Diabetologia 9 Springer-Verlag 1985

Transcription

1 Dibetologi (1985) 28: Dibetologi 9 Springer-Verlg 1985 riginls xercise s provoctive test in erly renl disese in Type 1 (insulin-dependent) dibetes: lbuminuric, systemic nd renl hemodynmic responses B. Feldt-Rsmussen 1, L, Bker 2 nd T. Deckert 1 1Steno Memoril Hospitl, Gentofte, Denmrk nd 2Children's Hospitl of Phildelphi, Phildelphi, Pennsylvni, USA Summry. The vlue of exercise s provoctive test for erly renl disese in Type 1 (insulin-dependent) dibetes ws reevluted. Three crefully chrcterized groups of mles were studied: 10 non-dibetic controls, 16 dibetic ptients (group1) with norml urinry lbumin excretion (< 15 ~tg/min) nd 14 Albustix-negtive dibetics (group 2) with incresed urinry lbumin excretion ( xg/min). Assignment to study group ws mde on the bsis of three 24-h urine collections, nd the groups were well mtched for ge, weight, height, nd serum cretinine concentrtion. The two dibetic groups were similr with regrd to durtion of disese ( versus 16_+3 yers), metbolic control (HbAlo: versus %) nd degree of dibetic complictions (bet-to-bet vrition nd retinopthy). An exercise protocol of 450 nd 600 kpm/min worklods ws employed. In the resting stte group 2 ptients hd elevted systolic blood pressure compred with the norml subjects ( versus mmhg), nd their glomerulr filtrtion rte ws significntly reduced compred with group 1 (123 _+ 19 versus ml/min per 1.73 m 2, p <0.05). During exercise the urinry lbumin excretion rte incresed significntly in ll three groups (norml subjects: 6_+0.7 to 8_+ 1.3 (~tg/min); group 1:6_+0.6 to 9_l~tg/min nd group 2:48-0 to ,g/min), the reltive increse being higher in group 2 (p < 0.01). The chnges in systemic hemodynmics were similr in ll three groups in spite of reduced mximum working cpcity in group 2 (949 _+ 249 versus group 1:1163 _+ 200 nd norml subjects 1267 _+ 264 kpm/min (p<0.05). The renl hemodynmic chnges were qulittively similr for the three groups, but the filtrtion frction during exercise incresed in groups 1 nd 2 to lmost identicl vlues nd were significntly higher thn in norml subjects (group 1 + group 2:0.29_+0.02 versus norml subjects: 0.26_+0.03, p<0.02). These findings suggest tht n elevted trnscpillry pressure grdient, s obtined during moderte exercise, will not cuse n bnorml increse in lbumin excretion per se. A functionl glomerulr lesion, lredy recognisble t rest (elevted lbumin excretion) must lso be present. Keywords: Type 1 dibetes, incipient nephropthy, exercise, lbuminuri, renl hemodynmics, glomerulr filtrtion rte, blood pressure, working cpcity. The exercise provoctive test ws introduced for detection of erly chnges in dibetic renl disese by Mogensen nd co-workers in the erly 1970s [1]. Specificlly, moderte physicl exercise could cuse incresed urinry lbumin excretion (Ulb V) in ptients with Type 1 (insulin-dependent) dibetes, who hd norml levels of U]bV in the resting bsl stte. Their observtions were confirmed by others [2], but were lso subject to criticism [3, 4]. Recently, the reltive increse in UlbV during exercise ws found to be equl in ptients with either norml or elevted bseline UlbV [5]. This observtion indicted tht minor bnormlities in the glomerulr hndling of lbumin might lredy be recognisble t rest. The discrepncies between the observtions in these previous studies cnnot redily be explined, but differences in the wy the exercise test ws dminis- tered nd in the composition of the study groups mke comprisons difficult. The mechnism underlying exercise induced lbuminuri is unknown. The glomerulr filtrtion rte (GFR), the renl plsm flow (RPF) nd the filtrtion frction re signifcntly elevted in dibetic ptients from the time of dignosis compred with norml subjects [6-9]. It hs been speculted tht further exggertion of the bnorml renl hemodynmics my be responsible for the exercise-induced increse in UlbV [10]. Furthermore, positive correltion between exercise-induced systolic pressure nd exercise-induced UlbV hs been demonstrted [5]. Thus the exercise test my be of importnce s dignostic test s well s tool for investigting systemic

2 390 B. Feldt-Rsmussen et l.: xercise test in erly renl disese Tble 1. Clinicl chrcteristics of the study groups Age Height Weight Serum- (yers) (cm) (kg) cretinine (~mol/1) Dibetes HbAlc Bet-to- Retinodurtion (%) bet pthy ~ (yers) vrition (per rin) Normlsubjects _ (n=10) (28-53) ( ) (64-83) (85-111) Dibetic ptients with urinry 32_ _ _ _ 8 lbumin excretion <15 gg/min (19-40) ( ) (71-89) (77-108) (6-24) ( ) (3-38) (Group 1) (n = 16) Dibetic ptients with urinry _ _ _ _0 lbumin excretion >15 ~tg/min (20-47) ( ) (57-80) (77-105) (10-22) ( ) (4-33) (Group 2) (n =14) 7/9/0 5/9/0 Vlues given s men + SD with rnge in prenthesis. No significnt differences between the groups. < 3 microneurisms/simplex retinopthy/prolifertive retinopthy nd renl hemodynmic bnormlities in erly dibetic renl diseses. The present study ws undertken to re-evlute the lbuminuric response to exercise in Type I dibetic ptients with norml nd elevted UlbV compred with norml subjects. Systemic nd renl hemodynmics were lso studied. Subjects nd methods Ptient recruitment nd selection Thirty dult mle Type 1 dibetic ptients were studied. Ten ge mtched non-dibetic mles served s controls. The ptients were chosen on the bsis of durtion of dibetes (5-25 yers), Albustix-negtive urine, norml serum cretinine level, nd negtive urine culture. All ptients gve informed consent for their prticiption, nd the study ws pproved by the Regionl Medicl thics Committee. The ptients were subdivided into two groups ccording to their level of lbuminuri, identified on the bsis of the men U~bV in three 24-h urine collections performed t home during norml ctivity. This ws done to tke into ccount the lrge (50%) coefficient of vrition of the 24-h urinry lbumin excretion rte (Ulb V) [11,12]. Sixteen ptients formed group 1 nd were defined s normolbuminuric, with UlbV of< 15 gg/min. The 14ptients in group 2 were chrcterized by elevted UlbV with the men U,IbV of three 24-h urine smples rnging from ~g/min; 12 of these ptients were in the lower rnge of microlbuminuri with UlbV < 60 gg/min. The distribution of UlbV in 24-h urine smples of 239 norml subjects is skewed (medin 6.1, 95% percentiles: lxg/min) [13]. The chosen level of 15 lxg/min is the sme s used recently by Christensen [5], slightly bove the level used by Viberti et l. [2], but consistent with previously suggested definition of incipient nephropthy [14]. Ptient nd control dt re shown in Tble 1. The groups were well mtched for ge, weight, height, nd serum cretinine. The two dibetic groups did not differ significntly with regrd to durtion of disese, level of metbolic control, nd degree of dibetic complictions. The exercise protocol The exercise protocol of Mogensen et l. [14] ws used for these studies. The ptients reported to the exercise lbortory t h in the fsting stte, the most recent insulin dose hving been given before supper the previous evening. Alcohol nd tobcco were proscribed for t lest 12 h before the study. A cnnul ws inserted into n nte- cubitl vein in ech rm. After creful ttention to the chievement of stedy stte wter diuresis [15], two bsl timed urine specimens (20 min ech) were collected. The ptient ws exercised t 450 kpm/min (W 450), nd then t 600 kpm/min (W600) for 20 min; timed urine ws obtined t the end of ech period. Two post-exercise recovery periods of 20 min were ech ccompnied by urine collections. The ptients st in chirs except when voiding or exercising. The exercise lod ws performed on mechniclly brked electroniclly controlled ergometercycle (Monrk, model 669-1, Vrberg, Sweden). Systemic hemodynmics The blood pressure ws mesured by the indirect usculttory method, using sphygmomnometer nd cuff. The blood pressure ws mesured twice in the middle of ech period, nd lso fter 15 min of exercise t ech of the two work lods. During exercise the distolic pressure s ssessed by this method is not relible [16] nd is therefore not reported. The hert rte ws recorded from surfce electrodes, nd the men hert rte in 20-s periods ws clculted. Renl hemodynmic mesurements The GFR ws mesured by the clssicl constnt infusion technique with urinry collections [17] using 125I-iothlmte s the filtrtion mrker [18]. The results were corrected to body surfce re of 1.73 m 2. The intr-ssy coefficient of vrition in our lbortory ws 4.1%. The RPF ws defined s the extrction of hippurn, using 31Ihippurn [18]. This hs been shown to be relible technique for renl plsm flow, even during exercise [19]. These results were lso corrected to body surfce re of 1.73 m 2. The intr-ssy coefficient of vrition ws 4.3%. The filtrtion frction ws clculted s GFR/ RPF. Mximl working cpcity The mximl working cpcity ws determined t the end of the forml exercise study, pproximtely 60 min fter completion of the 600 kpm/min work lod. The ptients were llowed 5 min to wrm up t work lod of kpm/min. The work lod ws then incresed stepwise until the ptient becme exhusted. ch work lod ws mintined for 2 min, or until the hert rte ws stble in consecutive 20-s periods. At high work lods, this procedure ensures the chievement of stedy stte conditions, nd good correltion between hert rte nd oxygen uptke [20]. The work lod t which mximl oxygen uptke will occur Wm~x2) ws clculted from the following eqution: mximl hert rte - bsl hert rte Wmx02 = W 600 X hert rte t 600 kpm/min - bsl hert rte

3 B. Feldt-Rsmussen et l.: xercise test in erly renl disese 391 Lbortory mesurements xz~ :~ i ~ ~ ~ t"q +~ +[ t"q (-q +[ m..= ~D b -== HbAI~ ws mesured by chromtogrphic technique [21]; vlues for the non-dibetic for this procedure re 4.1%-6.4%. Urinry lbumin ws mesured by rdioimmunossy [22]. Bet-to-bet vrition ws ssessed ccording to wing nd Clrk [23]. Clssifiction of retinopthy ws done on the bsis of ophthlmoscopy through the dilted pupil. Sttisticl methods Albumin dt were log10 trnsformed nd then, s with the systemic nd renl hemodynmic results, nlyzed using the pired nd unpired t-test (two tiled). A liner regression nlysis ws used to exmine correltions. o6 o Results e- c~ +l ~D Bseline dt ==o.~ ~. ~.~ ==o.~ ~.~ I I ~ ~ 0 ~ ~ ~J <5 ~ N d ~ d g ~ d +l r 3.=~ 4-e ~'~ ix bg ~.. e~ 0,'~,.0 b All vlues presented represent the men of two preexercise bsl periods. The ptients hd been chrcterized ccording to UlbV levels in 24-h urine collections. This vlue correlted with UlbV during wter diuresis on the dy of study (r = 0.93, y = x). In consequence, the lbuminuric levels in the two groups were confirmed except for ptient 5, group 2, found to be excreting 10 ~tg/min t the time of the study (Tble 2). The bsl hert rte in group 1 ws elevted compred with the norml subjects (p < 0.02). The hert rte in group 2 ws between the other two groups nd sttisticlly indistinguishble (Tble 3). The systolic blood pressure in group 2 ws significntly elevted compred with the control group (Tble 3). The GFR vlues t rest re shown in Figure 1. The GFR ws elevted in both dibetic groups compred with the norml subjects. The GFR in the normolbuminuric group ws significntly bove tht seen in the microlbuminuric group ( versus ml/min per 1.73 m 2, p < 0.05). The three ptients in group 2 with the lowest GFR vlues hd men 24-h UlbV levels of 19, 54, nd 27 ~tg/min. These ptients nd the three group 1 ptients with the lowest GFR vlues ll hd utonomic neuropthy (bet-to-bet vritions < 15 per min), but were in better metbolic control compred with the other ptients (ll six ptients hd HbA~c levels < 8.3%). The RPF vlues differed between groups 1 nd 2 ( versus ml/min per 1.73 m 2, p < 0.05); the clculted filtrtion frction (GFR/RPF) ws similr in the two groups. o-- Systemic hemodynmic response to exercise Five of the dibetic ptients, four in group 1 nd one in group 2, filed to initite voiding within the first minute fter the 600 kpm/min worklod. Since urine lbumin excretion is high in both the exercise void nd the first post exercise urine, UlbV is not very sensitive to this dely. n the other hnd, renl hemodynmics chnge

4 392 B. Feldt-Rsmussen etl.: xercise test in erly renl disese Tble 3. Bsl clinicl dt nd dt on mximum working cpcity test Age Dibetes Hert rte Bsl Blood Pressure Mximum Wm~2 (yers) durtion work lod (kpm/min) (yers) bsl mximl systolic distolic (kpm/min) (bets/rin) (bets/rin) (mmhg) Norml subjects 35 _ t _ _+ 264 (n = 10) Dibetic ptients with c urinry lbumin excretion < 15 txg/min (Group 1) (n = 12) Dibetic ptients with c cb b cb urinry lbumin excretion >~ 15 p~g/min (Group 2) (n = 13) Vlues given s men _+ SD. Differences between groups considered significnt when p < 0.05 (two tiled). Significnt differences between norml subjects nd group 1 ; b significnt differences between norml subjects nd group 2; ~ significnt differences between group 1 nd group 2 This tble includes norml subjects nd the 25 ptients who completed the renl hemodynmic study (five ptients re missing (compre Tbles 1 nd 2) s explined in the text) 170- i 150! ~ C 0.m 110 e 90 m (.9 7 e 9 9 l 8 9! 9 Group 1 Group 2 Norml subjects Fig. 1. Bsl glomerulr filtrtion rte in young Type I dibetic ptients with (group 1, n = 14) nd without (group 2, n = 16) microlbuminuti (urinry lbumin excretion rte > 15 lxg/min), nd in helthy subjects (n =10). Horizontl brs indicte men vlues. Difference between group I nd group 2, p < Difference between norml subjects nd group 2, p < 0.05 rpidly. These mesurements re dependent on close time reltionship between exercise nd urine collections. Therefore, ptient 5, 9, 11, nd 13 in group I nd ptient 3 in group 2 (Tble 2) were excluded from the nlyses of the renl hemodynmics during exercise. The durtion of dibetes of these ptients ws slightly longer (10-24yers). They did not differ with regrd to so the other vribles, nor with regrd to metbolic control during exercise. During exercise, blood glucose levels were bsiclly unchnged, between the dibetic groups (Tble 4). Two ptients vomited before exercise due to excess wter lod. They hd no ketonuri nd felt comfortble enough to continue the test. Urine flow ws very similr in the three groups t rest, but ws significntly reduced during exercise in ll three groups (p < 0.01). There ws no difference between the two dibetic groups (Tble 4). When tested for mximl working cpcity, the microlbuminuric group chieved mximl hert rte of bets/min (p < 0.05) lower thn seen in the normolbuminuric group (177 +_ 12) or the non-dibetic subjects (176 15). However, the fixed work lod of 600 km/min represented significntly greter stress for the ptients in group 2 (Tble 5). The ctul mximl work lod performed by group 2 ws kpm/min, which ws significntly lower thn seen in norml subjects ( , p<0.05). In this instnce, group 1 ( kpm/min) ws lso significntly different from norml, but clcultion of Wmx2, more relible indictor of mximl working cpcity, reveled tht group 2 ( kpm/min) ws significntly lower thn both group 1 (1163_ 200) nd the control subjects ( ); the differenze between group 1 nd non-dibetic subjects ws no longer significnt (Tble 3). During the exercise provoctive test, the 600 kpm/ min worklod elicited lmost identicl hert rtes ( , bets/min) nd systemic blood pressures 1642, mmhg) in groups 1 nd 2, respectively. These vlues were not significntly higher, thn those obeobserved in norml subjects (1150 bets/min, mmhg). Furthermore, the chnges in hert rte nd systolic blood pressure were similr for ll groups (Tble 5).

5 B. Feldt-Rsmussen et l.: xercise test in erly renl disese 393 Tble 4. Urine flow nd blood glucose concentrtions before nd during exercise Urine flow (ml/min) Blood glucose (mmol/l) Resting 600 kpm/min Resting t 600 kpm/min Post-exercise Norml subjects (n = t0) Dibetic ptients with urinry lbumin excretion < 15 ~tg/min (Group 1) (n = 12) Dibetic ptients with urinry lbumin excretion >~ 15 p,g/min (Group 2) (n = 13) 12.0_ _ _+3: _ _+4.1 Tble 5. Systemic nd renl hemodynmic responses to exercise (600 kpm/min) Norml subjects (n = l) Dibetic ptients with urinry lbumin excretion < 15 ~tg/min (Group 1) (n = 12) Dibetic ptients with urinry lbumin excretion 15 gg/min (Group 2) (n = 13) Urinry lbu- A Ulb V 600 kpm/min A Hert rte A Systolic A GFR A RPF A Filtrtion min excretion (!~g/min) s reltive (bets/min) blood pres- (%) (%) frction(%) bsl (U~lbV) work lod sure (mmhg) 0tg/min) (%) , _ _ b 70_+59 b b Vlues given s men_+ SD. Differences between groups considered significnt when p < 0.05 (two tiled). Significnt differences between norml subjects nd group 2; b significnt differences between group I nd group 2 Albuminuric response The U~bV seen fter exercise provoction ws the sme in group I s in the norml group (Tble 2, p < 0.01). In group 2 the bnorml bsl U~bV ws further excerbted by exercise. Both mximum UlbV nd bsolute s welt s reltive chnge in U~IbV provoked by exercise were higher in this group compred with either of the other two groups (p <0.01). A significnt correltion ws found between the bsl UlbV nd exercise-induced increse in UlbV in group 2 (r = 0.89, p < 0.001). Renl hemodynmie response The renl hemodynmic chnges during exercise were qulittively similr for the three groups (Fig. 2). The percentge reduction in GFR nd RPF ws greter in the dibetic groups, especilly in group 2, where it reched sttisticl significnce (p < 0.05, Tble 5). This corresponds to the higher reltive work lod represented by 600 kpm/min in this group (68 _+ 20% of mximum work cpcity) when compred with group 1 (53 11%) or norml subjects (49 11%) (Tble 5). This reltionship (A GFR nd A RFP versus 600 kpm s reltive work lod) ppered to be consistent, lthough it could not be expressed s linier correltion. As previously noted, the filtrtion frction in the bsl stte ws slightly elevted in the dibetic group, but not significntly so when compred with the norml subjects. During exercise, however, the filtrtion frction seen in the dibetic ptients ws significntly higher thn tht recorded for the non-dibetic control subjects (0.292_ 0.02 versus 0.260_ 0.012, p < 0.03). The filtrtion frction for group 2 (0.294_ 0.02) ws virtully identicl to tht seen in group I ( ), despite the lrge difference between the two groups in the bsolute nd reltive chnges in the urinry lbumin excretion rte (A Ulb V) provoked by exercise (Tbles 2 nd 5). No significnt correltions were found between the A UlbV nd ny of the renl hemodynmic vribles. There ws lso no correltion between A UlbV nd A blood pressure. The only significnt correltion between systemic nd renl hemodynmic chnges ws found in the A blood pressure nd A RPF in group 2 (r = 0.66, p < 0.05).

6 394. t- r C 0 v,. t~ _o, D. r 3: o. t- er oJ oc e, o.30- ".25-0 U I i I i i I! b xercise xercise 450 kpm/min 600 kprn/min Fig.2. A Glomerulr filtrtion rte. B Renl plsmflow nd C filtrtion frction before, during nd fter physicl exercise in young Type 1 dibetic ptients nd norml subjects (men_+ SM). n the horizontl xis 20-rin periods re mrked. 9 Norml subjects (n=10). 9 Dibetic ptients with norml urinry lbumin excretion < 15 gg/min (group 1, n = 12). ~ Dibetic ptients with urinry lbumin excretion ~> 15 ~xg/min (group 2, n = 13). Difference between group 1 nd group 2 (p <0.05), b Difference between normls nd group 1 s well s group 2 (p < 0.05). A Group 1 nd the norml subjects differ significntly throughout the test (p < 0.05). B No significnt difference between norml subjects nd group 2 Discussion B. Feldt-Rsmussen et l.: xercise test in erly renl disese The dt in this study indicte tht those dibetic ptients who demonstrte U~bV which is norml (< 15 ~tg/min) respond to exercise with n increse in UlbV which is not significntly different from tht seen in non-dibetic individuls. Norml subjects hve often been reported not to increse UlbV t this exercise level [1, 2, 5]. This my be due to differences in the interprettion of the exercise induced UlbV. The mximl U~bV my occur when ptients re resting during the first post-exercise periods, s well s immeditely following the 600 kpm/min worklod. We hve reported the highest vlue obtined in ny of these periods. If this procedure is pplied to the dt in the study by Viberti et l. [2], his norml subjects lso incresed UlbV significntly. Dt re not vilble for the other studies cited. The reson why mximl U~bV my occur in the post-exercise period is unknown. It could be speculted tht some of the lbumin filtered in excess during exercise (when urine production is low) is retined in the tubulr system nd then wshed out, when urine production is rpidly incresed following exercise. A wshout phenomenon is described during the initition of wter-diuresis in the resting stte [15]. xercise did pper to exggerte further lbuminuri in ptients who lredy were known to demonstrte n incresed UjbV during bsl conditions, thus confirming the work of Christensen [5]. However, even in this group some of the ptients demonstrted very modest increse in UIbV, not distinguishble from the increse observed in group 1. Thus group 2 ptients, who from severl studies [24, 25, 26, 27] re known to be t high risk for the lter development of overt dibetic nephropthy, in mny cses hve "norml" lbuminuric response to exercise. The dignostic vlue of n bnorml response mong group I ptients would, on these grounds, be difficult to interpret. We therefore believe tht this lborious test hs no plce in dignosing erly dibetic renl disese. However, our results indicte tht exercise is n interesting tool. Group 2 hd significntly higher mximl U~bV compred with the other groups, both in bsolute nd reltive terms. Christensen [5] found no difference in the reltive increse of U~IbV between ptients with norml nd elevted U~lbV. We cnnot offer ny explntion for this discrepncy, but the renl disese in his ptients ws more dvnced, s judged from their bsl UlbV levels. The difference in the response to exercise observed in our study between the two dibetic groups might be explined by the fct tht the fixed work-lod of 600 kpm/min constituted greter frction of the mximl working cpcity in group 2 ptients. The 600 kpm/ min work-lod therefore represented significntly greter stress for them. However, the difference in working cpcity ws not reflected in differentil increse in hert rte or systolic blood pressure. n the contrry, the systemic hemodynmic response to exercise ws

7 B. Feldt-Rsmussen et l.: xercise test in erly renl disese similr in both dibetic groups (Tble 5). It might be speculted tht this indicted impired sympthetic outflow in the group 2 ptients, but the only objective dt regrding this issue demonstrte no differences between the dibetic groups in bet-to-bet vrition. The renl hemodynmic responses to exercise ws similr in the two dibetic groups. The somewht lrger chnges in GFR nd RPF in group 2 did rech sttisticl significnce when compred with the norml control group, nd probbly reflect the greter reltive work-lod experienced by these ptients. Mogensen nd collegues found tht dibetic ptients who demonstrted significnt increse in UlbV upon exercise provoction hd filtrtion frction which ws significntly elevted when compred with non-dibetic subjects [10]. The dt presented here confirm tht the filtrtion frction during exercise in the dibetic subjects ws significntly bove tht found in norml subjects. However, despite the enormous difference between groups 1 nd 2 in terms of the functionl consequences of exercise (A U,lbV), the filtrtion frction in these two groups t 600 kpm/min ws nerly identicl. If the elevtion during exercise of the filtrtion frction cn resonbly be interpreted s representing n increse in trnsglomerulr pressure, then these dt indicte tht n elevtion of trnsglomerulr hydrulic pressure to the levels chieved t 600 kpm/min will only be followed by significnt increse in UluV when the glomerulr membrne hs lredy demonstrted impired properties of permebility (i. e. n elevted bsl UlbV). The fct tht the two dibetic groups hd levels of filtrtion frctions which were nerly identicl, both in the bsl stte nd with exercise, lso indictes tht the increse in U~bV seen in dibetic ptients with incipient nephropthy is not dependent on trnsglomerulr pressure which is incresed bove tht seen in ptients with norml rtes of lbumin excretion. The elevtion of the filtrtion frction during exercise (or during norml dily ctivity) my ply n importnt role in the progression of dibetic nephropthy in those ptients who lredy demonstrte bnormlities in the glomerulr hndling of lbumin. This would be in greement with the observtions of Prving et l. [28] nd Mogensen [29]. They were ble to lower UlbV in ptients with dibetic nephropthy who were ggressively treted for hypertension. In these ptients renl utoregultion is impired [30]. Therefore it is likely tht lowered systemic blood pressure is lso ccompnied by reduced trnsglomerulr pressure resulting in reduced U~tbV. The stte of dibetic renl disese preceding overt nephropthy hs been termed "incipient nephropthy" [14]. It is chrcterized by n elevtion of bsl UlbV t time when the serum cretinine level is norml nd the Albustixtest for urinry protein is negtive. Retrospective studies suggest tht these ptients re t much higher risk for developing full-blown clinicl nephrop- thy thn subjects whose bsl Ulb V is norml [24-27]. ur dt extend these observtions further nd suggest tht ptients with incipient nephropthy my be different from ge- nd durtion-mtched dibetic ptients with norml UlbV in severl importnt spects other thn the rte of lbumin excretion. The ptients in this study with incipient nephropthy hd significntly lower mximum working cpcity, nd significntly elevted bsl systolic blood pressure when compred with norml subjects. This observtion concerning the significnt elevtion of blood pressure (while still within the norml rnge) corrobortes our findings in previous cross-sectionl study [25] nd those of Wisemn et l. [31]. In ddition, the levels of GFR nd RPF in these microlbuminuric ptients were significntly lower thn those observed in those with norml Ulb V, even though the levels were still elevted when compred with controls. This difference could not be explined on the bsis of sex, ge, height, weight, durtion of dibetes, degree of dibetic control, or presence of other dibetic complictions. Ptients with normolbuminuri under the usul insulin tretment progrms demonstrted n elevted GFR [6-9]; ptients with erly overt dibetic nephropthy (persistent proteinuri > 0.5 g/24 h, but norml serum cretinine concentrtion) generlly hve norml GFR vlues [28, 29]. If hyperfiltrtion is primry fctor in the initition of dibetic nephropthy s suggested by others [32, 33], then the dt presented here suggest tht chnge in renl function (from hyperfiltrtion to norml rtes of filtrtion to deteriortion) my occur s the ptient psses cross n importnt threshold into the stge of incipient nephropthy chrcterized by persistent microlbuminuri. This finding is different from wht hs been previously reported. In our own cross sectionl study of the GFR of smller group of ptients [25], no significnt difference ws observed when compring ptients with norml UlbV versus those with microlbuminuri. Wisemn et l. [31] lso found tht the GFR of ptients with microbluminuri ws not significntly different from tht observed in ptients with norml rtes of urinry lbumin excretion, lthough the men vlues ws lower. This difference in results might be due to the more rigorous pproch (men UluV of three 24-h urine collections) used in this study to clssify ptients into groups with norml or elevted UlbV. In plnning future studies to confirm this importnt observtion it would seem prudent to ctegorize ptients only on the bsis of severl (t lest three) 24-h urine collections over period of 1-3 months. Ptients who demonstrte persistent microlbuminuri under these conditions should be used in prospective studies to trce the true nturl history of incipient nephropthy. Acknowledgements. this work ws performed while Dr. L. Bker ws Fogrty Senior Interntionl Fellow (TW00790). Mrs. H. Foght nd Mrs. M. Deckert re thnked for their skillful, technicl ssistnce. 395

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