of age have normal GFR as a rule.16,87 The findings of GFR within normal range among SCD children in steady states in this study gives further support to earlier reports21,22,150 that Nigerian children with SCD in steady states have mild to moderate degree renal pathology.
The finding of higher mean GFR value in the SCD subjects compared to the controls demonstrated in this research is in concordance with works of Hatch et al,151 Oyinade,152 as well as Addae and Addae.153 Similar findings were also reported by the much cited early works on increased GFR in SCD children from West Indies and North America.16,154 The early renal functional changes seen in SCD patients are increases in the renal cortical blood flow (RBF) and GFR. Enlargement in the glomerular size is seen and it is postulated that increased glomerular perfusion leads to the glomerular enlargement that is seen. The increase in RBF and GFR result from increased sludging of red blood cells in the microcirculation due to low oxygen tension.
This leads to ischaemia and micro infarctions, which result in an increased production of renal vasodilatory prostaglandins155 leading to vasodilatation and Hyperfiltration in the glomeruli.
These increase in RBF, GFR and glomerular size were reported to start beyond the age of 2
49
years.12,156 This is also in concordance with the finding in this study of no significant difference between the subjects and controls in the age group less than 5 years as their GFRs are similar. It is reasonable to suggest that the glomerular changes seen in SCD are haemodynamically
mediated. This is based on the findings of higher GFR that may have resulted from early Hyperfiltration that lead to glomerular enlargement.
However, the finding of significantly higher mean GFR in steady state SCD children as compared to healthy haemoglobin AA controls in this study is at variance with works of Okoro and Onwuameze,21 Olowu et al,22 and Aikhionbare et al.17 Furthermore, the finding of
significant difference in mean GFR between steady state SCD children and healthy haemoglobin AA controls in this study is not in keeping with that of Ocheke.28 Working in Jos, a middle-belt area of Nigeria with its peculiar cold weather, he found a statistically significant lower mean GFR using endogenous creatinine clearance in steady state SCA children than in age and gender matched controls with HbAA.28 The reason for Ocheke’s finding of lower mean GFR in steady state SCA children was not apparent despite the large sample size and the use of endogenous creatinine clearance. However, Aikhionbare had earlier documented non significant lower GFR in steady state SCA children compared to age and sex matched HbAA controls but using a smaller sample size.157
The finding of higher mean GFR in SCD children in steady state as compared with HbAA children is also not in keeping with the work of Calcagno et al,158 published in 1950 appeared to be one of the earliest literature on GFR study in SCA children. They used the thiosulphate clearance method to study GFR in five SCA children and found a reduction in GFR value. The reason for the small sample size by Calgagno may also not be unconnected to the cumbersome nature of the analytic technique used.158 It demanded constant infusion of
50
thiosulphate to ensure steady plasma level. Notwithstanding, a larger sample size will be needed to authenticate the finding.
The gradual increase in GFR with age among the SCD subjects observed in this study is in conformity with the previous works that showed relationship between age and GFR for the SCD group.91-93,99,107 The finding is however, at variance with the documentation of Olowu et al22 and Aikhionbare et al.157 Olowu showed that no significant differences exist between the different age groups. While Aikhionbare in 1988 demonstrated higher mean endogenous creatinine clearance in younger SCA children aged between 1 and 4 years as against the
corresponding older age group, this difference was however not significant. This varying finding on the effect of age on GFR could be attributed to small sample size of 22 in case of Aikhionbare et al.157 The reason for the finding in the work by Olowu with similar sample size to this work is not clear.
Children and young adults with SCD have been shown to have increased renal plasma flow, increased GFR and reduced filtration fraction,91-93,99,107 but GFR decreases progressively beyond the second decade of life.33,34 Both the GFR and renal plasma flow are reported to be frequently subnormal after the age of 40 years.91 Although, the change in haemodynamic parameters is not correlated with time of onset of renal histopathological lesions.108
The finding of normal GFR in the group of SCD children with previous episodes of crises studied in steady states, gives further support to earlier reports21,22 that Nigerian children with SCD in steady states have mild to moderate degree renal pathology. However, the finding in this study of normal GFR in SCA children with previous episodes of crises is not in keeping with that of Etteldorf et al16 working in Memphis, USA that used Inulin clearance technique to evaluate
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GFR in 8 SCA children in crises and documented increased GFR. When the study was conducted again in steady state, only one had a normal GFR while all the other 7 still maintained an
elevated GFR. While apart from the grossly inadequate sample size, the fact that one out of the eight subjects had normal GFR value when the study was conducted again in steady state could mean finding may change with adequate sample size.
It is however, suggested that it is likely Nigerian children with SCA in steady state have
normal GFR that is hardly influenced by previous episodes of vaso-occlusive or anaemic crises.
The pathophysiologic factors that lead to the early functional changes of increase in the renal cortical blood flow (RBF) and GFR appear to result from altered glomerular autoregulation,109 and prostaglandins have been shown to be important in this process, mediating afferent arteriolar vasodilatation.111 It is observed that prostaglandin inhibition with indomethacin led to a 16%
reduction of GFR, as opposed to no alteration in control patients. The ratio between the urinary prostaglandins PGE2 and PGF2α is increased in patients with SCA, favoring peripheral
vasodilatation.110 The increase in prostaglandin synthesis is thought to be related to ischaemic damage to the renal medulla.96
Similarly, no significant difference was found between the SCA children with previous blood transfusion and those with no history of transfusion in steady state. The lack of significant difference between children with SCD with previous transfusion and those with no previous transfusion in this study could be due to the fact that children with recent blood transfusion (at least 3 months) were excluded. It is known that haemodynamic equilibration occurs within 48 to 72 hours after blood transfusion is accomplished,159 with this equilibration, changes in GFR may not be obtained. However, literature search did not find similar study to compare.
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This work did not show any significant gender influence on GFR in SCA children. This is in conformity with the findings of Okoro and Onwuameze21 and Ocheke.28 The basis for the finding in this study as well as those cited earlier may be related to the fact that gender is not a key determinant of anthropometric status in SCD patient.160 Thus the prospect wherein GFR is expected to be higher in male than female of the same age,161 may therefore not be entirely true for sickle cell disease patients, as most of the changes related to gender occurs after puberty.
The lower serum creatinine levels in subjects with SCD compared with controls is similar to the documentation of Joanne et al.162 The level of serum creatinine is inversely related to GFR and is also affected by factors independent of GFR, which include age, sex, race, body size and diet.137,163 In this study, serum creatinine levels in subjects with SCD were equal to that predicted from the inverse relationship between GFR and serum creatinine. In the steady state, the rate of creatinine generation approximates to creatinine excretion. It seems likely that increased GFR contributes to lower serum creatinine in subjects with SCD. Although, various renal
consequences of the SCD in children have been documented with attempts at identifying the underlying pathways of such consequences,7,33,151,154,164-167 however, the documentations of the effect of SCD on the GFR are quite conflicting.16,21,22,27,28,152-154,168,169
Another finding in this research is the significantly low mean blood pressure among subjects with SCD compared with controls which is in concordance with the documentation of Ernst et al,130 Sergeant et al 170 and Pegelow et al.171 This may be due to the chronic hypoxia secondary to the chronic anaemic state in these subjects, the hypoxia causes vasodilatation leading to lower peripheral vascular resistance and hence lower systemic blood pressure in the subjects. Reduced peripheral vascular resistance in subjects is also explained by relatively larger plasma volume resulting from lower packed cell volume. There is therefore, reduced blood
53
viscosity and hence lower peripheral vascular resistance. Another contributory factor to
vasodilatation and hence reduced peripheral vascular resistance in sickle cell anaemia subjects is higher level of prostaglandin (a potent platelet aggregation inhibitor).172-174 Renal tubular damage with concentration defects and sodium loss, alterations in circulating aldosterone, renin,
vasopressin levels and stimulation of production of renal prostaglandins are other mechanisms that are explanatory for the reduced blood pressure documented in adults with SCA.172-174 This defect of reduced concentrating ability in the kidney increases with age in Nigerian children with SCD.175
CONCLUSIONS
Based on the findings of this study, the following conclusions were drawn;
1. Sickle cell anaemia children in steady state have GFR within normal range.
2. Sickle cell anaemia children in steady state have higher GFR compared to age and sex matched HbAA children.
3. GFR increases with increasing age among SCA children in steady state, while such is not the case among the controls.
4. Previous episodes of crises have no association with GFR among SCD children while in steady state.
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RECOMMENDATIONS
1. Nationally sponsored multicentre studies on the effects of sickle cell disease on GFR in a larger population of paediatric subjects with SCA are desirable and recommended in view of the large population of SCA patients in Nigeria.
2. Conscious and focused efforts should be directed nationally towards both prevention and efficient management of sickle cell crises in children in order to prevent the cumulative long term effects of these crises may have on the renal function.
55 LIMITATIONS OF STUDY
1. Haemoglobin genotype was done using cellulose acetate electrophoresis. This was not differentiating HbSS from other haemoglobinopathies such as haemoglobin D. The Citrate agar gel electrophoresis could have helped but this reagent is not available in our centre, because it is very expensive the pack available is meant for teaching purposes. Therefore other haemoglobinopathies such as HbD, though rare, might have been included in the research.
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2. The samples were collected once and only in steady state for the study. A serial longitudinal study to include when in crisis would have been more informative to determine the effect of crisis on the glomerular filtration rate.
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