Continuous Functions
3.2 Continuous functions Note: 2–2.5 lectures
Chronic kidney disease is a common disease with a rising incidence mainly driven by ageing and increased survival from cancers and major cardiovascular accidents70. It is associated with numerous complications, one of which is dyslipidemia. Dyslipidemia known as a traditional risk factor is associated with increased cardiovascular risk in CKD patients. The spectrum of dyslipidemia in patients with CKD is distinct from that in the general population.70,71 This disorder involves all classes of lipoproteins, and it occurs in all stages of CKD, including mild disease, in patients without supportive treatment, and in patients on dialysis or after kidney transplantation.70,72
Plasma lipids and lipoprotein profiles in CKD are changed quantitatively, qualitatively, structurally and functionally74 and this is usually influenced by progressive renal loss.
In the earliest stages of primary kidney disease dyslipidemia occurs, with a decline in renal function, and the lipid profile is altered initially in terms of reduced high-density-lipoprotein (HDL) (due to reduced plasma levels of ApoA-Ⅰ and ApoA Ⅱ, primary proteins forming HDL, higher concentrations of Apo-B and to lecithin-cholesterol-acyltransferase enzyme, LCAT, deficiency) and moderately increased triglycerides (TG) serum concentrations, due to impaired clearance.74-77
The results of this study agree with the documented evidence that dyslipidemia is prevalent in CKD with the earliest dyslipidemia being a reduction in HDL-C levels. Using the WHO16 cut off values for hypercholesterolemia, 94.4%
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of the study population had dyslipidemia which was higher than that observed in controls 46.9% (p<0.01).
HDL-C was noted to be the earliest affected component of the lipid profile accounting solely for the dyslipidemia observed amongst cases in CKD stage 1.
In stage 1, 33.3% of cases had dyslipidemia and this was reduced HDL-C.
Elevated Tg was also noticed in the earlier stages of CKD; CKD stage 2 with a prevalence as high as 66.7%.
The prevalence of dyslipidemia in the different components of the lipid profile in this study showed that 73.1% had reduced HDL-C, 66.2% had hypertriglyceridemia, 25.6% had hypercholesterolemia, and 25% had elevated LDL-C. These prevalence values were higher than those observed in the control group with 11.2% having reduced HDL-C, 26.9% hypertriglycidemia, 18.1%
Results of this study also differed from that reported by Khalid et al in which elevated Tg had a prevalence of 46%, reduced HDL-C 16% and elevated total cholesterol 16%, however the mean values of the different components
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were lower in this study (153.29 ± 44.52mg/dl, 33.69 ± 12.09 mg/dl and 170.90 ± 47.84 mg/dl for triglyceride, HDL-C and total cholesterol respectively) when compared to that reported by Khalid et al in which mean values were 225.87 mg/dl, 30.62 mg/dl and 264.5 mg/dl for triglyceride, HDL-C and total cholesterol respectively.78 This may also be due to the fact that the study by Khalid et al was carried out in a small population – 50 CKD patients who were not on dialysis.
Reduced HDL-C levels and increased triglyceride rich lipoproteins are the major lipid abnormalities. Reductions in plasma concentrations of apoprotein (Apo) A-I and Apo A-II are thought to play a large role in the low HDL cholesterol (HDL-C) levels. ApoA-I and ApoA-II are mandatory components of the HDL particle. Patients with CKD have been shown to have reduced genetic expression of these apoproteins at sites of HDL production in the liver. Another factor contributing to low HDL-C levels is the profound inflammation present in these patients. Chronic inflammation results in decreased albumin levels.
Albumin serves as a carrier of free cholesterol from the peripheral tissues to HDL, and a reduction in albumin may contribute to reduced HDL-C levels. The increased plasma triglyceride levels can be explained in part by significant increases in plasma ApoC-III levels. Apoprotein C-III is a potent inhibitor of the enzyme lipoprotein lipase, which is responsible for the degradation of triglyceride-rich particles.43
A plasma concentration of LDL-C is usually normal and only occasionally elevated in ESRD patients.
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respectively.
In this study, the most prevalent pattern of dyslipidemia was the combination of reduced HDL-C and elevated triglycerides with a prevalence of 33.1%. This finding is in keeping with that reported by Atman and Ritz et al in which the most prevalent dyslipidemia combinations were HDL-C and triglycerides.68 The next most common was reduced HDL-C alone occurring in 23.8%. Dyslipidemia affecting all the components of the lipid profile followed in line with a prevalence of 13.3%. Other combinations contributed to the minority with elevated total cholesterol and the combination of elevated LDL-C and triglycerides accounting for just 0.7% each.
In addition to the quantitative abnormalities seen in CKD, the composition of plasma lipoproteins is altered in CKD.34 The cholesterol content of VLDL is relatively increased and its triglyceride content is relatively reduced in CKD. In contrast, CKD results in a relative reduction in cholesterol and relative increase in the triglyceride content of LDL. Similarly, cholesterol ester and free cholesterol content of HDL are consistently reduced, whereas its triglyceride content is elevated, in CKD. The above compositional abnormalities are present in nearly all patients with mild to severe renal insufficiency (even those with normal plasma
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total cholesterol and triglyceride levels) and point to redistribution of cholesterol from HDL to VLDL and IDL and defective removal of triglycerides from LDL and HDL particles. It should be noted that in many instances development and progression of renal insufficiency are accompanied by heavy proteinuria, leading to superimposition of nephrotic dyslipidemia 80 on CKD-induced lipid disorders. In these circumstances, plasma total cholesterol and LDL cholesterol concentrations are frequently elevated. However, with progression to ESRD and the consequent decline in proteinuria (reduced filtered protein), a lipid profile typical of CKD emerges. This study however did not reveal proteinuria as an independent predictor of dyslipidemia, using the multiple logistic regression.
Despite the neutral effect of dialysis on serum lipid profile, certain dialysis-related parameters may significantly affect lipoprotein metabolism and modify the features of dyslipidemia in HD patients. Thus, it has been shown that the use of high-flux polysulfone or cellulose triacetate membranes instead of low-flux membranes is accompanied by a significant reduction in serum triglyceride levels as well as by an increase in apolipoprotein A1 and HDL-cholesterol levels. (79,80) This improvement could, at least in part, be attributed to an increase in the apolipoprotein C-II/C-III ratio which increases the activity of lipoprotein lipase and facilitates the intravascular lipolysis of triglyceride rich-lipoproteins.81 In addition, the type of dialysate may also significantly affect the serum levels of lipoproteins in HD patients. Indeed, it has been shown that the use of bicarbonate dialysate may result in higher HDL-cholesterol concentrations than the use of acetate dialysate.82 Another factor that can potentially affect lipoprotein metabolism in HD
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patients is the repeated use of heparin as an anticoagulant. Heparin releases lipoprotein lipase from the endothelial surface and thus its chronic use may result in lipoprotein lipase depletion and defective catabolism of triglyceride-rich lipoproteins. In this study however, among dialyzing and non-dialyzing cases, reduced HDL-C was the commonest dyslipidemia observed; was present in 76.1% and 66% respectively and this difference was not statistically significant.
Elevated triglyceride was the next most common in dialyzing and non-dialyzing cases, present in 69% and 59.6% respectively. This also had no statistically significant difference.
The mean fasting blood glucose was higher in cases than control (105.88
± 32.27 vs. 92.35 ± 9.86 mg/dl. This can be accounted for by the fact that DM contributed significantly to the aetiology of CKD among cases.
Mean PCV was lower in cases than controls (23.50 ± 6.25 vs. 38.44 ± 3.14%). This again is expected as anaemia is one of the common complications of CKD setting in as early as in CKD stage 3.
Mean estimated GFR was lower in cases than controls, 26.26 ± 18.01ml/min as against 96.41 ± 16.54 ml/min as is expected (p<0.01), with eGFR in non-dialyzing cases being 45.719 ± 23.52 and in dialyzing cases 22.42 ±8.51 (p<0.01).
In this study, CGN (35.6%) was the leading cause of CKD, followed by hypertension (33.1%) and DM in 20.6% of cases. These findings are in keeping with previously documented literature. Chijioke et al at Ilorin reported CGN to be
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the leading cause of CKD with a prevalence of 50%, followed closely by hypertension 44.2%.
The frequency of the different CKD stages in this study revealed very few cases in stages 1 and 2, 1.9% respectively of case population. This may be due to the fact that patients in our environment prefer to seek alternative methods of therapy rather than orthodox medicine and then present late to us after all else have failed in any disease condition.83Although 13.1% of cases in this study were in CKD stage 5, as much as 70.6% of cases were on dialysis. This can be explained by the fact that most cases present in renal emergencies warranting dialysis and so may not necessarily be in end-stage kidney disease. The duration of dialysis noted among cases on HD ranged from 1 to 12 months with a majority having been on HD for a month (49.6%) with cases on dialysis accounting for a minority. Only 0.9% had being on HD for 12 months. Inability to sustain HD due to the financial constraints in our environment is the major reason for this. The mode of management (conservative or dialysis) had no effect on the prevalence or pattern of dyslipidemia in the case population.
In this study, the prevalence of dyslipidemia was observed to progressively increase from stage 1 through to stage 4 and then reduced very slightly in stage 5. Stage 1 had a prevalence of 33.3%, stage 2 had 66.7%, stage 3, 4 and 5 had prevalences of 94, 2%, 97.5% and 95.2% respectively. This was statistically significant. The slight reduction in the prevalence of dyslipidemia in stage 5 may be accounted for by the fact that virtually all the cases in this group are undergoing hemodialysis which has been noted to alter the lipid profile in this
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group of CKD patients. However, using the multiple logistic regression the estimated GFR which indicates the progression of CKD was not found to be an independent predictor of dyslipidemia. And neither was proteinuria. This differs from that reported by Keane et al who in his report from available clinical data suggested a relationship between progressive, proteinuric renal disease and abnormal lipid metabolism. These lipid abnormalities might contribute not only to the increased prevalence of cardiovascular disease in these patients, but also to the progressive loss of renal function84
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CHAPTER SIX
CONCLUSION AND RECOMMENDATION