Indian Journal of Nephrology Indian J Nephrol 2001;11: 6-11

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1 6 Indian Journal of Nephrology Indian J Nephrol 2001;11: 6-11 ARTICLE Prevalence of microalbuminuria in essential hypertension: A study of patients with mild to moderate hypertension. S Jalal *, FA Sofi **, MS Alai **, MA Sidiqqi***, MA Bhat #, KA Khan #, VM Jan #, NA Lone**, HA Rather**, * Prof. & Head, Deptt. of Cardiology, ** Senior Resident, *** Professor, Deptt. of Immunology, # Lecturer, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, Kashmir. Abstract To determine the frequency of increased urinary albumin excretion (UAE) in essential hypertension and to establish whether this abnormality is associated with deranged renal function, we measured UAE in a group of 288 patients with essential hypertension and 240 normal subjects. Mean arterial pressure (MAP) in patients with essential hypertension and control subjects was ± 5.82 and ± 5.66 mmhg respectively (P<0.001). Mean UAE was 5.35 ± 0.84 mg/24 hr. in normal subjects and ± 4.91mg/24 hr. in patients with essential hypertension (P<0.001). One hundred and eight (37.5%) patients with essential hypertension manifested microalbuminuria (UAE> 30mg/24hr.) and had an average UAE of ± mg/24hr. versus ± 6.53mg/24 hr. in normo-albuminuric patients (P< 0.001). MAP and creatinine clearance in patients with micro-albuminuria and normoalbuminuria were comparable (122.3 ± 6.20 versus ± 5.66 mmhg; ± 6.75 versus ± 8.74ml/min; P>0.1 and >0.5 respectively). We noted a UAE of 5.35,26.61 and mg/24 hr. in normal subjects, patients with mild and moderate essential hypertension respectively (P <0.001); signifying an increasing trend in UAE with the presence and severity of essential hypertension. Long term prospective studies are needed to establish whether an increase in UAE may predict future nephrosclerosis in essential hypertension. Key words : microalbuminuria, essential hypertension, prevalence, severity Introduction Hypertension is a major public health problem all over the world. The incidence of hypertension in India is 5 15% in the adult population against 10 12% in the West. 1 Essential hypertension produces clinical proteinuria and a significant reduction in renal function in 5 15% of patients. 2 The advent of more sensitive methods to quantitate the urinary albumin excretion (UAE) has revealed higher frequency (25 100%) of microalbuminuria in patients with hypertension than in normotensive population 3,4,5. This wide variability in the incidence of micro-albuminuria in these studies may be related to the severity of hypertension, selection criteria, racial difference and, in some cases, to smaller number of patients studied. Address for Correspondence: Prof. S. Jalal Head. Deptt. of Cardiology & Dean Medical faculty. Sher-i-Kashmir Institute of Medical Sciences,Soura, GPO Post Bag No. 27 Srinagar Several epidemiological studies have shown that proteinuria as well as micro-albuminuria are independent predictors of cardiovascular morbidity 6,7 and mortality in patients with essential hypertension. Morever, 25% of patients with end stage renal disease have hypertension as the primary diagnosis 2. It becomes of paramount importance to study UAE and progression of nephropathy in hypertensive patients. The purpose of this study was to evaluate the frequency of microalbuminuria in a large population with mild to moderate hypertension and its relation with severity of hypertension and renal function. Material and Methods This study was conducted at outpatient clinic of Cardiology and General Medicine department of SK. Institute of Medical Sciences, Srinagar, Kashmir. Three hundred patients with mild to moderate hypertension in the age range of years with diastolic blood pressure (DBP) consistently ranging between 95 and 115 mmhg during the three subsequent visits to the outpatient clinic and creatinine clearance greater than

2 Indian J Nephrol 2001;11: 6-11 Microalbuminuria in essential hypertension 7 80 ml/min/1.73m 2 were included in the study. Antihypertensive drug therapy was withheld at least for four weeks prior to the entry into the study in patients already on treatment. The diagnosis of secondary hypertension was adequately excluded in an appropriate manner with the regular laboratory analyses. Renal cause for hypertension was excluded by finding of normal urinalysis, serum electrolytes, serum creatinine, creatinine clearance and renal ultrsonography, and when clinically indicated, by magnetic resonance angiography. Patients with clinical or laboratory evidence of hepatic, renal, thyroid or any other major disease like diabetes mellitus, females on birth control pills and patients with doubtful history of essential hypertension were excluded from the study. A control group consisting of 240 healthy volunteers (normotensive), age and sex matched were also entered into the study. They were thoroughly screened for any disease especially hypertension, renal disease and diabetes mellitus. All patients and control subjects were encouraged to continue their regular diet and to refrain from stressful physical activity on the day of urine collection. During the third outpatient clinic visit, each patient and control subject brought his/her previous 24 hours urine collection for UAE and creatinine clearance estimation. Blood and urine creatinine were measured by autoanalyser. Urine for estimation of microalbuminuria was stored at C till processing of samples. UAE was estimated by an immunoturbidometry method which permits the quantitative determination of albumin by immunoprecipitin analysis using an automated Biochemistry Analyser (Hitachi 704). Microalbuminuria was defined as UAE between mg/24 hours 8. Arterial blood pressure was measured by mercury sphygmomanometer after 5 minutes of rest; the values reported represented the average of three consecutive measurements taken over a 15 min period. Mean arterial pressure was calculated as diastolic blood pressure plus one third of pulse pressure. Statistical analysis was performed by standard methods for rates and proportions; chi square test, paired t -test, un-paired t test, one- way analysis of variance. A two tail p-value was used for calculating statistical significance. A p value of < 0.05 was taken statistically significant. Observations Among the hypertensive group, 12 patients were excluded from the study because of their poor Table 1 : Clinical characteristics of study subjects. S.No. Parameter Hypertensive group Control group P- value n = 288 n = Age (years) > 0.05 Mean + S.D (44-64) (45-64) 2. Sex M : F 156 : : 112 > BMI (kg/m2) > 0.1 Mean + S. D ( ) ( ) 4. Smokers No.(%) 114 (39.58) 84 (35) > 0.25 Males No. (%) 78 (68.42) 60 (71.43) Females No.(%) 36 (31.58) 24 (28.57) 5. Blood pressure (mmhg) SBP; Mean + SD < ( ) ( ) DBP; Mean + SD < (96-119) (70-82) MAP; Mean + SD < ( ) ( ) BMI : Body mass index SBP : Systolic blood pressure DBP : Diastolic blood pressure MAP : Mean arterial pressure. Figures in parenthesis indicate range, unless specified.

3 8 Indian Journal of Nephrology Indian J Nephrol 2001;11: 6-11 compliance; thus only 288 patients completed their follow up. Among the hypertensive patients, 258 (89.58%) patients had never received antihypertensive drugs prior to the study and the remaining 30 (10.42%) patients had stopped the drugs at least four weeks prior to the study. Mean age of these patients was ± 5.56 years. One hundred and fiftysix (54.17%) of these patients were males. The hypertensive patients and control subjects were of comparable age, sex and BMI. Mean arterial pressure in hypertensive patients was ± 5.82 mmhg against ± 5.66 mmhg in control group (P < 0.001) [Table 1]. Serum creatinine, urea, uric acid (although in normal range) were significantly higher in hypertensive group than in controls (P < 0.001). Mean creatinine clearance, although in normal range, was significantly lower (P < 0.001) in hypertensive patients than in normotensive subjects. The hypertensive patients manifested a mean urinary alumin excretion (UAE) of ± 4.91 mg/24 hour, which is significantly higher (P < 0.001) than that of control group (Table 2). One hundred and eight (37.5%) patients in hypertensive group had microalbuminuria while none among normotensive group had it. Comparison of various parameters between microalbuminuric and normoalbuminuric hypertensive patients did not reveal any significant difference except in their UAE rate and chest X-ray. Out of 108 microalbuminuric patients, 45 (41.66%) had hypertensive retinopathy (grade I in 14 and grade II in 31 patients; Keith Wagener Barker classification) while in normoalbuminuric group, 50 (27.78%) patients had hypertensive retinopathy (grade I in 36 and grade II in 14 patients) [P> 0.05]. Fortytwo (38.89%) patients in microalbuminuric group had abnormal chest x-ray in the form of cardiomegaly compared to 48 (26.67%) patients in normoalbuminuric group (P < 0.05) [Table 3]. Out of 288 hypertensive patients, 78 (27.08%) had mild and 210 (72.92%) patients moderate hypertension. Microalbuminuria was present in 24 (30.77%) and 84 (40%) patients with mild and moderate hypertension Table 2 : Laboratory characteristics of study subjects. S.No. Parameter Hypertensive group Control group P- value n = 288 n = Haemoglobin (gm/dl) > 0.5 ( ) ( ) 2. Blood Glucose (mg/dl) > 0.25 (66-100) (76-101) 3. Serum cholesterol (mg/dl) < (90-260) (90-208) 4. Serum uric acid (mg/dl) < ( ) ( ) 5. Serum proteins (gm/dl) > 0.1 ( ) ( ) 6. Serum albumin (gm/dl) > 0.1 ( ) ( ) 7. Serum urea (mg/dl) < (18-40) (22-40) 8. Serum creatinine (mg/dl) < ( ) ( ) 9. Serum soduim (meq/l) > 0.25 ( ) ( ) 10. Serum potassuim (meq/l) < ( ) ( ) 11. Creatinine clearance < (ml/min) ( ) ( ) 12. Urinary albumin * * < excretion (mg/24 hr.) ( ) ( ) 13. Patients with Micro - albuminuria No. (%) 108 (37.50) Nil Values are expressed mean ± SD, unless specified; Figures in parenthesis indicate range *Standard error of mean (SEM)

Indian J Nephrol 2001;11: 6-11 Microalbuminuria in essential hypertension 9 Table 3 - Characteristics of microalbuminuric and normoalbuminuric hypertensive patients. S.

4 Indian J Nephrol 2001;11: 6-11 Microalbuminuria in essential hypertension 9 Table 3 - Characteristics of microalbuminuric and normoalbuminuric hypertensive patients. S.No Parameter Microalbuminuric gr. Normoalbuminuric gr. P-value n = 108 n = MAP (mmhg) > Serum creatinine >0.3 (mg/dl) 3. Serum cholesterol >0.05 (mg/dl) 4. Serum albumin >0.1 (gm/dl) 5. Cr. Cl (ml/min) > UAE (mg/24hr.) < Abnormal CXR. 42 (38.89) 48 (26.67) <0.05 No. (%) 8. Abnormal EKG 30 (27.78) 36 (20) >0.1 No. (%) MAP : Mean arterial pressure; Cr. Cl : Creatinine clearance. UAE : Urinary albumin excretion. Values expressed as Mean + S.D, unless specified CXR : Xray chest respectively (P > 0.1). Mean UAE was 5.35 ± 0.84 mg, ± 6.82, ± 6.22mg/24hr. in normotensive subjects, patient with mild hypertension and moderate hypertension respectively. A positive correlation was found between severity of hypertension and UAE (P< 0.001) [Fig.1]. Discussion The conventional method of detecting renal damage in hypertensive patients which include the measurement of blood urea nitrogen creatinine and proteinuria, are relatively insensitive and only show abnormalities when the disease process is advanced. There has recently been considerable interest in the quantitative measurement of albuminuria to detect subtle effects of hypertension on the kidney. The term micro-albuminuria was first used by Viberti et al to describe the subclinical elevation of urinary albumin ( mg/24 hours) in patients with diabetic nephropathy 8,9. In the present study, we documented microalbuminuria in 37.5% of patients with hypertension, possibly pointing toward the subclinical and subtle changes occurring in the glomeruli of these patients. The prevalence of microalbuminuria is not well established and it may vary from 15 Fig. 1 - Showing increasing trend of UAE with the presence and severity of hypertension (p< 0.001).

5 10 Indian Journal of Nephrology Indian J Nephrol 2001;11: % 2,5,10. This variation is probably due to difference in the age, race, severity of hypertension and coexistent renal disease in these study populations. We studied 288 patients with hypertension and 240 healthy, normotensive control subjects drawn from the same general population with similar demographic and clinical characteristics and found that urinary albumin excretion rates were significantly greater in hypertensive patients than in control subjects (P < 0.001). which is consistent with previous studies 2,11. In addition to this, hypertensive patients had significantly higher levels of urea, creatinine, uric acid and lesser levels of creatinine clearance compared to control subjects (P < 0.001); although, all these values fell well in the normal laboratory range. These differences are again, probably the result of subclinical ultrastructural changes going on in the glomeruli of these hypertensive patients due to ill effects of persistently elevated blood pressure over some period. We did not find any difference in the prevalence of microalbuminuria between mild and moderate hypertensive patients (P> 0.1). However, an increasing urinary albumin excretion rate was noted with presence and severity of hypertension which goes with the previous studies 4,10,12. We failed to document any significant difference in creatinine clearance between microalbuminuric and normo-albuminuric hypertensive patients; however, we excluded patients with significant decrease in renal function. It is conceivable that patients with essential hypertension and more advanced nephrosclerosis and renal insufficiency might display greater amounts of UAE. Several studies have indicated that the presence of proteinuria or microalbuminuria is an independent predictor of cardiovascular morbidity and mortality in patients with essential hypertension We could demonstrate cardiomegaly (roentegenographically) in significant number of patients with microalbuminuria compared to hypertensive patients with normoalbuminuria. Proteinuria has been shown to represent a significant predictor of progressive renal failure in virtually all forms of glomerulonephritis 19,20. Viberti 9, Mogensen 21 and Parving 12 have shown that the presence of microalbuminuria in early phases of the disease is an important independent predictor of progressive renal failure in patients with insulin and non-insulin dependent diabetes mellitus. No long-term studies have been performed to ascertain whether microalbuminuria can be used as a predictor of progressive deterioration in renal function in patients with essential hypertension. It is of interest, however, that elevated UAE has been found to be associated with more severe hypertension in many studies including our own study 4,10,12. Obviously further prospective studies are needed to assess the predictive value of microalbuminuria in essential hypertension. In summary, our data suggest that microalbuminuria is prevalent in 37.5% of patients with essential hypertension and has a positive correlation with the severity of hypertension and thus may be an early marker for end-organ damage susceptibility. Reference 1. Datey KK, Kumar M, Goyal BK. Recent advances in the management of hypertension. Indian Heart Journal 1982; vol. 34, No. 6 : Bigazzi R, Bianchi S, Campese VM, Baldari G. Prevalence of microalbuminuria in a large population of patients with mild to moderate hypertention. Nephron 1992; 61 : Parving HH, Jensen HE, Mogensen CE, Evrin PE. Increased urinary albumin excretion in benign essential hypertension. Lancet 1974 ; 1 : Losito A, Fortunati F, Zampi I, Del Favero A. Impaired functional reserve and albuminuria in essential hypertension. Br Med J 1988 ; 1 : Giaconi S, Levanti C, Fommei E, Innocenti F, et al. Microalbuminuria and casual and ambulatory blood pressure monitoring in normotensives and in patients with borderline and mild hypertension. Am J Hypertens 1989; 2 : Bianchi S, Bigazzi R, Baldari G, Campese VM. Microalbuminuria in patients with essential hypertension. Effect of several anti hypertensive drugs. Am J Med 1992; 93 : Yudkin JS, Forrest RD, Jackson CA. Microalbuminuria as a predictor of vascular disease in non-diabetic subjects. Lancet 1988; 2 : Ljungman S. Microalbuminuria in essential hypertension. Am J Hyperten 1990 ; 3 : Viberti GC, Hill RD, Jarrat RD, Argyropoulos A, Mahumud U, Keen H. Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet 1982 ; 1 : Pedersen EP, Mogensen CE. Effect of antihypertensive treatment on urinary albumin excretion, glomerular filtration rate and renal plasma flow in patients with essential hypertension. Scand J clin lab Invest 1976; 36: 100 : Gerber LM, Shmukler C, Alderman MH. Differences in urinary albumin excretion rate between normotensive and hypertensive, white and non-white subjects. Arch Intern Med 1992;152 : Parving HH, Oxenboll B, Svendsen PA, Christiansen JS, Andersen AR. Early detection of patients at risk of developing diabetic nephropathy: A longitudinal study of urinary albumin excretion. Acta Endocrinol 1982 ; 100:

6 Indian J Nephrol 2001;11: Lewin A, Blaufox D, Castle H, Entwisle G, Langford H. Apparent prevalence of curable hypertension in the hypertension detection and follow up programme. Arch Intern Med 1985; 145 : Samuelsson O, Wilhelmsen L, Elmfeldt D, Pennert K, Wedel H, Wikstrand J, Berglund G. Predictors of cardiovascular morbidity in treated hypertension: Results from the primary preventive trial in Goteborg, Sweden. J Hyperten 1985 ; 3 : Wolf FW, Lindeman RD. Effects of treatment on hypertension: Results of a controlled study J Chronic Dis 1966 ; 19 : Bulpitt CJ, Beevers DG, Butler A. et al. The servival of treated hypertensive patients and their cause of death: A report from the DHSS hypertensive care computing project (DHCCP). J Hypertens 1986 ; 4 : Microalbuminuria in essential hypertension Kannel WB, Stamfer MJ, Castelli WP, Verter J. The prognostic significance of proteinuria: The Framingham Study. Am Heart J 1984 ; 108 : Pedrinelli R, Giampietro O, Carmassi F, Mellillo E. et al. Micro- albuminuria and endothelial dysfunction in essential hypertension. Lancet 1994 ; 344 : Neelakantappa K, Gallo GR, Baldwin DS. Proteinuria in IgA nephropathy. Kidney Int 1988 ; 33 : Maschio G, Oldrizzi L, Rugin C, Valvo E, Lupo A, Loschiavo C, Tessitore N, Fabris A, Gammoro L.Factors affecting progression of renal failure in patients on longterm dietary protein restriction. Kidney Int 1983 ; 32 (suppl.22) : Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity onset diabetes. N Eng J Med 1986 ; 310 :

elevated urinary albumin levels have been found to be a predictor of cardiovascular disease in some studies. 5 9

elevated urinary albumin levels have been found to be a predictor of cardiovascular disease in some studies. 5 9 AJH 1998;11:1321 1327 Assessment of a New Dipstick Test in Screening for Microalbuminuria in Patients With Hypertension Linda M. Gerber, Karen Johnston, and Michael H. Alderman The prevalence of elevated