Glomerular Structure in IDDM Women With Low Glomerular Filtration Rate and Normal Urinary Albumin Excretion PASCALE H. LANE, MICHAEL W. STEFFES, AND S. MICHAEL MAUER
Eight women with insulin-dependent diabetes mellitus (IDDM) with low creatinine clearance rate (CCR) and normal urinary albumin excretion (UAE) were compared with three other groups of diabetic women: 19 with normal creatinine clearance rate (CCR) and UAE, 7 with normal CCR and microalbuminuria, and 7 with low CCR and microalbuminuria. The four groups were similar in age, duration of diabetes, HbA.,, incidence of urinary tract infection, prevalence of bladder neuropathy, and urinary urea nitrogen excretion rate. The prevalence of hypertension was similar among the groups, although mean arterial pressure was higher in the low CCR and microalbuminuria group. Renal area index was lower in the low CCR and normal UAE groups than in the other groups of diabetic patients, but was not different from normal. Morphometric measures of mesangial expansion and estimates of arteriolar hyalinosis and global glomerulosclerosis were increased to a similar degree in the low CCR and normal UAE, normal CCR and microalbuminuria, and low CCR and microalbuminuria groups compared with the group without abnormalities of renal function. Therefore, it is likely that diabetic glomerulopathy is, at least in part, responsible for the loss of glomerular filtration rate seen in the low CCR and normal UAE patients. Thus, the definition of incipient nephropathy may have to be expanded beyond the concept of microalbuminuria if longitudinal study of such patients reveals an increased risk of the subsequent development of overt nephropathy. Finally, screening for diabetic kidney disease among IDDM patients should include determination of glomerular filtration rate and measurement of UAE and blood pressure, especially among women. Diabetes 41:581-86,1992 From the Department of Pediatrics, St. Louis University School of Medicine, St. Louis, Missouri; and the Departments of Laboratory Medicine and Pathology and Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota. Address correspondence and reprint requests to Pascale H. Lane, Cardinal Glennon Children's Hospital, Division of Pediatric Nephrology, 1465 South Grand Boulevard, St. Louis, MO 63104. Received for publication 12 March 1991 and accepted in revised form 2 January 1992.
DIABETES, VOL. 41, MAY 1992
O
vert diabetic nephropathy classically begins with dipstick-positive proteinuria (urinary albumin excretion [UAE] 200 mg/24 h) followed or accompanied by the development of hypertension and/or falling glomerular filtration rate (GFR; 1,2). At this stage, renal lesions of diabetes, including diffuse mesangial expansion and consequent loss of filtration surface, arteriolar hyalinosis, and global glomerular sclerosis are advanced, and the progression toward endstage renal disease may be slowed but not reversed (3). Overt nephropathy is preceded by a variable period, which has been called incipient nephropathy (2). This phase of the natural history of diabetic nephropathy has been defined as an elevation of UAE to levels considered predictive of nephropathy risk but less than the levels that usually give positive dipstick results. The lower limit of UAE, which is said to be predictive of the later development of overt nephropathy, has been variably reported as 22, 45, and 100 mg/24 h (4-7). Some patients with microalbuminuria 45 mg/24 h may also have hypertension or a falling GFR, and this group of patients with microalbuminuria more regularly have advanced glomerular lesions than patients with microalbuminuria (often 22-45 mg/24 h) but normal blood pressure and GFR (8). Before these stages are many silent years during which no clinical or laboratory parameter is indicative of underlying renal structural lesions or of eventual nephropathy risk. These years are characterized by normal UAE and blood pressure and normal or elevated GFR (1,2). Glomerular structure during the silent period can range from normal to lesions bordering on those of overt nephropathy (3,8). Although the patterns described above are typical, not all patients developing significant renal pathological changes of diabetes fall into these recognizable categories or stages. We have studied 174 patients with insulin-dependent diabetes mellitus (IDDM) with renal function tests and
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LOW GFR AND NORMAL UAE IN IDDM
biopsies. Eighty-five of these patients have overt nephropathy. From the 89 patients with less pronounced functional abnormalities, we identified an unusual group of 8 patients, all women, with low GFR and normal albumin excretion. We have studied the renal biopsies of this group and compared these results with those of three other groups of female IDDM patients.
RESEARCH DESIGN AND METHODS
One hundred seventy-four IDDM patients with native kidneys have undergone evaluation for possible pancreas transplantation or improved metabolic control in the Clinical Research Center (CRC) at the University of Minnesota. One hundred twenty (69%) were female. Although these patients may not be representative of the diabetic population as a whole, this group does include the full spectrum of renal findings of IDDM, from normal renal function and structure to clinical nephropathy with advanced structural changes. This potential selection bias should not affect the structural-functional relationships described herein. All patients had 24 h urine collections for creatinine clearance rate (CCR) and UAE. Serum and urine creatinine was measured according to an automated kinetic method that used the Jaffe reaction (9). We previously demonstrated a nearly perfect correlation between multiple CCR collected under supervision in our CRC and inulin clearance in patients whose CCR was 40 ml • min1 • 1.73 m2 of body surface area (10). UAE was quantitated with nephelometry (11). Normal UAE was
Eight women with insulin-dependent diabetes mellitus (IDDM) with low creatinine clearance rate (CCR) and normal urinary albumin excretion (UAE) were compared with three other groups of diabetic women: 19 with normal creatinine clearance rate (CCR) and UAE, 7 with normal CCR and microalbuminuria, and 7 with low CCR and microalbuminuria. The four groups were similar in age, duration of diabetes, HbA.,, incidence of urinary tract infection, prevalence of bladder neuropathy, and urinary urea nitrogen excretion rate. The prevalence of hypertension was similar among the groups, although mean arterial pressure was higher in the low CCR and microalbuminuria group. Renal area index was lower in the low CCR and normal UAE groups than in the other groups of diabetic patients, but was not different from normal. Morphometric measures of mesangial expansion and estimates of arteriolar hyalinosis and global glomerulosclerosis were increased to a similar degree in the low CCR and normal UAE, normal CCR and microalbuminuria, and low CCR and microalbuminuria groups compared with the group without abnormalities of renal function. Therefore, it is likely that diabetic glomerulopathy is, at least in part, responsible for the loss of glomerular filtration rate seen in the low CCR and normal UAE patients. Thus, the definition of incipient nephropathy may have to be expanded beyond the concept of microalbuminuria if longitudinal study of such patients reveals an increased risk of the subsequent development of overt nephropathy. Finally, screening for diabetic kidney disease among IDDM patients should include determination of glomerular filtration rate and measurement of UAE and blood pressure, especially among women. Diabetes 41:581-86,1992 From the Department of Pediatrics, St. Louis University School of Medicine, St. Louis, Missouri; and the Departments of Laboratory Medicine and Pathology and Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota. Address correspondence and reprint requests to Pascale H. Lane, Cardinal Glennon Children's Hospital, Division of Pediatric Nephrology, 1465 South Grand Boulevard, St. Louis, MO 63104. Received for publication 12 March 1991 and accepted in revised form 2 January 1992.
DIABETES, VOL. 41, MAY 1992
O
vert diabetic nephropathy classically begins with dipstick-positive proteinuria (urinary albumin excretion [UAE] 200 mg/24 h) followed or accompanied by the development of hypertension and/or falling glomerular filtration rate (GFR; 1,2). At this stage, renal lesions of diabetes, including diffuse mesangial expansion and consequent loss of filtration surface, arteriolar hyalinosis, and global glomerular sclerosis are advanced, and the progression toward endstage renal disease may be slowed but not reversed (3). Overt nephropathy is preceded by a variable period, which has been called incipient nephropathy (2). This phase of the natural history of diabetic nephropathy has been defined as an elevation of UAE to levels considered predictive of nephropathy risk but less than the levels that usually give positive dipstick results. The lower limit of UAE, which is said to be predictive of the later development of overt nephropathy, has been variably reported as 22, 45, and 100 mg/24 h (4-7). Some patients with microalbuminuria 45 mg/24 h may also have hypertension or a falling GFR, and this group of patients with microalbuminuria more regularly have advanced glomerular lesions than patients with microalbuminuria (often 22-45 mg/24 h) but normal blood pressure and GFR (8). Before these stages are many silent years during which no clinical or laboratory parameter is indicative of underlying renal structural lesions or of eventual nephropathy risk. These years are characterized by normal UAE and blood pressure and normal or elevated GFR (1,2). Glomerular structure during the silent period can range from normal to lesions bordering on those of overt nephropathy (3,8). Although the patterns described above are typical, not all patients developing significant renal pathological changes of diabetes fall into these recognizable categories or stages. We have studied 174 patients with insulin-dependent diabetes mellitus (IDDM) with renal function tests and
581
LOW GFR AND NORMAL UAE IN IDDM
biopsies. Eighty-five of these patients have overt nephropathy. From the 89 patients with less pronounced functional abnormalities, we identified an unusual group of 8 patients, all women, with low GFR and normal albumin excretion. We have studied the renal biopsies of this group and compared these results with those of three other groups of female IDDM patients.
RESEARCH DESIGN AND METHODS
One hundred seventy-four IDDM patients with native kidneys have undergone evaluation for possible pancreas transplantation or improved metabolic control in the Clinical Research Center (CRC) at the University of Minnesota. One hundred twenty (69%) were female. Although these patients may not be representative of the diabetic population as a whole, this group does include the full spectrum of renal findings of IDDM, from normal renal function and structure to clinical nephropathy with advanced structural changes. This potential selection bias should not affect the structural-functional relationships described herein. All patients had 24 h urine collections for creatinine clearance rate (CCR) and UAE. Serum and urine creatinine was measured according to an automated kinetic method that used the Jaffe reaction (9). We previously demonstrated a nearly perfect correlation between multiple CCR collected under supervision in our CRC and inulin clearance in patients whose CCR was 40 ml • min1 • 1.73 m2 of body surface area (10). UAE was quantitated with nephelometry (11). Normal UAE was
