The data from a 10-years prospective study among 85 boys and 64 girls, mean age 14,1 ±3,8 years with mean diabetes duration 8,45 ±3,7 years are analyzed. Using a complex prospective screening we found the frequency of microalbuminuria (MAU) and estimated some parameters of progression of the renal damage. The patients were divided into 3 groups: no MAU, with MAU and with clinical signs of nephropathy. We traced the dynamics of glomerular fdtration, albumin excretion and arterial pressure. The effect of ACEIs was according to the level of proteinuria. In diabetics with macroalbuminuria a short-lasting effect run out to the end of the 2-nd year. In MAU-positive ptients ACEIs led to delay of nephropathy for 10-years in 86,48%, progression in 8,1% and regression to normoalbuminuria in 5,4%. In 15% of all the diabetics we found a significant raise of proteinuria. In 21,73% of patients with "borderline" albuminuria there was a progression after the 5-th year with a cumulative index 4,58% or 0,91%

Delijski, M.

Madzhova, V.

Tsaneva, V.

English

Varna Medical University Press: Journals

Scripta Scientifica Medica, vol . 34 (2002), pp 55-58 Copyright © Medical University, Varna A 10-YEARS L O N G I T U D I N A L STUDY O F A D O L E S C E N T D I A B E T I C S W I T H I N I T I A L N E P H R O P A T H Y V. Madzhova, A. Klisarova 1, V. Tsaneva 2, M. Delijski Department of General Medicine, 1 Department of Image Diagnostics and2 Department of Pediatrics and Medical Genetics, Prof. Paraskev Stoyanov Medical University of Varna A B S T R A C T The data from a 10-years prospective study among 85 boys and 64 girls, mean age 14,1 ±3,8 years with mean diabetes duration 8,45 ±3,7 years are analyzed. Using a complex prospective screening we found the frequency of microalbuminuria (MAU) and estimated some parameters of progression of the renal damage. The patients were divided into 3 groups: no MAU, with M A U and with clinical signs of nephropathy. We traced the dynam-ics of glomerular fdtration, albumin excretion and arterial pressure. The effect of A C E I s was according to the level of proteinuria. In diabetics with macroalbuminuria a short-lasting effect run out to the end of the 2-nd year. In MAU-positive ptients A C E I s led to delay of nephropathy for 10-years in 86,48%, progression in 8,1% and regression to normoalbuminuria in 5,4%. In 15% of all the diabetics we found a significant raise of proteinuria. In 21,73% of patients with "borderline" albuminuria there was a progression after the 5-th year with a cumulative index 4,58% or 0,91%. Key words: diabetes mel l i tus , diabetic nephropathy, mic roa lbuminur ia , glomerular fi l tration rate, adolescence I N T R O D U C T I O N Diabetes mellitus ( D M ) as a group of metabolic diseases, characterizing with hyperglycemia is a result of offence in insulin secretion, insulin action or (and) both (9,10) and damages all organs and systems in the organism, but con-cerns most o f all the blood vessels (1). Nowadays a 112 000 healthy Bulgarian child is diabetic and the annual incidence rate of disease is 7-10/100 000 children (4) . The renal in-volvement in D M is the second very important complica-tion and its clinical appearance is 5.45% (6). M A T E R I A L AND M E T H O D S Using a complex prospective screening to establish the fre-quency o f microalbuminuria ( M A U ) as a marker of an ini-tial diabetic nephropathy ( D N P ) in children and adoles-cents, to trace its evolution, by assessing the indexes of pro-gression: M A U , blood pressure ( B P ) and glomerular filtra-tion rate ( G F R ) for a 10-year period. We studied 149 patients with D M type-1, 85 boys and 64 girls, mean age 14.1 ±3.8 years and D M duration 8.45 ±3.7 years for a 10-years period. In 89 patients (59.73%) the treatment was conventional insulin regimen and in 60 pa-Address for correspondence: V. Madzhova, Dept. of General Medicine. Prof. P. Stoyanov Medical University of Varna. 55 Marin Drinov St, BG-9002 Varna, BULGARIA E-mail: officeub@mail. bg tients (40.27%) - intensified insulin regimen with human insulin ( H M ) . The patients fonned 2 groups, according to the albumin excretion ( A E ) : diabetics without M A U (109), diabetics with M A U (37) and 3 patients withdrew the study, because o f their macroalbuminuric excretion. 1. M A U : 1) semi-quantitative methods: a 24h urine sample with immunochemical tests: a) Micral (Boehringer -Mannheim); b) Microbumintest (Miles Inc., U S A ) 2) a quantitative method: immunoturbidometry with analyzer Cobas mira plus (Hoffman-La Roche) with Randox test, using original program: Randox urinary albumin control-low and elevated; sensitivity limits: 9.7-206.2 mg/1 albumin in urine. 2. G F R : a) standard 4h - creatinine clearance - normal values: 60-100ml/min/1.73mI; b) Tc-99m D T P A clearance - normal values 180-236ml/min/1.73ml, "Diacanf', Siemens 3. Metabolic control: IMX-Abbot, U S A by M E I A method; referent values of HbAlc-4.4-6.4%. 4. Test for provoking M A U by graded exercise - using veloergometry type K E 22 Medicor, Budapest on 75W and 100W by original method for children and adolescents. 5. Sphygmomanometry: with aneroid sphygmo-manometer, using Korotkoff method (Vth phase): in rest and at graded exercise 6. Dynamic renal scintigraphy with Tc-99m D T P A using "Diacam*' (Siemens) for the first time in Bulgaria (Varna) for studying an initial DNP. 7. Indexes for progression: a) A E : 55 V . Madzhova, A . Klisarova, V . Tsaneva . 1) raising o f A E versus the initial values per year (ug/min/year or mg/l/year); 2) % o f its raising versus the initial per year (A%/year): b) G F R : 1/ rate of reduction o f G F R (ml/min/month or ml/min/year); 21% of its reduction versus the initial (supra-nonnal) per year (Д%/уеаг) 3) B P : 1) raising o f B P versus the initial per year (mm Hg/year); 2) % of raising B P versus the initial per year -(Д%/уеаг). We used the following statistic methods: graphic analysis, alternative analysis, statistic assessment, variation analysis - statistic significant is the value under 5% (p < 0.05) and Microsoft Excel - Windows' 98 for data processing. R E S U L T S AND D I S C U S S I O N In our study for a 10-years period 5 of nonnoalbuminuric patients progressed to M A U after the 5-th year and all were in the beginning with borderline albuminuria, litis showed a cumulative risk o f 4.58% (5/109 patients). In the M A U-group, treated with angiotensin-converting en­zyme inhibitors ( A C E I ) , 3 patients developed macroalbuminuria or the progression in MAU-diabetics was 8.10% for the treated patients . In the normoalbuinuric patients there were 23 with borderline values: 7.2-20ug/min. After the 5-th year 5 of them progressed to microalbuminuria, so 8 diabetics fell in the group of progressors. Their share was 5.48% of all examined cases. In the MAU-diabetics, 2 patients regressed to normal albu­min excretion, using Enalapril (Renitec). The values of their M A U were not so high - between 50-70mg/ml or the share of diabetics "regressors" was 5.40% among the MAU-group. I f we show the data for the evolution of proteinuria, B P and G F R for the 10 years in the different groups of patients ac­cording to A E , G F R and B P , we wil l receive the following results: (Tables 1,2 and 3; Figures 1, 2, 3 and 4). 2 years 5 years 10 years Fig. 1. Dynamics of proteinuria for 10 years Our results about the dynamics of proteinuria in children and adolescent diabetics correlate with these reported by ather authors. According to the data of patients in the Microalbuminuria Captopril Study Group (1996), in 7.2% ?f the cases there was a progression of the persistent M A U during 24 months (6). Ahmad et al. showed that for 5-years treatment with Enalapril - 7 . 7 % of their patients developed macroalbuminuria (3). 2 years 5 years 10 years Fig. 2. Dynamics of GFR for 10 years The data for 5.40% regression in our MAU-patients are corresponding to El l is et al. (5) . For a 4-year period 7 out of 124 patients (5.64%) with D N P undergone a reverse devel­opment to normal albuminuria and in 33.87% there was an improvement (5). normo-AU borderline micro-AU Fig. 3. Dynamics of systolic BP for 10 years We consider that the most vulnerable and suitable for active observation is the group of adolescent diabetics with bor­derline albuminuria. Their evolution shows that almost 1/5 of them (21.74%) are progressors towards M A U and even­tually to clinical D N P . These are patients in puberty, worse metabolic control and more often (40%) with familial pre­disposition to hypertension (2 out of 5 progressors in the group of borderline albuminuria). So they possess determi­nant risk factors like the patients with initial D N P (the MAU-group). njnno-AU borderline micro-AU Fig. 4. Dynamics of diastolic BP for 10 years When MAU-patients are early treated with A C E I they have a stable course of A E and in 91.89% the renal function did not get worse. We establish that there is not a significant difference in the reduction of G F R using various A C E I . Values of 2.3 ml/min/year are average referent values, mentioned in the literature (4,8,11). i6 A 10-years longitudinal study of adolescent diabetics with initial nephropathy ible I . Dynamics of proteinuria for 10 years Groups of pts: In the beginning; After 2 years: After 5 years: At the 10d'vear: Nonno - A U 2,1 ±0 ,2 2,18 ±0,3 2,29 ±0,32 2,48 ± 0,42 Borderline - A U 2,42 ±0 ,3 2,46 ±0,38 2,49 ±0,43 2,51 ±0,56 Micro - A U 6,93 ± 0,32 9,8 ± 0,40 23,6 ±0,36 25,2 ±0,2 able 2. dynamics ofDFRfor 10years Groups of pts: In the beginning: After 2 years: After 5 years: At the 1 О* year: Normo- A U 108,6 ±4,5 109,4 ±3 ,9 110,0 ±4,1 115,2 ±4,4 Borderline - AU 1 I0.3r. 3.4 117,4 ±3 ,9 119,3 ±4 ,6 121,5 ±3 ,7 hyphparOMicro - A U 135,4 ±4,1 139,4 ±4 ,3 128,3 ±3 ,9 125,4 ±3 ,8 Table 3. Dynamics of BP for 10 years Groups of pts: BP (mmHg) In the beginning: After 2 years: After 5 years: At the 10th year: Nonno- A U SBP 103,6 ± 11,3 104,4 ± 13,9 106,3 ± 14,1 108,2± 14,4 NS DBP 67,6 ± 15,7 68,1 ± 11,4 69,0 ± 12.6 70.9 ±10,8 NS Borderline-AU SBP 113,6 ± 14,8 114,9 ± 13,9 117,3 ± 14,1 118,8 ± 13,7 p<0.06 DBP 72,4 ± 16,7 73,2 ± 14,8 76,3 ± 12,9 78,9 ±13,4 p<0.05 Micro - A U SBP 114,6 ±21,2 115,4 ± 18,3 117,6 ± 13,9 118,4± 13,4 p<0.06 DBP 72.6 - 17,4 74,5 ± 17,3 77,4 ± 15,8 81,3 ±14,3 p- 0.01 fact that in 8.1 % of MAU-positive patients there is a progression and in 5.4% regression of the renal complica­tion shows that D N P has not an inevitable malignant course, which justifies early therapeutic interference even in childhood. C O N C L U S I O N S 1. The frequency of M A U in our patients is 24.83% 2. Some 2 1 . 1 % of normoalbuminuric patients are with borderline albuminuria; in 5 o f them (21.74%) it progresses for 5 years to M A U with cumulative index 0.91 % per year. 3. In MAU-positive group the treatment with A C E I avoids the progression for 10 years in 86.48%, progression in 8.2% and regression to normal albumin excretion in 5.40%. 4. Diastolic B P doesn't change significantly by graded exercise, but raises significantly in MAU-positive patients and correlates with the elevated albumin excretion for the 10-year period. R E F E R E N C E S К о е в , Д . Клинична ендокринология. София, 1993,269, 308-314. Ц а н е в а , В . Епидемиология на захарния диабет и неговите усложнения в детската възраст. Докт. дис. Варна, МУ-Варна, 1998. A h m a d , J . , М . A . S i d d i q u i , Н. A h m a d . Effec­tive postponement of diabetic nephropathy with enalapril in normotensive type 2 diabetic pts with microalbuminuria.- Diabet. Care, 20, 1997, 1576-1581. B j o r c k , S . , H . M u l e c , S . Johnsen . Renal pro­tective effect of enalapril in diabetic nephropathy .-BMJ, 304, 1992,339-343. E l l i s , D . , C . L l o y d , D . J . B e c k e r . The chang­ing course of diabetic nephropathy: low density lipo­protein cholesterol and blood pressure correlate with regression of proteinuria.- Am. J. Kidney Dis., 27, 1996, No 6, 809-818. K o e v a , L . , D . K o e v . Epidemiology of diabetes mellitus in Bulgaria.- Biomed. Rev., 5, 1996, 57-63. The Microalbuminuria Captopril Study Group. Captopril reduces the risk of nephropathy in I D D M 57 V . Madzhova, A . Klisarova, V . Tsaneva . patients with microalbuminuria.- Diabetologia, 39, 1996, No 5, 587-593. 8. Penno, G . , N . C h a t u r v e d i , et a I . Effect of A C E gene polymorphism on progression of renal disease and the influence of A C E inhibition in IDDM pa-tients. Findings from the E U C L I D randomized con-trolled trial.- Diabetes, 47, 1998, 1507-1511. 9. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.- Diabet. Care, 20, 1997, 1183-1197. 10. R u d b e r g , S . , R . Os te rby . Decreasing glomerular filtration rate-an indicator of more advanced diabetic glomerulopathy in the early course of microalbuminuria in I D D M adolescents?- Nephrol. Dial. Transplant., 12, 1997, No 6, 1149-1154. 11. Y i p , J . M . , S . L . Jones , M . J . W i s e m a n . G l o -merular hyperfiltration in the prediction of nephropathy in I D D M : a 10-year follow-up study.-Diabetes, 45, 1996, No 12, 1729-1733. 

A 10-YEARS LONGITUDINAL STUDY OF ADOLESCENT DIABETICS WITH INITIAL NEPHROPATHY

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A 10-YEARS LONGITUDINAL STUDY OF ADOLESCENT DIABETICS WITH INITIAL NEPHROPATHY

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