Early detection of patients at risk of developing diabetic nephropathy.

Transcription

1 Early detection patients at risk developing diabetic nephropathy. A longitudinal study urinary albumin excretion H.-H. Parving, B. Oxenb\l=o/\ll,P. Aa. vendsen, J. andahl Christiansen and A. R. Andersen The teno emorial Hospital, Gentte and Department Clinical Physiology and edicine C, Bispebjerg Hospital, Copenhagen Abstract. n an attempt to detect patients at high risk developing diabetic nephropathy, a longitudinal study urinary albumin excretion rate (radial immunodiffusion) was carried out in female and male long-term insulin-dependent diabetics without proteinuria (negative Albustix test). ive females and males had an elevated urinary albumin excretion at the time screening, mean 5 \m=+-\26 (sd) mg/ h. Our upper normal range for urinary albumin excretion is \m=le\0 mg/ h. The 5 patients with the highest albumin excretion subsequently developed persistent albuminuria, 2 \ar=r\ 0 mg/ h, P < 0.05, elevated serum creatinine, \ar=r\ \g=m\mol/l,p < 0.05, and raised blood pressure, 5/6 \ar=r\ /1 mmhg, intermittent albumin- P < One patient developed uria (positive Albustix test), while the variables in the remaining 2 patients were about the same during the 6 years observation period. ifteen patients had a normal urinary albumin excretion, mean 1 \m=+-\9 (sd) mg/ h, at the time the screening. ntermittent and persistent albuminuria developed in 2 patients, while albumin excretion, serum creatinine, and blood pressure were nearly unchanged in the remaining patients after 6 years. Our longitudinal study indicates that early detection patients at high and low risk developing persistent proteinuria i.e. diabetic nephropathy, is possible by using a sensitive method for measuring urinary albumin excretion. The onset diabetic nephropathy is insidious, the earliest and most important clinical sign is protein uria (positive Albustix). n the early stages protein uria tends to come and go, but later it persists and increases in amount. Approximately 0% juvee-onset insulin-dependent diabetics (DD) develops persistent proteinuria (Knowles ; Cameron et al. 5; Decken et al. ). Renal failure due to diabetic nephropathy is the single major cause death (0%) in DD patients (Decken et al. ). t is well documented that urinary albumin excretion can be to times higher than normal, without being detected by conventional laboratory test, e. g. Albustix (Parving etal. ). The aim our study was to elucidate if a sensitive method for determination urinary al bumin concentration can be used to detect patients at high risk developing diabetic nephropathy (persistent proteinuria). aterial and ethods All diabetic patients without proteinuria visiting the out-patient clinic at teno emorial Hospital during a day period in were systematically recorded. All patients ( female and 9 male) fulfilling the following criteria participated in the present study: age between and 0 years, onset DD before years age, duration between and 25 years, no clinical or laboratory evidence renal disease, normal serum creatinine (< 0 umol/1), sterile urine without ketone bodies, negative Albustix tests, and diastolic blood pres sure < 0 mmhg. All 25 subjects were insulin-depend ent (ketosis-prone) from the time diagnosis and all

2 patients received two daily injections insulin. None the patients were taking drugs, except insulin. The urine was collected at home for one h period in from all 25 patients. The urine was stored deepfrozen until analyses. Urinary albumin concentration was measured using a radial immunodiffusion technique (ancini et al. 65). The inter-assay variation expressed as a variation coefficient is 5.5%. The upper normal range for urinary albumin excretion is in our laboratory < 0 mg/ h. This value is in close agreement with previous studies in apparently healthy subjects, as re viewed by kaarup (). To test the sensitivity the Albustix readings urinary albumin concentration was measured in DD patients with trace positive Albu stix test. The mean urinary albumin concentration was 9 mg/1, range to 222 mg/1. Assuming a log normal distribution urinary albumin concentration the confi dence limit is to mg/1 (mean ± 2 D) for trace positive Albustix test. Urinary albumin excretion was measured 1 to times each year until June 0 in the patients with an elevated value at the time the screen ing (Table 1). n the remaining patients urinary albumin excretion was only measured once or twice in 0 (Table 2). These repeated measurements were always carried out under ordinary conditions life. Nearly all subjects visited the out-patients clinic at 2 to months. teno emorial Hôpital regularly every At each visit post-prandial blood glucose, proteinuria, ketone bodies and Albustix tests the urine were performed. Blood and urinary glucose were measured by a glucose oxidase method. Daily urinary protein excre tion was measured according to Tsuchiaya (0) at each visit in the out-patient clinic, if Albustix test was positive. erum creatinine was measured using a reaction rate technique (Larsen 2). Blood pressure was measured twice in the supine position, at the start and at the end the 6 years observation period. ore frequent determi nations were carried out in the patients with elevated albumin excretion. Diastolic blood présure was recorded at the disappearance the Korotkf sounds (phase 5). ntermittent proteinuria is defined as positive Albustix tests which tends to come and go. At least % the urine samples were positive. Persistent proteinuria is defined as urinary protein excretion more than 0.5 g/ h on each consecutive visits (interval between visits 2 to months). Diabetic nephropathy was diagnosed clinically if the following criteria were ful filled : persistent proteinura, presence diabetic retinopathy and no clinical or laboratory evidence disease the or kidneys the renal tract other than diabetic ne phropathy. The -test for paired and unpaired observations was used for statistical analysis. Table. Clinical and laboratory data at the time screening in insulin-dependent diabetics with elevated urinary albumin excretion (). ubject No. ex Age deal body weight (%) Onset Duration nsulin dose (U/kg) Retinopathy erum creatinine (umol/1) Blood pressure (mmhg) Albumin uria (mg/ h) /0 0/0 0/90 0/0 5/90 0/90 0/90 5/5 5/0 0/0 10/0 /1 10/0 / /0 0/0 5 ean ±D / /9 2/99 / * : simplex; P: proliferative. : values obtained at the time screening in. : values obtained at the end the observation period in 0. Blood pressure in subjects 5 to represents values before start antihypertensive treatment. the latest

3 Table 2. Albuminuria during 6 years in long-term insulin-dependent diabetics. All patients had slightly elevated urinary albumin excretion at the time screening. ubject No. screening Urinary albumin excretion rate (mg/ h) (-6) (-1) (-22) 29 (-) 92 0 (-51) (21-6) 21 (-) (-2) 1 (-) (9-6) 5 (5-61) 1 (-9) 221 (9-60) 2 (0-) 6 (250-60) 6 9 (69-) 5 (6-) (2-5) 655 (5-2) 1 (5-9) 00 (0-0) (6-61) 91 (26-) 692 (2-9) (56-) 22 (-) 65* (16-6) 66* (-99) ** 0 0 (5-5) 0 (-1) (5-10) 2 (9-52) * (-) (2-66) 59 (6-0) 55 (900-90) 90 (6-2) 50* (06-60) ean with range indicated in parentheses. Values without range represent single determination. * Values obtained during anti-hypertensive treatment. ** Died in 0 from acute myocardial infarction. Results Urinary albumin excretion was elevated in 5 fe males and males at the time screening in (Table 1). n subject 1 and 2 all subsequent values, including those obtained in, were normal (Table 2). n the remaining females and males albuminuria persisted and increased progressively with time (Table 2). ntermittent proteinuria de veloped after 65 months in subject, while persi stent proteinuria developed after 26 to 56 months (mean months) in the last 5 patients. These 5 patients had a rise in serum creatinine,» pmol/1 (P < 0.05), and in blood pressure, 5/6 -+ /1 mmhg (P < 0.05) during the observation period (Table 1). A reduction albuminuria was found after the start antihypertensive treatment in out patients (No. 5 to ). Patient No. 6 died from an acute myocardial infarction in 0. eventeen patients had a normal urinary albumin excretion at the time screening, and it remained normal in these patients after 6 years (Table ). erum creatinine and blood pressure remained nearly unchanged, (P > 0.1). Positive Albustix tests have never been found in any these patients. ntermittent and persi stent proteinuria developed in 2 patients (No. and ). One female and one male dropped out during the investigation in and 9, respec tively. Positive Albustix tests had never been de monstrated in these 2 patients. Urinary glucose excretion measured on the samples used for the initial albumin determination in showed a mean 1 g/ h (range 0 0 g/ h) in the patients with elevated albumin excretion compared to 0 g/ h (range 0 6 g/ h) in the remaining patients, P < Ketone bodies were not present in any the urine samples.

4 Table. Clinical and laboratory data in insulin-dependent diabetics with normal urinary screening (). albumin excretion at the time ubject No. ex Age deal body weight (%) Onset Duration nsulin dose (U/kg) Retinopathy erum creatinine (Hmol/1) Blood pressure (mmhg) Albuminuria (mg/ h) P 'î 92 5/90 5/95 0/0 5/0 5/5 5/0 0/0 0/0 0/0 0/0 5/0 5/0 0/60 0/95 0/0 0/5 0/95 5/0 5/5 0/0 0/5 0/5 0/90 0/90 0/90 0/0 5/0 5/0 5/0 0/ ean ±D /1 /9 0/2 / ** ** * : simplex; P: proliferative. ** ubject and not included in mean values. : values obtained at the time screening in ; : values obtained at the end the observation period in 0. Discussion The present DD patients were selected, as men tioned above, in order to obtain a homogeneous group patients with the usual risk (about 0 0%) developing clinical diabetic nephro pathy i.e. persistent proteinuria. Persistent pro teinuria is rare before years age and within the first years duration (Knowles ). Persistent proteinuria is nearly always due to diabetic nephropathy in DD patients less than 1 years age, while the number other causes (biopsy-proven) increases with increasing age (alins 6). DD patients who have survived for 0 years have a low risk developing clinical diabetic nephropathy (Decken et al. 1). A completely reversible increase in urinary albu min excretion has been demonstrated in poorly 6; Par- controlled DD patients (ogensen ving et al. 6). Thus only patients without ketonuria were included in our study. Patients with diastolic blood pressure > 0 mmhg were ex cluded, since elevated urinary albumin excretion has been demonstrated in patients with diastolic blood pressure > 0 mmhg due to essential hypertension (Parving et al. ). inally it should be stressed that none our patients had Albustix positive urine samples prior to the screening test. Our study showed that out 25 DD patients had an elevated urinary albumin excretion at the time the screening. Diabetic retinopathy was present in all these patients, while only 5 the remaining patients had this complication in. The mean age was higher and the duration longer in the patients with elevated albumin excretion. The urinary albumin excretion remained elevated in 6 out patients with initial abnormal values. Our longitudinal study showed that 5 these patients developed persistent proteinuria (diabetic nephro-

5 pathy) months after the time the screening. One patient progressed to intermittent protein uria. We have no obvious explanation for the normalization the urinary albumin excretion in the 2 female patients (No. 1 and 2) with an elevated initial value. Regression towards mean may contri bute to the findings. t is well established that nearly all (> 95%) DD patients with diabetic nephropathy have diabetic retinopathy (Cameron et al. 5). This implies that DD patients with retinopathy are high risk patients who deserve careful screening for diabetic nephropathy. n the other patients urinary albumin excretion re mained normal in, while intermittent and persi stent proteinuria developed in 2 patients. Diabetic background retinopathy was present in these 2 patients in 0. Our findings indicate that early detection patients at high and low risk devel oping persistent proteinuria is possible by using a sensitive method for urinary albumin excretion. n contrast, kidney biopsy can not be used as a valid method for early detection clinical diabetic nephropathy, since less than half the DD patients with histological evidence diabetic glomerulosclerosis develops persistent proteinuria, deterioration in kidney function, and end stage renal failure (Honey et al. 62; Cameron et al. 5). While serum creatinine and blood pressure re mained normal and unchanged in patients with normal urinary albumin excretion, a clear rise in both variables was found in patients developing persistent proteinuria. Recently, we have demon strated that elevation in blood pressure to a hyper tensive level is an early feature diabetic nephro pathy in young DD patients (Parving et al. 1b). Early detection patients at high risk developing diabetic nephropathy is important from a prognostic point view but probably also from a therapeutical point view. Elevated arte rial blood pressure enhance the development diabetic nephropathy in man and in rats (Berkman & Rifkin ; auer et al. ). Early and aggressive antihypertensive treatment reduces albuminuria in young DD patients with diabetic nephropathy (ogensen 0; Parving et al. 1a). ore important, ogensen (0) has shown that satisfactory control blood pressure in diabetic nephropathy may reduce the rate de cline in glomerular filtration rate. Viberti et al. (9) have demonstrated that days strict metabolic control achieved by using continuous sc insulin infusion can reduce an abnormally elevated urinary albumin excretion in DD patients with out proteinuria (Albustix negative). Urinary albu min excretion was about the same as in our with elevated values at the time the patients screening. The reversible nature the raised albumin excretion in the very early stages diabe that strict metabolic tic nephropathy might suggest control for a prolonged period might delay or even prevent development persistent proteinuria and deterioration in glomerular filtration rate. References Berkman J & Rifkin H (): Uateral nodular diabe tic glomerulosclerosis (Kimmelstiel-Wilson). Report acase. etabolism 22: -22. Cameron J, reland J T & Watkins P J (5): The kidney and renal tract. n: Keen H Jarrett J (eds). Complications Diabetes, p Edward Arnold, London. Decken T, Poulsen J E & Larsen (): Prognosis diabetics with onset before the age thirtyone. Diabetologia : 6-0. Decken T, Andersen A R, Christiansen J e Andersen J K (1): Course diabetic nephropathy. actors related to development. Acta Endocrinol (Copenh), uppl2: -. Honey G E, Pryse-Davils J e Roberts D (62): A survey nephropathy in young diabetics. Q J ed : -. Knowles H C (): agnitude the renal failure problem in diabetics. Kidney nt, upp : 2. Larsen K (2): Creatinine assay by a reaction-kinetic principle. Clin Chim Acta 1: alins J (6): Renal disease in. n: alins J (ed). Clinical Diabetes ellitus, p 2. Eyre and pottiswoode, London. ancini G, Carbonara A O & Heremans J (65): mmunochemical quantitation antigens by single radial immunodiffusion. mmunochemistry 2: auer, teffes W, Azar, andberg K & Brown D (): The effect Goldblatt hypertension on development the glomerular lesions mellitus in the rat. Diabetes : -. ogensen C E (6): Renal function changes in dia betes. Diabetes, uppl 2: 2-9. ogensen C E (0): Antihypertensive treatment in hibiting the progression diabetic nephropathy. n: Ditzel J (ed). Diabetes and Diabetes Treatment. Acta Endocrinol (Copenh), uppl : -. Parving H-H, Jensen H AL, ogensen C E & Evrin P-E (): ncreased urinary albumin-excretion rate in benign essential hypertension. Lancet 1:

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