CARACTERÍSTICAS

Microalbuminuria represents an early stage of chronic kidney disease in patients with diabetes mellitus and persistent microalbuminuria is an early clinical marker for the development of nephropathy in patients with DM.In this study, the prevalence of microalbuminuria was 72% in the diabetics.

This is high compared with other studies, for example Guptal et al reported a prevalence of 26.6% in 65type 2 North Indian non proteinuric patients¹¹³, while John et al reported a prevalence of 19.7% from a tertiary hospital in Velone, South India¹¹⁴, and Vijay et al reported that 15.7% had proteinuria among 600 type 2 diabetic patients studied at a diabetic centre in Chennia City^115. Studies in the white UK population revealed a prevalence of microalbuminuria of 7.9%¹¹⁶, while in Mexican American, it was 31.0%¹¹⁶, Pima Indians 20.0%¹¹⁷, Naurau 42%^118, and Hispanic American 35.0%¹¹⁹. In Nigeria, Unuigbe et al, found microalbuminuria in 50% of diabetic and 8%

of control³⁴, Erasmus reported a prevalence of 54.0% and 59% respectively in male and female diabetics³⁵, Agaba et al, in Jos, Nigeria recorded microalbuminuria in 49.5% of diabetics³⁶.

The higher prevalence seen in this study may be due to the fact that most of the patients had been diabetic for a very long time, 90(30.0%) had been diabetic for over 10years, 70(23.3%) between 6-10years and 136(45.3%) less than 5years. Most of them were on irregular treatment, some not on any medication.

More also, they have poor glycaemic control, 62(20.7%) had fasting blood sugar greater than 10mmol/l, 146(48.7%) had fasting blood sugarbetween 7 and 10mmol/l, while 92(30.7%) had fasting blood sugar less than 7mmol/l.

Method of estimation of microalbuminuria as well as ethical differences would have also played a role in giving the prevalence in this study.The variation in prevalence seen generally can be attributed to factors such as differences in population, in the definition of microalbuminuria and method of urine collection.

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However, this could also reflect true differences in the ethnic susceptibility to nephropathy. Early studies by Vijay et al from Madras have demonstrated a familial clustering of diabetic nephropathy among South Indians type 2 subjects^120. Other studies had also supported this familial clustering⁶⁸. Genetic susceptibility linked to angiotensin encoding gene as shown in Oji- Cree Indians could also be determinant for development of diabetes renal disease⁶⁹.There was significantly association between CKD and microalbuminuria (p=0.02) but this disappeared after adjusting for other confounding factors (OR, 0.65; p=0.18).

This study showed that 28% (29.2%) of diabetic patients with CKD stage 3 were normoalbuminuric. This result was similar in other reported studies, in

‘‘unrecognized prevalence of CKD’’, albuminuria was absent in 52.6% of subjects¹¹. In another study ‘‘assessing the prevalence, monitoring and management of CKD in patients with diabetes’’, nearly 2/3 (63%) of patients with diabetes with eGFR less than 60ml/min/1.73m² had normoalbuminuria¹⁰⁴. These results indicate that testing for microalbuminuria has poor sensitivity and used alone is not a sufficient screening test for renal function, thus reinforcing the need for a superior functional measurement of GFR, as produced using the eGFR. However, this study also showed that serum creatinine was within normal range in 68 (31.4%) of microalbuminuric patients and in a study ‘‘prevalence of microalbuminuria in newly diagnosed type 2 DM, serum creatinine was within normal range in microalbuminuric patients¹²¹, thus the presence of microalbuminuria will alert the clinician to prevent further renal damage by timely administration of ACEI and correction of risk factors, this is further supported by a study, ‘ In the reduction of end points in NIDDM with the angiotensin TI antagonist losartan (RENAAL) study evaluating various risk markers for the development of renal disease in patients with type 2 DM (including age, gender, cholesterol, serum creatinine, albuminuria, haemoglobin, glycated haemoglobin) albuminuria was the strongest predictor for the development of kidney disease. Patients with high base albuminuria (>

3.09/g creatinine) showed a 5.2 fold increase in renal end point (doubling of

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serum creatinine, ESRD, or death) and an 8.1 fold increase in risk for progressing to ESRD compared with the low albuminuria group (<1.5g/g creatinine)¹⁰¹.

There was significant association (p<0.001) between fundoscopic observation and the subjects with microalbuminuria status. This agree with some results which have linked retinopathy to increase urinary albumin excretion in patients with either insulin or NIDDM diabetes¹²² , it also agree with a study by Unuigbe et al which saw retinopathy in 23 % of diabetic³⁴ and with another by Arije et al which observed retinopathy in 16% of diabetics.³⁵

Many observational studies suggest that lipid may play a role in the development and progression of glomerular injury, Klein et al, ¹²³ in the study of type 1DM individual, found that higher total serum cholesterol and lower HDL cholesterol were associated with incidence of renal insufficiency.

The result of this study showed a prevalence of 34.7%, 21.3%, and 26.0%

respectively for total serum cholesterol, triglyceride, high density lipoprotein (Hypolipoproteinemia) and low density lipoprotein (hyperlipoproteinemia) across various stages of CKD.

There was significant association between CKD and triglyceride level (p=0.02), the significant persisted after adjusting for other confounding factors 2.33(1.12-4.83); p<0.05).

The pattern of dyslipidemia observed in this study was similar to other report from Saudi Arabia^124, where the incidence of dyslipidemia was noted to vary from 25-60% among diabetic patients. Studies from Nigeria reported similar findings where hypercholesterolemia was present in 43.5% and hypertriglyceridemia in 34.8% of type 2 DM^125.

The result of this study also agrees with reports from the DCCT/EDIC¹²⁵, Cohort group study where the lipid profile relating to albumin excretion rate (AER) is elevated TG, TC, and LDL-C. This may be related to reduce metabolic processes and impaired excretion of metabolic waste products worsened by poor glycermic control, insulin resistance and poor control of hypertension observed in this groups of patients.

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The potential etiologic role of dyslipidemia in CKD has been earlier elucidated.

Thomas et al in their work noted the link between serum lipids and progression of CKD (DN), this relationship was independent of glycemic and blood pressure control in a population of intensively treated patient followed for over 7-8years¹²⁶. The nature of the lipid interaction was also noted to be different at different stages of renal disease, in normoalbuminuria patients progression was linked to the LDL-C, in microalbminuria subjects, progression was linked to the TG content of VLDL and IDL patients, while for macroalbuminuric patients, progression to ESRD was associated with LDL size but not with triglyceride linked indexes. This observation is consistent with findings of Conrad et al¹²⁷, who reported that TG and cholesterol had differing effects on progression of nephropathy depending on the duration of diabetes. This study however could not assess a casual relationship because it was not a prospective study, but it was noted that dyslipidemia was more prevent in CKD stage2.

Triglyceridemia showed a significant association with CKD in this study and it has been shown that hypertriglyceridemia is regarded as an independent risk factor for developing proteinuria. Metcalf et al reported that the degree of albuminuria showed piecewise log linear relationship with hypertriglyceridemia and hypercholesterolemia, and a negative piecewise linear relationship with HDL-C^128, on the contrary, Tozawo et al, reported that hypertriglyceridemia was a significant predictor of proteinuria, but hypercholesterolaemia and low HDL-C were not, within the 3years follow-up period¹²⁹.

The effect of hyperlipidaemia on progression of renal dysfunction produced more complex results. Shaeffner et al¹³⁰ reported that the relative risk for elevated creatinine was 1.77 for hypercholesterolaemia and 2.116 for low HDL-C in male subjects. However, Mutner et al¹³¹, reported that the relative risk for elevated creatinine was 1.65 for hypertriglyceridemia and 2.13 for low HDL-C, but that hypercholesterolaemia was not a significant risk factor.

Hypertension is an important risk factor in chronic kidney disease. In this study, the mean systolic blood pressure was 122.97+ 13.4 compared to 114.+

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8.04 in the control group, this was statistically significant (p<0.001). The mean diastolic blood pressure in the diabetic group was 76.61+ 7.27 higher than the mean in the non diabetic which was 72.28+5.88, though this was not statistically significant.

The prevalence of systolic and diastolic hypertension in the diabetic subjects was 21.6% and 12.8% respectively. It is likely that more patients would have had higher values of blood pressure if no intervention was made. This study is similar to other studies. Mogensen et al⁷³, observed a prevalence of 19% in type 1 diabetics, while a prevalence of 39% was seen in type 2 diabetics.⁷⁴ In Nigerian studies, 41% was seen in Ilorin^34, while Alebiosu37 found 79.2% of diabetics hypertensive.

An association between subsequent development of nephropathy and higher systemic pressure, particularly if it is in the hypertensive range, has been observed in prospective studies¹³².

The effect of antihypertensive therapy is noted as 57.6% of the patients were on combination of antihypertensive therapy (Diuretic, ACEI, ARB, CGB, and others).It is possible that the use of ACEI in some of these patients reduced the number of patients who developed microalbuminuria and chronic kidney disease.

The benefit of blood pressure control includes decreasing risk of cardiovascular mortality, retarding progression of renal disease and other neurological complications. Long term tight BP control usually to a target of less than 130/85mmHg in type 2 diabetes is a highly effective strategy in reducing the risk of cardiovascular complication, progressive proteinuria and decline in renal function and is now embodied in many guidelines on hypertension and DM management. In the multiple regression modules, there was significant use of ACEI among subjects with DM, this finding may be due to the fact that majority of the patient with DM were placed on ACEI to delay their progression to ESRD. Majority of clinical studies showed, by either univariate or multivariate analysis that raised blood pressure is associated with a faster rate of progression of CKD¹³. This study could not assess the role of blood pressure control in the progressive of CKD because it is a

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sectional study and the patients were not followed up. Nevertheless, intervention studies in proteinuric diabetes and proteinuric non diabetics have shown that the rate of decline in CKD is almost minimized by a reduction in mean arterial pressure by either an ACEI or ARB to levels around 90mmHg (BP 125/75)¹³. The National Kidney Foundation (NKF) task force has suggested different blood pressure targets depending on the stage of kidney disease, in CKD stages 1-4 with proteinuria less than 1g/day, recommended target is less than 130/85mmHg, and with proteinuria greater than 1g/day, a blood pressure of 125/75mmHg is recommended¹³.

Obesity is a known risk factor proteinuria⁸⁵. The renal effects of obesity include an increased GFR, increased renal blood flow, and hypertrophy and weight loss of obese subjects ameliorates the abnormalities as well as reducing urinary excretion.

In the study, the prevalence of obesity was 24.7%. The mean body mass index was 26.78+4.46 compared to 25.36+3.14 in the control subjects which was statistically significant (p<0.01). This study agrees with a report by Idogun.et al¹³³ in Nigeria which reported high BMI among DM patient compared to normotensive and hypertensive diabetics with normal renal function.

Although in this study, the unadjusted logistic regression analysis did not show statistical association between CKD and BMI, multivariate analysis of the data of the Prevention of Renal and Vascular End-stage Disease (PREVEND) study showed that the BMI is independently associated with urinary albumin excretion¹³⁴.

The higher value of BMI found in this study could in part be related to the fact that majority of the patients were type 2 diabetes where obesity is known to play an etiologic role, also the altered metabolism and circulation changes in obesity could affect and worsen renal function.

The effect of obesity in developing or worsen CKD remains controversial. Iseki et al¹³⁵ reported that obesity was not a major factor for development of ESRD in a 10-year follow-up period; Recently, Fox et al¹³⁶ and reported that obesity

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was an independent risk factor for development of renal dysfunction following 17 – 18.5years follow-up.

Consequently it is possible that obesity might be a significant relative risk for renal dysfunction after a longer follow-up duration in both genders.

Age was found to be a key predictor of CKD prevalence during an analysis of data from a subpopulation of 15,625 individuals enrolled in the NHANESIII¹⁵. This analysis confirmed the frequent occurrence of CKD also showed that there was a progressive decrease in GFR with increasing age. In particular, 10.8% of individuals older than 65years, but with no evidence of HTN or diabetic had CKD stage III or more.

In this study, the unadjusted logistic regression showed statistically significance between age and CKD (OR, 1.03; p< 0.001) and indicated that for over 1 year increased in age, the risk for CKD also increased by 1.03times.

This study agrees with other reports, Mulder.et al¹³⁷ reported a substantially reduction in kidney function with ageing, and it was earlier elucidated by Rowe et al¹³⁸ that kidney function declines naturally with increasing age.

Gall.et al¹³⁹ found that increasing age was significantly associated with abnormally increasing urinary albumin excretion rate in both univariate and multivariate analysis. However, Klein et al ¹⁴⁰ found that younger age at diagnosis was significantly associated with decrease in the eGFR in patients with type I DM.

Smoking is an independent risk factor for the development of CKD. In this study, smoking was not statistically associated with CKD either for current smokers (p=0.12) or former smokers (p=0.11). It was not significant in this study probably because of the gender related history of smoking (only males had positive history of smoking both in diabetics and control). This gender prediction to smoking was similar to the findings of Unuigbe et al ³⁴, where smoking was found only in male diabetics. It has earlier been documented that there is low prevalence of smoking among African diabetics and especially among female diabetic compared with their European counterparts.

This is probably due to the socio-cultural practices in African where smoking is a taboo among the female gender. This is further confirmed in a study

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prevalence of CKD in Nigeria population practice where smoking was found not be associated with CKD and it was stated that smokers might have not wanted to be identified because in Nigerian communities it is seen as an antisocial habit¹⁴¹. However, a study^142, showed that it increases the risk of proteinuria and renal dysfunction in both genders and that being an ex-smoker was not a risk factor for developing proteinuria and renal dysfunction.

Consequently, cessation of smoking has a favourable effect on preventing the development of CKD.

The effects of alcohol consumption on development of CKD remain controversial. In this study, 68(22.7%) of the patients were documented as current alcohol users, though there was no significant association alcohol consumption and CKD both for current and former users.

Knight et al¹⁴³ reported that moderate alcohol intake had no substantial adverse effect on renal function in women, whereas Perneger et al¹⁴⁴ reported significantly increases odds of developing ESRD in subjects who drank more than 2 alcohol beverages per day. Another study showed that alcohol intake of less than 20g/dl reduced risk of developing renal dysfunction in both gender. The favourable effect was diminished after ethanol intake of more than 20g/day.

In one Nigerian study¹⁴¹ alcohol was not found to be a risk factor for CKD, also Ulasi et al found no association¹⁴⁵.This study agree with the above and further agree with report of Vuppturi and Sandler who reported no significant association with alcohol consumption¹⁴⁶.

Glycaemic control in this appeared sup-optimal with 20.7% of subjects having average plasma fasting blood sugar level greater than 10.0mmol/l, 48.7% had between 7-10mmol/l, and 30.7% having less than 7mmol/l. This is confirmed by the fact that American Diabetes Association recommended that treatment should aim at achieving target preprandil glucose of 80-120mg/dl (4.4-6.6mmol/l whole blood) or 90-130mg/dl (5.0-7.2mmol/l whole blood or 110-150mg/dl (6.1-8.3mmol/l plasma) and HbAIC (glycated haemoglobin of less than 7%)⁹⁰.

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Poor glycemic control is known to be a risk factor for initiation and progression of diabetic complication including diabetic nephropathy. The United Kingdom Prospective Diabetes study (UKPDS) of patients with type 2 diabetes found that fewer patients treated with intensive versus conventional therapy had progression of microalbuminuria (27 versus 39%) and proteinuria (7 versus 13%) over 15years of follow-up¹⁴⁷. The Diabetes Control and Complication Trial (DCCT) compared conventional (mean achieved glycosylated HbA1c 9.1%) with intensive treatment (mean achieved HbA1c 7.3%) in 1,441 type 1 diabetic patients. In the combined Cohorts, intensive treatment reduced the development of microalbuminuria and clinically albuminuria by 39% and 56% respectively⁸¹.

Targeted blood sugar levels can be achieved using oral hypoglycemic agents, insulin or combination of both, in this study, a greater percentage used oral hypoglycemic agent alone (24.0%), this may due to the fact they are mostly type 2 diabetics.