Renal function and structure in albuminuric type 2 diabetic patients without retinopathy

Nephrology Dialysis Transplantation, Dec 2001

Background. In type 2 diabetic patients without retinopathy the cause of albuminuria is heterogeneous and our knowledge of the relationship between kidney structure and function in these patients is limited. Therefore, a long‐term study evaluating the structural–functional relationship in albuminuric type 2 diabetic patients without retinopathy was performed.

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Renal function and structure in albuminuric type 2 diabetic patients without retinopathy

Nephrol Dial Transplant Renal function and structure in albuminuric type 2 diabetic patients without retinopathy Per Knud Christensen 1 2 Svend Larsen 0 1 Thomas Horn 0 1 Steen Olsen 0 1 Hans-Henrik Parving 1 2 0 Department of Pathology, Herlev Hospital , Herlev , Denmark 1 Diabetes Center , Niels Steensens Vej 2, DK-2820 Gentofte 2 Steno Diabetes Center , Gentofte albuminuria; diabetic glomerulopathy; glomerular filtration rate; hypertension; mesangium; non-diabetic glomerulopathies; retinopathy; type 2 diabetes mellitus Introduction In both type 1 and type 2 diabetic patients with retinopathy the development of persistent albuminuria )300 mgu24 h is the major criterion for the clinical diagnosis of diabetic nephropathy w1,2x. However, biopsy studies have revealed a prevalence of nondiabetic kidney disease in 5% of albuminuric type 1 diabetic patients w1x as compared with 10–24% in albuminuric type 2 diabetic patients w2,3x, and an even higher prevalence (31%) in type 2 diabetic patients without retinopathy w4x. Despite the heterogeneous nature of the underlying causes of albuminuria in patients with type 2 diabetes, and an increasing prevalence of end-stage renal disease among these patients, most studies of renal morphology in diabetes have mainly concentrated on type 1 diabetes. Only a relatively few long-term studies have dealt with the relationship between kidney structure and function in albuminuric type 2 diabetic patients w2,5–9x Originally Østerby et al. w5x found a close correlation between renal structure and functional changes in albuminuric type 2 diabetic patients. Furthermore, a correlation between severity of retinopathy and the severity of structural lesions in the kidney was revealed. The association between retinopathy and albuminuria underlines the generalized nature of the diabetic angiopathy. However, the association is not always complete, since a high percentage (22–62%) of albuminuric type 2 diabetic patients do not have diabetic retinopathy. Unfortunately the course of glomerular filtration rate (GFR) and the structural– functional relationship in albuminuric type 2 diabetic patients without retinopathy has only been scantily investigated. The aim of the present longitudinal observational long-term study was to evaluate the clinical course of GFR in a large group of consecutive albuminuric type 2 diabetic patients without retinopathy. Secondly, we evaluated the relationships between the decline in kidney function and kidney structure, arterial blood pressure, albuminuria, glycaemic control, lipids, known duration of diabetes and baseline GFR. A cross-sectional report on the present patients has been presented previously w4x. Subjects and methods Subjects Patients were considered to have type 2 diabetes if they were treated with diet alone, or in combination with oral hypoglycaemic agents, or if they were treated with insulin and had an onset of diabetes after the age of 40 years and a body weight in excess of the ideal body weight at the time of diagnosis. All insulin-treated patients who were lean at the time of diagnosis had a glucagon test performed, and type 2 diabetes was diagnosed if a stimulated C-peptide value was equal to or above 0.60 pmoluml. All Caucasian (n s 347) patients with type 2 diabetes and persistent albuminuria ()300 mgu24 h in at least two out of three consecutive, sterile non-ketotic 24-h urine samples), who had attended the out patient clinic at Steno Diabetes Center between 1978 and 1998, were evaluated. Ninety-three of these patients had no retinopathy. After 1992 our nephrologists decided not to perform kidney biopsy in patients with type 2 diabetes without retinopathy when albuminuria was less than 1 gu24 h. Consequently 15 patients without retinopathy with albuminuria -1 gu24 h were excluded. Twenty of the remaining 78 patients were not referred for a kidney biopsy for several reasons; (i) four patients died shortly after onset of albuminuria, (ii) seven patients were older than 65 years, and (iii) contraindications were present in nine patients (four had a solitary kidney, one had contracted kidneys and four patients were treated with anticoagulant medication because of cardiovascular disease). The rest (n s 58) of the patients were referred for a kidney biopsy, six of these patients later decided not to participate, and one kidney biopsy was not successful. Two of the remaining 51 patients were later excluded: one because of long-term treatment with acetazolamide and in one patient it was not possible to estimate the rate of decline in GFR, because fewer than three GFR measurements were performed. All (n s 52) patients gave informed consent and the study was performed in accordance with the Helsinki declaration. Methods The biopsies were evaluated by three masked nephropathologists. To excludeuminimize bias with respect to presence of diabetic kidney lesions and to increase possible variability in the morphometric analyses, we mixed biopsies from diabetic patients with 14 biopsies from patients without diabetes from our file, who had normal renal function, and normal structure by light microscopy. All morphometric measurements were made by one of the authors (S.O.). Light microscopy The tissue preparation has been described in detail previously w4x. Diffuse diabetic glomerulopathy, hyaline arteriolosclerosis, tubular atrophy, and interstitial fibrosis were semiquantitatively estimated. The final reading (0, q1, q2, q3) was made by agreement of the three nephropathologists watching together at a video screen attached to the microscope. The number of totally sclerotic glomeruli was counted and expressed as percentage of the total number. Morphometry The mesangial volume fraction (mesangium in fraction of the total glomerular volume (Vv (mesuglom)) was measured at light microscopy by point counting using a computer-assisted stereological system (GRID, Interactivision, DK). Magnification on the video screen was 3 1650. The grid had 5 3 6 points. The number of points hitting the mesangium (matrix as well as cells) was expressed as the fraction of the points hitting the reference space, which was the glomerulus defined as the circumscribed minimal polygon. The measurements were made on one silver methenamine stained 2 m section from each biopsy. One field from each of 6–10 glomeruli was measured (corresponding to 180–300 reference points), excluding totally or partially sclerosed glomeruli. Interstitial fibrosis and tubular atrophy always occurred in sharply defined focal areas. Each fibrotic scar was circumscribed and their areas automatically computed by the system. The sum of these areas was expressed as the percentage of the total cortical area in the biopsy. In order not to miss any diffuse interstitial fibrosis outside these focal areas, we also measured the fibrosis outside the focal areas by point counting. The interstitial tissue including capillaries was expressed as a fraction of the cortical labyrinth (cortex minus glomeruli and vessels larger than capillaries). Tubular basement membranes were not included in the interstitial tissue. Immunofluorescence microscopy Kidney specimens were frozen using dry ice, embedded in Tissue-Teck (Miles, Naperville, Illinois, USA) gelatin, and 2 mm sections were cut at 248C on a Leitz Histocryotome (Wetzlar, Germany). Direct immunofluorescent staining technique was applied, using FITC-conjugated rabbit or goat antisera specifically reactive to human IgG, IgM, IgA as well follow-up GFR was measured 8 times ( 3–20 ), albuminuria 29 as complement C1q, C3 and C4. ( 4–75 ), arterial blood pressure 30 ( 5–90 ), HbA1c 20 ( 4–20 ), total serum cholesterol 11 ( 1–30 ) and serum HDL cholesterol 8 ( 1–18 ) times (medians (ranges)). Laboratory techniques Retinopathy was assessed following pupillary dilation with direct ophthalmoscopy until 1989 and afterwards by fundus photography and graded: nil, simplex, or proliferative retinopathy. Eighty per cent of the present patients were evaluated by fundus photo alone. Albuminuria was measured by radioimmunoassay in all urine samples until 1992. After 1992 an ELISA method was used. The correlation between the two methods was r s 0.99. Serum creatinine concentration was assayed by a kinetic Jaffe method. GFR was measured after a single i.v. injection of 3.7 MBq 51Cr-labeled EDTA by determination of the radioactivity in venous blood samples taken 180, 200, 220 and 240 min after the injection w10,11x. Additional blood samples were obtained after 270 and 300 min, when the GFR dropped 2 below 20 mluminu1.73 m . The small underestimation (10%) of w51CrxEDTA clearance versus clearance of inulin was corrected for by multiplying EDTA clearance by 1.10 w10x. Extra renal loss was corrected by subtracting 3.7 mlumin w10x. We standardized the GFR results for 1.73 m2 body surface area, using the patients’ surface area at the start of the studies, for the entire study period. We used the plasma clearance of w51CrxEDTA for GFR determination because this method is accurate, precise (coefficient of variation 4%), and do not require frequent timed urine collections as the classical renal clearance procedures w10,11x. Furthermore, we did not use the classical renal plasma clearance of insulin, because residual urine, which is frequently found in longstanding diabetic patients due to diabetic cystopathy w12x, may affect the results. All plasma clearance studies were carried out between 09.00 and 13.30 hours. Patients had their usual breakfast and morning medication before the investigation, which was carried out with the patient in supine position. They drank 200 ml tap water per hour during the clearance study. Arterial blood pressure was measured with a clinical sphygmomanometer after 10 min of rest. Diastolic blood pressure was measured at the disappearance of the Korotkoff sounds (phase V). Arterial hypertension was diagnosed according to the World Health Organization Criteria, systolic blood pressure P160 mmHg anduor diastolic blood pressure P95 mmHg, or if antihypertensive treatment was being prescribed. Mean arterial blood pressure (MABP) was calculated as diastolic blood pressure plus one third of the pulse amplitude. Body mass index (BMI) was calculated as body weightuheight2 (kgum2). Serum lipids, serum total cholesterol and serum highdensity lipoprotein (HDL) cholesterol were measured using conventional laboratory techniques. Haemoglobin A1c (HbA1c) was determined by DIAMAT Analyser, BIO-RAD, California, USA until 1995, and thereafter by Variant Bio-Rad. Normal range for HbA1c was 4.1 to 6.1% for both methods. Follow-up evaluation Patients were scheduled to visit the outpatient clinic every 3 to 6 months when antidiabetic treatment and antihypertensive therapy were adjusted. During the 7 (1.1–17) years Statistical analysis Normally distributed data are expressed as means with standard deviation (SD) in demographic data or standard errors of means (SE) in follow-up data. Values for albuminuria were logarithmically transformed before statistical analysis because of their positively skewed distribution. All comparisons of normally distributed parameters were done with a Student’s t-test, using unpaired design between groups and paired design within groups. A Mann–Whitney’s U-test was used to evaluate independent samples and a Wilcoxon in related variables not normally distributed. Fisher’s exact test was performed in dichotomous variables. Univariate linear regression and multivariate backwards stepwise linear regression analysis were used to assess the association between the rate of decline in GFR and putative progression promoters (GFR at entry, baseline albuminuria, baseline blood pressure, known duration of diabetes, Vv (mesuglom), FF, GuS (%) and mean values during follow-up of systolic blood pressure, diastolic blood pressure, albuminuria, total serum cholesterol, serum HDL cholesterol and HbA1c). All variables significant at P-0.10 in the univariate analyses were included in the multiple regression analysis. All calculations were made using SPSS for Windows (SPSS Inc., Chicago, USA). A P value of -0.05 was considered significant (two-tailed). Results The kidney biopsy revealed diabetic glomerulopathy in 34 (69%) and normal glomerular structure (n s 9) or glomerulonephritis (n s 6) in 31% of the patients. The clinical features revealed no significant differences in demographic, clinical or laboratory data at baseline between patients with or without diabetic nephropathy (Table 1). Mean age was approximately 55 years and a male predominance was found in both groups. Most patients had elevated body mass index and metabolic control was poor in both groups. HbA1c increased from 8.3"1.8% to 8.9"1.7% in the DG group (NS) and from 8.9"2.1% to 9.3"2.2% (NS) in the NDG-group, even though antidiabetic treatment was intensified in both groups during follow-up. Although approximately 1u3 of the patients in both groups were treated with lipid lowering drugs, mean serum total cholesterol was elevated in both groups. There was no significant difference between groups in number of patients receiving antihypertensive drugs at baseline or at end of follow-up. Furthermore, the numbers of patients receiving two or more drugs at the end of the study in the two groups are not significantly different. However, all patients in the DG-group (41%) who did not receive antihypertensive treatment at entry to the study were prescribed antihypertensive drugs during follow-up and an increasing number of patients Mean (SD).a Calculated from all measurements during follow-up for each patient. bNumber of patients treated with ACEI or AngII receptor blocker. were at the end of the study treated with two or more drugs. In patients with non-diabetic glomerulopathies less profound change in antihypertensive treatment were seen. Despite a 100% prevalence of hypertension, 13% of patients in this group were not treated with antihypertensive drug at the end of the study (Table 1). The rate of decline in GFR in the DG-group in patients (n s 23) treated with ACE inhibitors or angiotensin II receptors blockers during follow-up was 4.8"0.9 mluminuyear compared to 6.3"1.9 mluminu year in patients (n s 11) not treated with these drugs (NS). In the NDG-group the rate of decline in GFR was 2.2"1.9 mluminuyear vs 3.6"1.0 mluminuyear (NS) in patients treated with (n s 11) and without (n s 4) ACE inhibitors or angiotensin II receptors blockers, respectively. During the 7 years of follow-up more than 50% of patients developed retinopathy. Approximately half of the patients in the DG-group and a third of the patients in the NDG-group were smokers (NS). The rate of decline in GFR among smokers and non-smokers in the DG-group was 5.6"1.1 mluminu year vs 4.9"1.3 mluminuyear (NS), and in the NDGgroup 0.2"0.4 mluminuyear vs 4.3"1.0 mluminuyear (P-0.05), respectively. Data on the course of GFR, serum creatinine, albuminuria and arterial blood pressure are presented in Table 2. One patient with previously persistent albuminuria in the DG-group had albuminuria -300 mgu24 h at entry, because antihypertensive treatment was initiated before entry to the study. All patients had GFR determined at least three times and the follow-up was more than 1 year in all patients. Both groups had a significant reduction in GFR during follow-up (Table 2). The mean difference (95% confidence interval) in the rate of decline in GFR between the two groups was 2.1 ( 0.3 to 4.5) mluminuyear, P s 0.09. Albuminuria decreased significantly in the NDG-group, whereas it remained unchanged in the DG-group. MABP decreased from 109"2 to 100"2 mmHg in the DG group (P-0.001), and from 107"3 to 104"3 mmHg in the NDG-group (NS). The individual renal pathology, rate of decline in GFR, mean albuminuria and mean MABP during follow-up in patients with diabetic glomerulopathy, normal glomerular structure and with glomerulonephritis are shown in Tables 3, 4 and 5, respectively. A detailed description of the renal pathology in all patients has been presented previously w4x. An association was found between Vv (mesuglom) and rate of decline in GFR mainly in the NDGgroup (Fig. 1). The rate of decline in GFR was associated with FF only in patients with non-diabetic glomerulopathies (Fig. 2). No significant association was revealed between the rate of decline in GFR and the percentage of totally sclerotic glomeruli in any of the groups (Fig. 3). In the DG-group the rate of decline of GFR raised with arteriolar hyalinosis P valuea P s 0.09 NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS Median (range) or mean (SE). aSignificance of difference between and bwithin the two groups. increasing from slight to severe from 5.9"5.1, NS. 3.5"1.7 to In the NDG-group In the DG-group Univariate analysis revealed significant correlations between rate of decline in GFR and baseline systolic blood pressure (r s 0.40, P-0.02), and known duration of diabetes (r s 0.39, P-0.03), but not with GFR at entry, baseline log10 albuminuria, and baseline diastolic blood pressure. The same analyses based on mean values during follow-up of systolic blood pressure, diastolic blood pressure, log10 albuminuria, total serum cholesterol, serum HDL cholesterol and HbA1c, revealed significant correlations between the rate of decline in GFR and systolic blood pressure (r s 0.34, P s 0.05), and log10 albuminuria (r s 0.47, P-0.01). A multiple regression analysis was performed with known duration of diabetes, Vv (mesu glom), mean values during follow-up of systolic blood pressure and log10 albuminuria as independent variables and rate of decline in GFR as dependent variable. The mean log10 albuminuria during follow was the only variable associated with the rate of decline in GFR (r s 0.40, P-0.02). The same variables as mentioned above were introduced in the univariate analyses, and correlations between the rate of decline in GFR and GFR at entry (r s 0.64, P-0.02), baseline log10 albuminuria (r s 0.58, P-0.05), Vv (mesuglom) (r s 0.74, P-0.01), mean values during follow-up of systolic blood pressure (r s 0.63, P-0.01) and log10 albuminuria (r s 0.69, P-0.02) were found. A multiple regression analysis was then performed with GFR at entry, Vv (mesuglom), FF and mean values during follow-up of systolic blood pressure and log10 albuminuria as independent variables, and rate of decline in GFR as dependent variable. The mean log10 albumniuria during follow (r s 0.61, P-0.01) and GFR at entry (r s 0.53, P-0.02) were the only variables associated with the rate of decline in GFR. Albuminuria Univariate analyses were furthermore performed including; Vv (mesuglom), FF, SuG, and mean values during follow-up of MABP, and HbA1c as independent variables and mean log10 albuminuria as dependent variable. The analyses were performed in both groups, FF Vv (mesuglom), mesangial volume as percentage of the total glomerular volume; FF, fractional area of focal cortical interstitial fibrosis; SuG, percentage of sclerosed glomeruli of the total number of glomeruli in each biopsy; slight s 1, medium s 2, severe s 3; ND, no data; TI, technical impossible; UAER, urinary albumin excretion rate. aAll deposits of immunoglobulins and complement fractions were mild or questionable, frequently only present in a few glomeruli and without characteristic pattern. DGS, diabetic glomerulopathy; Vv (mesuglom), mesangial volume as % of the total glomerular volume; FF, fractional area of focal cortical interstitial fibrosis; SuG, percentage of sclerosed glomeruli of the total number of glomeruli in each biopsy; slight s 1, medium s 2, severe s 3; ND, no data; UAER, urinary excretion rate. , , , , m b o A M A A A m l g g g g g I g I I 0 I I I 4 C , 3 M M M g g g I I I -up )g up )h P g w H ean BA irn lo m u l MMd fo (m n - 4 a R g i d E in ow 2gu e A ru ll MU d fo (m ) r a e in yu f n o e i n te li a ec FR lmu R d G (m n o i t a z i l s a it c ir y o h p L ep sco n o o r l c u i r e m m ec lo n itgh srcee itsso w ou ep d fl d n o e a n n y u u th m m a m m p I I o n i t e r w c i t e b a i d t u o h t i s t n e i t a p c i t e b a i d 2 e p y t c i te r b la a u id re sn on lom iso N g le te ry n a i n l i ca ru it , r R co E ca U o ; f l e f b o is ea so r p a m l i io ic t n c a ch fr te , , F I F T ;e ;ta m a u d l o o v n r , la D reu ;N 3 m lo s g re l e a v t e to ,s m u s l t o h v g l li a s ig ; n sy sa p m b ,) ch gu in s i e l (m reu v m V lo ; g is f s o o r r e e lc b so um l u n re la and revealed that Vv (mesuglom) was associated to mean log10 albuminuria during follow-up (DG group; r s 0.38, P-0.03 and NDG group; r s 0.51, P s 0.09). Furthermore log10 albuminuria was associated with average MABP during follow-up (r s 0.56, P-0.01) in the DG group, but not in the NDG group. Metabolic control was not related to mean log10 albuminuria during follow-up in any of the groups. Discussion The present long-term observational study of albuminuric patients with type 2 diabetes without diabetic retinopathy showed a large variation in rate of decline in GFR and a tendency to a faster rate of decline in kidney function in patients with biopsy proven diabetic glomerulopathy (DG-group) compared to patients with normal glomerular structure (n s 9) or glomerulonephritis (n s 6). Albuminuria was reduced in the NDG-group despite unchanged blood pressure during follow-up, whereas albuminuria remained unchanged during follow-up despite intensified antihypertensive treatment and blood pressure reduction during follow-up in the DG-group. The differences in blood pressure and antihypertensive treatment might be responsible for the lack of significant differences in rate of decline in GFR and albuminuria at the end of the study. However, a close correlation between albuminuria and rate of decline in GFR was demonstrated in both groups. Several other studies have shown that albuminuria and blood pressure are independent risk factors for the progression of renal diseases w13–15x, in agreement with our results. Vv (mesuglom) was the main structural predictor of the rate of decline in GFR and albuminuria during follow-up. The histological classification of the renal lesions was performed according to the World Health Organization standard. All biopsies were reviewed by three masked and experienced nephropathologists. Since only a part of our biopsies included tissue for EM, we used a morphometric point count technique for estimation of Vv (mesuglom) on light microscopic specimens. Furthermore, the conventional method of measuring fractional volume of cortical fibrosis in biopsies with rather few and small focal fibrotic areas is very insensitive since the fibrosis will largely ‘disappear’ in the many measured fields outside the areas with fibrosis. Therefore, we also selected another objective to evaluate fibrosis. It must be emphasized, that the sole indication for kidney biopsy in our study was the presence of albuminuria and lack of diabetic retinopathy. Selection bias in the present study may be possible, since 15 patients with albuminuria -1 gu24 h were not included. However, these patients were not different Fig. 3. Percentage of sclerosed glomeruli of the total number of glomeruli in each biopsy from albuminuric type 2 diabetic patients without retinopathy in relation to glomerular filtration rate. m Patients with diabetic glomerulopathy (r s 0.21, NS). h Patients with glomerulonephritis or j normal glomerular structure (r s 0.42, NS). to the included patients with respect to demographic, clinical or laboratory data. Recently, six studies evaluating clinical and histological correlations of the course of renal function have been reported in albuminuric patients with type 2 diabetes w3,5–9x. However, the results from the studies are difficult to compare because of differences in the methods used for estimations of renal structure and renal function. One study has estimated the renal lesions by combining the basement membrane thickness and Vv (mesuglom) w5x, while others have combined glomerular and vascular and interstitial changes w7x. Both these studies showed a relationship between the course of kidney function and renal structure. Two studies have divided patients in accordance to histology diagnosis w6,7x. One long-term (7.7 years) study revealed a faster rate of decline in GFR in albuminuric type 2 diabetic patients with diabetic glomerulopathy compared to patients without glomerulopathy w6x, whereas a shortterm study (1.8 years) did not show such a relationship w7x. Finally, three studies have used individual measurements such as glomerular basement membrane width, Vv (mesuglom), mean glomerular volume, interstitial fibrosis, capillary volume, percent of sclerosed glomeruli and cortical interstitium fractional volumes w3,8,9x. Their results suggested that cortical interstitium fractional volumes, glomerular basement membrane width, Vv (mesuglom) and interstitial fibrosis might be related to the course of kidney function, but results are conflicting. The abovementioned results should be interpreted with caution, since they are based on mixed populations of patients with micro- or macroalbuminuria w3,9x, type 1 or type 2 diabetes w5,8x and with or without retinopathy w3,5–9x. Only one study includes more than 40 albuminuric type 2 diabetic patients, however the follow-up was less than 2 years w7x. Even though there are differences and limitations, the results from previous and the present study show that kidney biopsy has a prognostic role in albuminuric type 2 diabetic patients. Furthermore, exact knowledge of the underlying cause of albuminuria may play an important role in offering the correct treatment, as demonstrated in patients with type 2 diabetes suffering from non-diabetic glomerulopathies w16–18x or diabetic glomerulopathy w3x. The most characteristic and clinically important glomerular lesion in diabetes mellitus is mesangial expansion. In agreement with previous findings, we found a tendency of a relationship between Vv (mesuglom) and rate of decline in GFR. This relationship probably resulted from the expanding mesangium compromising the structure of glomerular capillaries and reducing the ultrafiltration coefficient filtration (defined as the product of effective hydraulic permeability and total glomerular capillary surface area of the kidney), as demonstrated in a pathophysiological study of albuminuric Pima Indians with diabetes w19x. A correlation between FF and rate of decline in GFR was found in the patients without diabetic glomerulopathy, indicating that the interstitial lesions are important determinants of the progression in kidney disease, as suggested by Mauer w20x. Large glomeruli have been found in elderly albuminuric type 2 diabetic patients, indicating that they are capable of producing glomerular growth w5x. There are good reasons to believe that this represents a compensatory hypertrophy, which is induced in order to prevent loss of filtration surface. This may explain the lack of association between the rate of decline in GFR and the percentage of totally sclerotic glomeruli found in our study. Several subjects with diabetic glomerulopathy had marked mesangial lesions anduor marked interstitial lesions anduor severe glomerulosclerosis but only modest reduction in GFR; but it was not possible to find a pattern within this group. Other studies have calculated a global score of tissue injury, but even when renal tissue lesions are combined in a global score system the underlying glomerular lesions have less predictive value in patients with heavy albuminuria w7x. These findings are in agreement with our study, where patients with heavy albuminuria irrespectively of the underlying glomerular lesions had a rather fast rate of decline in GFR. A small subgroup of patients without diabetic glomerulopathy had moderate or severe arteriolar hyalinosis and a great relative number of sclerosed glomeruli. This is not uncommon in kidneys from nondiabetic persons with normal renal function and no albuminuria in the same age group as our patients w21x. Furthermore, due to the restricted number of glomeruli in a biopsy, the relative number of sclerosed glomeruli present in a biopsy is subjected to considerable sampling error. The rate in decline of GFR compared with the relative number of sclerosed glomeruli in the biopsy in our group of patients without diabetic glomerulopathy did not reveal a significant pattern. Albuminuria and deterioration of renal function in some of our patients with normal renal structure may reflect one of the following causes: minimal-change nephropathy, focal segmental glomerulosclerosis (undetected), silent diabetic glomerulosclerosis (electron microscopic glomerulopathy) and finally, a hypothetic entity with normal renal structure but increased glomerular permeability to macromolecules (sizeucharge defects). Furthermore arteriolar structural abnormalities may lead to impaired vascular responses to changes in systemic blood pressure and thereby contribute to increased leakiness of glomerular filter w22,23x. Urinary albumin excretion is the net result of interactions of factors within glomeruli as well as extra-glomerular renal and systemic conditions w24x, which makes it difficult to establish the pathogenesis of albuminuria in individual subjects. The marked heterogeneity of severity of glomerular disease combined with marked differences in severity of albuminuria and blood pressure elevation might explain the difference in rate of decline in GFR seen in patients with non-diabetic kidney diseases. A rate of decline in GFR close to the age dependent decline in kidney function seen in normal subjects was revealed in patients who had minimal structural lesion and low levels of albuminuria combined with relatively low blood pressure. These findings are in agreement with other studies evaluating renal structure and function as mentioned above. However, the data on the structural and functional relationship in patients with both diabetic and non-diabetic kidney disease are limited and such a subgroup needs to be studied in the future. The impact of metabolic control on the progression of kidney disease in type 2 diabetic patients is debated. In agreement with our findings several other studies have failed to demonstrate a significant correlation between glycaemic control and rate of decline in GFR in albuminuric type 2 diabetic patients w19,25x. In contrast, studies in type 1 diabetic patients have shown that hyperglycaemia is a progression promoter of diabetic nephropathy w26,27x. We found no difference in the rate of decline in GFR between patients treated with or without ACE inhibitors or angiotensin II receptors blockers, but a variety of antihypertensive drugs were used during follow-up. The WHO criteria of hypertension from 1978 were used to describe our patients at baseline, several new criteria have since then reduced the arterial blood pressure limit for hypertension. Consequently antihypertensive treatment was initiated and increased at different time points. It is therefore possible that the differences in antihypertensive treatment may have induced a bias in the structural and functional relationships despite the above-mentioned findings. Two patients in the NDG-group with isolated systolic hypertension did not receive antihypertensive treatment during follow-up, since they died before 1996 and data justifying such therapy was lacking until 1996 w28x. In agreement with our findings, the effect of smoking on the progression in kidney disease is not clear; while some studies w29,30x do not support smoking as a putative progression promoter others have shown that smoking may increase the progression of nephropathy in diabetic patients w31x. Our study has several limitations including a relatively small number of patients, selection of patients without retinopathy may result in less glomerulopathy compared to patients with retinopathy w5x, lack of tissue for electron microscopy material made our histological evaluation less precise, the biopsies only provides a ‘snap-shot’ and sequential biopsies would probably provide more complete information on the evolution profile of the underlying diseases, and finally the design and power of the study make it impossible to evaluate the effect of different antihypertensive regimens on rate of decline in GFR. In conclusion, our study revealed a tendency to a faster rate of decline in GFR in the DG-group compared to the much smaller NDG-group, characterized by marked heterogeneity of the underlying kidney lesions and rate of GFR loss. A large mesangial volume fraction was associated with increased albuminuria and loss in GFR. 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Christensen, Per Knud, Larsen, Svend, Horn, Thomas, Olsen, Steen, Parving, Hans‐Henrik. Renal function and structure in albuminuric type 2 diabetic patients without retinopathy, Nephrology Dialysis Transplantation, 2001, 2337-2347, DOI: 10.1093/ndt/16.12.2337