Diabetologia Springer-Verlag 1986

Transcription

1 Diabetlgia (196) 29:22-26 Diabetlgia Springer-Verlag 196 Increased transcapillary escape rate f albumin in Type 1 (insulin-dependent) diabetic patients with micralbuminuria B. Feldt-Rasmussen Sten Memrial Hspital, Gentffe, Denmark Summary. The transcapillary escape rate, intravascular mass and utflux f albumin were measured in 75 Type 1 (insulindependent) diabetic patients. The grups were defined as: grup 1 : nrmal urinary albumin excretin, < 30 mg/24 h (n =21); grup 2: micralbuminuria, rag/24 h (n=36); grup3: diabetic nephrpathy, <300mg/24h (n= 1). Fifteen sex- and age-matched nn-diabetic persns served as cntrl subjects. The diabetes duratin was: grup1: 20 9years, grup2: 17_+5years, grup3: 19_+ 7 years. The transcapillary escape rate f albumin was similar in cntrls and grup I (5.0_+ 1. versus 5.2_+ 1.5%) and was significantly higher in the micralbuminuric grup2 and grup 3 (.1 _ 2.2 versus.1 _+ 2.3%). The differences were nt explained by differences in metablic cntrl r bld pressure at the time f investigatin. The utflux f albumin was als higher in grup 2 than in grup I and cntrls (7.1 _+ 2.0 versus 5.3_+1.5 and 5.1_+ 2.0 g/h 1.73 m2). It was indistinguishable frm cntrls in grup 3 (5. _+ 1.5 g/h x 1.73 m 2) because f a reduced intravascular mass f albumin (p < 0.01) in grup 3. In cnclusin, a universal vascular leakage f albumin is an early event in the develpment f diabetic nephrpathy, with the leakage f albumin being fully develped in the micralbuminuric patient. In cntrast, lng-term diabetic patients with nrmal urinary albumin excretin have a nrmal transcapitlary escape rate f albumin. Key wrds: Type 1 (insulin-dependent) diabetes, micralbuminutia, transcapillary escape rate, plasma vlume, intravascular mass f albumin. Increased transglmerular passage f plasma prteins as demnstrated by the presence f mre than 0.5 g prtein in 24-h urine is the diagnstic marker f clinical diabetic nephrpathy. Preceding this stage, i.e. in the stage f incipient diabetic nephrpathy, the urinary albumin excretin rate (UalbV) is slightly elevated ( mg/24 h, Albustix negative), but these patients are at high risk fr later develpment f clinical diabetic nephrpathy [1-4]. The pathphysilgical basis fr the slightly elevated urinary albumin escape seen in early diabetic renal disease has been debated intensively. It is usually ascribed t abnrmalities lcated specifically in the kidneys - haemdynamic alteratins [5, 6] and/r alteratins in the prperties f the glmerular filter [7, ]. Hwever, these changes might nt be restricted t the kidneys. Indicatins f mre generalized alteratins in the transcapillary passage f small mlecules [9] and f macrmlecules [10-12] in patients with diabetic micrangipathy have been presented. In previus studies the transcapillary escape rate f albumin (TERalb) was fund t be nrmal in shrt-term diabetic patients, but elevated in patients with clinical signs f micrangipathy r arterial hypertensin [10-12]. In the present study the TERalb was investigated in lng-term Type 1 (insulin-dependent) diabetic patients with different levels f UalbV (nrmal range t vert diabetic nephrpathy) as well as in nrmal cntrls. The aim was t investigate whether a generally increased passage f albumin (i. e. TERaIb) is the result f diabetes duratin alne r whether it is mre specifically cnnected t the early r late develpment f diabetic nephrpathy (i. e. the level f UalbV) in Type 1 patients. Subjects and methds Subjects Seventy-five Type I patients with a diabetes duratin f mre than five years were studied. They had n histry f nn-diabetic renal r cardiac disease, and all had a negative bacterial culture f the urine. Fifteen healthy nn-diabetic persns served as cntrls. All subjects gave their infrmed cnsent fr participatin, and the study was apprved by the Reginal Ethics Cmmittee. The patients were subdivided int three grups accrding t the level f albuminuria identified n the basis f the median UalbV in three 24-h urine cllectins perfrmed at hme during nrmal physical activity. This was dne in

2 B. Feldt-Rasmussen: Transcapillary escape rate in diabetes 23 rder t take int accunt the high (50%) day t day variatin f the 24 h UalbV [13]. Nrmal cntrls delivered ne 24-h urine. The three grups were defined as fllws: v-~ v-~ x--~ x--~,r ~ v-~ +1 I q-i I "t-i I +1 I +1 I +1 I q'~ +[ I r~v-~ +1 I Grup 1:21 Type 1 patients with nrmal UalbV, belw 30 mg/24 h, and with bld pressure belw 160/95 mmhg. Grup2: 36Type I patients with elevated UalbV in the range f mg/24 h, i.e. the patients with incipient diabetic nephrpathy. Twelve mnths prir t the study these patients had entered a clinical trial f the effect n the UalbV f imprved metablic cntrl using prtable insulin pumps (CSII) versus cnventinal insulin treatment (CIT) as previusly described [14]. g I I I I +1 I +1 I +1 I q 0 ~e4 ~"~ x-<,'q ~ Grup3:1 Typel patients with diabetic nephrpathy (UalbV > 300 mg/24 h). Any nging antihypertensive treatment had been discntinued fr weeks except in tw patients receiving diuretics due t mild edema. The clinical characteristics f patients and cntrls are shwn in Table 1. A clse match f sex distributin, age and diabetes duratin was btained. The patients in grup I and 3 and the CIT grup received cnventinal insulin treatment, i.e. 2-3 daily injectins f intermediate -acting insulin ften mixed with shrt-acting insulin. Methds " eq ~ +[I +1 I +[I +l I q-[ [ +1 I +1 I e,i "~ "~ ~ b~ ~ t-.~ e 3 +1 I "~ +1 I ~ The transcapillary escape rate f albumin was measured as described by Parring [15]. The investigatins were carded ut in the mrning preceded by a nrmal breakfast and insulin injectin at hme A canulla was inserted in the antecubital vein in each arm, and the patients had rested fr 60 min in the supine psitin. 125I-human serum albumin (Cde IFA-IT23S, Kjeller, sl, Nrway) was used. After intravenus injectin f the tracer (2 lxci) in ne arm, 7 bld samples were cllected frm the ther arm during the first hur. Plasma radiactivity was measured in each sample using a well-type scintillatin detectr and expressed as cpm/g ttal plasma prtein. These ratis were pltted in semilgarithmic scale, and the transcapillary escape rate was calculated as the disappearance rate cnstant. Thus, the TER~tb is the fractin f the intravascular mass f albumin leaving the vascular bed per hur (%/h). Plasma vlume (PV, ml/1.73 m 2) was determined by retrplatin f the disappearance curve t zer time and frm the injected vlume f tracer. The glmerularfiltratin rate (GFR) was measured with single intravenus injectin f 51Cr EDTA, pltting the plasma disappearance f the tracer fr 4 h [16]. The mean intraindividual cefficient f variatin was 4.1% b d~ g Serum albumin (g/l) was measured using an ELISA assay [13]. The interassay variatin was.3%. Frm these determinants the intravascular mass f albumin and the utflux f albumin per hur were calculated. Intravascular mass f albumin (IVM) was calculated as plasma vlume times s-albumin (g/1.73 m2). utflux f albumin was calculated as IVM times TER~Ib (g/h 1.73 m2). ~ '~., ~-.. = =ll ~ +~ ~1- ta ~ ~I r~ ~,. ~ The urinary albumin excretin was measured using an ELISA-assay [13]. HbA1c was measured by a chrmatgraphic technique [17]. The nrmal range was %. S-creatinine was measured by a reactin rate kinetic principle eliminating pseud-creatinines [1]. The interassay variatin was 2.5%.

3 24 B. Feldt-Rasmussen: Transcapillary escape rate in diabetes B-glucse was measured three times during the study using Hypcunt (Sufflk, UK). Statistical analysis Results are given as mean + SD. The paired and unpaired Student's t- tests were used fr cmparisns within and between grups. UalbV values were lg-transfrmed befre calculatins. Significance levels were 0.05 (tw-tailed). h e-i ~ rq e,i +[ +1 +l +[ +1 -~ h ~- 0 0 ~ rz ~5 ~4 ~eq Results The TERalb was similar in nrmal cntrls and grup I ~ (Fig. 1). It was significantly higher in grup 2 patients -~ with incipient nephrpathy (p<0.01), and the mean TERalb f grup 2 and 3 was identical (Fig. 1). There,= was n significant crrelatin between TERal b and age ~= r TERalb and UalbV in any f the grups. The bld pressure was higher and the GFR was lwer in grup 3 cmpared with the ther three grups (Table 1). The lng-term metablic cntrl (HbA~) was wrse in grup3 cmpared with the ther grups ~ (Table 1). B-glucse n the day f study was fund t be significantly higher (p<0.01) in this grup cmpared with grup I (Table 2). Hwever, in grup 2 the 1 cn- ~, ventinally treated patients had similar metablic cn- "? trl, whereas the 1 insulin pump treated patients were in a significantly (p<0.01) better metablic state (Tables I and 2). This difference in metablic cntrl,- was nt reflected in different levels f TERalb within grup 2 (CSII vs. CIT, Fig. 1). ~. S-albumin was significantly lwer in the cnven-.~= tinally insulin-treated patients in grup 2 cmpared ~, with the nrmalbuminuric grup I and nrmal cn- ) N ~n.e > - 3 ~r--- ~v z~ +l +1 +l +l +1 ~ ~[ r4 ~ ~==~1 +~ +, +, +, (N xl xl +l +l l q t~l ~ +l +l +l +l +l ~-... ~ 0" l +[ +l. ~. ~ eq ~Z ~eq >;2,.-~ ~.9 "a? ~ 12- ~ ~- = ~ - uj~ < s- _~_z cell. ~-..'; ' "i i. I I I t I I I I NRMAL GRUP 1 GRUP 2 GRUP 3 SUBJECTS Fig. 1. The transcapillary escape rate f albumin in Type I (insulindependent) diabetic patients with different levels f urinary albumin excretin. Grup1 (n=21): Nrmal urinary albumin excretin < 30 mg/24 h. Grup 2 (n = 36): Incipient diabetic nephrpathy, i. e. urinary albumin excretin frm mg/24 h, Grup 3 (n = 1): Diabetic nephrpathy, i.e. urinary albumin excretin >300mg/24h. Hrizntal bars indicate mean values. ~Cnventinal insulin treatment. ~Cntinuus subcutaneus insulin infusin (CSII) fr 12 mnths. The values in grup 2 and 3 are significantly higher than in nrmal cntrls and grup I (p< 0.01) y.= +l +l +l +l +l V ~,.~ em ~ ~ ~= ~ ~ ~:A.... = ~ ~.= ~ ~ ~ Z ~ D cq C~ t~ > +1 ~.~ -d = '~ll ~

4 B. Feldt-Rasmussen: Transcapillary escape rate in diabetes 25 tris, and even lwer in grup 3 (p< 0.05, Table 2). The plasma vlume was similar in all grups, with a tendency t lwer values in grup2 (all 36 patients, p< 0.05) and, in cnsequence, the intravascular mass f albumin was significantly reduced in the grups with lwer S-albumin (Table 2). The utflux f albumin in grup 3 was indistinguishable frm nrmal cntrls and grup I in spite f the elevated TERalb, because f the reduced intravascular mass f albumin. Discussin This study has shwn that the TERalb is nrmal in lngterm diabetic patients with nrmal UalbV. It has als shwn that the TERalb is elevated t the same level in patients with micralbuminuria and in patients with vert clinical diabetic nephrpathy. This bservatin crrbrates the hypthesis that there may be a ceiling fr the maximum rate f escape f albumin frm the circulatin [11]. Increased values f TERalb have been demnstrated previusly in lng-term diabetic patients with varius degrees f micrangipathy and nrmal bld pressure [10-12], and a nrmal TERalb has been fund in shrt-term diabetic patients withut micrangipathy [10, 11]. Hwever, ur bservatin f a bimdal distributin f the TERalb in lng-term diabetic patients with Albustix negative urine, but different albuminuric levels, is new. The grups were well-matched accrding t sex, age and diabetes duratin. The diabetes duratin was as lng r even lnger than in previus studies f TER~b and lng-term diabetes [10-12]. The TERalb is elevated in patients with arterial hypertensin [11, 15], and the bld pressure has been reprted t be slightly elevated in diabetic patients with micralbuminuria [19-21]. Hwever, befre entrance int this study, grup 2 patients with resting bld pressure higher than 160/95mmHg were excluded; therefre, the mean bld pressure was the same in grup I and 2 and thus culd nt accunt fr the elevated TER~bin the micralbuminuric grup 2. Imprved metablic cntrl reduces the TERa~b in prly regulated shrt-term diabetic patients, insulin-dependent [22] as well as nn-insulin-dependent [11]. Differences in metablic cntrl at the time f investigatin culd nt explain the bserved differences in TERalb in this study, because the metablic cntrl n the day f study was similar in grup 1 and the insulin pump treated grup 2 patients. Furthermre, the TERalb was unchanged during 12 mnths f strict metablic cntrl (data nt shwn). This is in cntrast t what was fund in shrt-term insulin-dependent diabetic patients [22]. Therefre, the metablically independent elevatin f TERalb seen in the micralbuminuric grup 2 patients may be a marker f a mre fundamental structural micrvascular lesin, leading t the clinical manifestatin f diabetic micrangipathy. The actual utflux f albumin frm the vas- cular bed was higher in the micralbuminuric grup 2 cmpared with nrmal cntrls and grup I in spite f a decreased intravascular mass f albumin in grup 2. In grup 3 (diabetic nephrpathy) an utflux f albumin was fund indistinguishable frm nrmal cntrls and grup 1. This was due t a lwer intravascular mass f albumin in these patients. The reduced intravascular mass f albumin fund in grups 2 and 3 will result in a decreased, intravascular cllid smtic pressure which might lead t the edema ften fund in patients with diabetic nephrpathy. Hwever, the interstitial cllid smtic pressure was nt measured in this study. The significance f an increased utflux f prteins is unknwn, but it might be an imprtant mechanism in the develpment f diabetic micrangipathy [, 23]. The cincident bservatin f micralbuminuria and increased TERalb may indicate that the structural and/ r haemdynamic abnrmalities underlying the increased escape f albumin in the glmerular and extrarenal capillaries are the same. These abnrmalities seem t be absent in lng-term diabetic patients with nrmal UalbV, pssibly explaining the almst nrmal life expectancy f Type 1 patients wh d nt develp prteinuria [24]. The structural abnrmalities are prbably different frm what is classically described as diabetic micrangipathy, since in grup 2 the increased UalbV and TER~b were bserved in many patients, even befre micraneurisms had appeared. Furthermre, the UalbV was fund nrmal in many lng-term diabetic patients, demnstrating glmerulsclersis and increased thickness f the glmerular basement membrane [25]. In cnclusin, lng-term diabetic patients with nrmal UalbV have nrmal TERalb values, whereas lngterm diabetic patients with persistent micralbuminuria have an increased TER~b, independent f current metablic cntrl and bld pressure. These patients als demnstrate a decreased intravascular mass f albumin. Thus, micralbuminuria indicates prfund alteratins in Type 1 patients, and these alteratins might be crucial in the develpment f lethal diabetic cmplicatins. Acknwledgements. This wrk was supprted by grants frm the J and Juhls Fundatin, the Michaelsen Fundatin, Diabetesfreningen, Landsfreningen fr Sukkersyge and the Danish Medical Research Fundatin. Ms. M. Deckert and Ms. H. Fght are thanked fr their skillful technical assistance. References 1. Parving H-H, xenbll B, Svendsen PAa, Christiansen JS, Andersen AR (192) Early detectin f patients at risk f develping diabetic nephrpathy. A lngitudinal study f urinary albumin excretin. Acta Endcrinl 100: Viberti GC, Hill RD, Jarrett RJ, Argyrpuls A, Mahmud U, Keen H (192) Micralbuminuria as a predictr f clinical nephrpathy in insulin-dependent diabetes mellitus. Lancet 1:

5 26 B. Feldt-Rasmussen: Transcapillary escape rate in diabetes 3. Mathiesen ER, xenbll B, Jhansen K, Svendsen PAa, Deckert T (194) Incipient nephrpathy in Type 1 (insulin-dependent) diabetes. Diabetlgia 26: Mgensen CE, Christensen CK (194) Predicting diabetic nephrpathy in insulin-dependent patients. N Engl J Med 311: Hstetter TH, Rennke HG, Brenner BM (192) The case fr intrarenal hypertensin in the initiatin and prgressin f diabetic and ther glmerulpathies. Am J Med 72: Parving H-H, Viberti GC, Keen H, Christiansen JS, Lassen NA (193) Hemdynamic factrs in the genesis f diabetic micrangipathy. Metablism 32: Mauer SM, Steffes MW, Getz FC, Sutherland DER, Brwn DM (193) Diabetic nephrpathy. A perspective. Diabetes Suppl 2: Deckert T, Feldt-Rasmussen B, Mathiesen ER, Baker L (194) Pathgenesis f incipient nephrpathy: a hypthesis. Diabetic Nephrpathy 3 : 3-9. Trap-Jensen J (1971) Permeability f small vessels in diabetes. Acta Diabet Lat (Suppl 1): Parving H-H, Munkgaard Rasmussen S (1973) Transcapillary escape rate f albumin and plasma vlume in shrt- and lng-term juvenile diabetes. Scand J Clin Lab Invest 32: 'Hare JA, FenSs JB, Twmey B, 'Sullivan DJ (193) Pr metablic cntrl bpyertensin and micrangipathy independently increase the transcapillary rate f albumin in diabetes. Diabetlgia 25: Fauchald P, Nrseth J, Jervell J (195) Transcapillary cllid smtic gradient, plasma vlume and interstitial fluid vlume in lng-term type 1 (insulin-dependent) diabetes. Diabetlgia 2: Feldt-Rasmussen B, Dinesen B, Deckert M (195) Enzyme immun assay - an imprved determinatin f urinary albumin in diabetics with incipient nephrpathy. Stand J Clin Lab Invest 45: Feldt-Rasmussen B, Mathiesen ER, Hegedus L, Deckert T (196) Kidney functin during 12 mnths f strict metablic cntrl in insulin dependent diabetic patients with incipient nephrpathy. N Engl J Med 314: Parving H-H, Gyntelberg F (1973) Transcapillary escape rate f albumin and plasma vlume in essential hypertensin. Cir Res 32: Brrchner-Mrtensen J, Giese J, Rssing N (1969) Renal inulin clearance versus ttal plasma clearance f 51Cr-EDTA. Scand J Clin Lab Invest 23 : Svendsen PAa, Christiansen JS, Segaard U, Welinder BA, Nerup J (190) Rapid change in chrmatgraphically determined haemglbin Aa induced by shrt-term changes in glucse cncentratin. Diabetlgia 19: Larsen K (1972) Creatinine assay by a reactin-kinetic principle. Clin Chim Acta 41 : Wiseman M, Viberti GC, Mackintsh D, Jarret R J, Keen H (194) Glycaemia, arterial pressure and micralbuminuria in type 1 (insulin-dependent) diabetes mellitus. Diabetlgia 26: Feldt-Rasmussen B, Brch-Jhnsen K, Mathiesen ER (195) Hypertensin in diabetes as related t nephrpathy. Early bldpressure changes. Hypertensin 7 (Suppl II): Feldt-Rasmussen B, Baker L, Deckert T (195) Excercise as a prvcative test in early renal disease in type 1 (insulin-dependent) diabetes: albuminuric, systemic and renal haemdynamic respnses. Diabetlgia 2: Parving H-H, Ner I, Deckert T, et al (1976) The effect f metablic regulatin f micrvascular permeability t small and large mlecules in shrt term juvenile diabetes. Diabetlgia t2: Lendrum AC (1963) The hypertensive diabetic kidney as a mdel f the s-called cllagen disease. Can Med Assc J : Brch-Jhnsen K, Kragh Andersen P, Deckert T (195) The effect f prteinuria n relative mrtality in Type 1 (insulin-dependent) diabetes mellitus. Diabetlgia 2: Mauer SM, Steffes MW, Ellis EN, Sutherland DER, Brwn DM, Getz FC (194) Structural-functinal relatinships in diabetic nephrpathy. J Clin Invest 74: Received: 24 ctber 195 and in revised frm: 3 February 196 Dr. B. Feldt-Rasmussen Sten Memrial Hspital DK-220 Gentfte Denmark