Incidence of proteinuria in type 2 diabetes mellitus in the Pima Indians

Transcription

1 Kidney Interntionl, Vol. 35 (1989), pp Incidence of proteinuri in type 2 dibetes mellitus in the Pim Indins CHARLES L. KUNZELMAN,' WILLIAM C. KNOWLER, DAVID J. PETTITT, nd PETER H. BENNETT Dibetes nd Arthritis Epidemiology Section, Ntionl Institute of Dibetes nd Digestive nd Kidney Diseses, Phoenix, Arizon, USA Incidence of proteinuri in type 2 dibetes mellitus in the Pim Indins. Little is known of the nturl history of nephropthy in type 2 (non-insulin-dependent) dibetes, yet type 2 dibetes is mjor cuse of end-stge renl disese in the United Sttes. The incidence rte of hevy proteinuri ws determined in Pim Indins prticipting in longitudinl popultion study of dibetes nd its complictions. Hevy proteinuri ws defined by urine protein (g/liter) to urine cretinine (g/ liter) rtio 1. ( 113 mg proteinlmmol cretinine), level which corresponds to urine protein excretion rte of bout 1 g/dy. The incidence rtes of proteinun in dibetic Pims were 4, 12, 37, nd 16 cses/i, person-yers t risk in the periods to 5, 5 to 1, 1 to 15, nd 15 to 2 yers fter the dignosis of dibetes. The cumultive incidence rtes were 2%, 8%, 23%, nd 5% t 5, 1, 15, nd 2 yers, respectively. The durtion of dibetes, severity of dibetes s determined by the degree of hyperglycemi nd type of tretment, nd blood pressure were risk fctors for proteinuri. The presence of hevy proteinun ws strongly ssocited with the development of renl insufficiency, defined by serum cretinine 2. mg/dl ( 177 mo1i liter). The incidence of proteinuri in type 2 dibetes in Pim Indins ws s high s tht reported in type I dibetes in other popultions nd represents frequent, serious compliction of the disese. The belief tht renl disese develops more frequently in type 1 (insulin-dependent) thn in type 2 (non-insulin-dependent) dibetes [1 3] is bsed primrily on studies in Cucsin popultions which show tht 3 to 6% of deths in type I dibetes re ttributble to renl filure [4 6], yet fewer thn 5% of deths in type 2 dibetes re ttributble to this cuse [7, 8]. Extensive studies of the nturl history of nephropthy in ptients with type 1 dibetes hve permitted chrcteriztion of course progressing to end-stge renl disese [9, 1]. The nturl history of nephropthy in subjects with type 2 dibetes, however, hs not been well described even though 8 to 9% of the dibetic popultion in the United Sttes hs type 2 dibetes, s do t lest 5% of the dibetic ptients receiving tretment for end-stge renl disese [4]. Some reports of the course of dibetic nephropthy hve included subjects with both type 1 nd type 2 dibetes [11, 121, wheres others hve been limited to those with type 1 dibetes [6, 13, 14]. 'Current Address: Deprtment of Medicine, Division of Nephrology, University of New Mexico, Albuquerque, New Mexico 87131, USA. Received for publiction Mrch 16, 1988 nd in revised form September 6, by the Interntionl Society of Nephrology 681 Since 1965, Pim Indins living in the Gil River Indin Community in southern Arizon, USA hve prticipted in longitudinl study of dibetes nd its complictions. This tribe hs the world's highest reported prevlence of dibetes (5% t 35 yers of ge) [15]. Pim Indins hve dibetes which is not ssocited with insulin dependency, ketocidosis, or islet-cell ntibodies, nd is, therefore, type 2 dibetes [16], even when it occurs in the young [17]. Dibetic nephropthy is the predominnt form of kidney disese in this popultion nd is similr in its clinicl chrcteristics nd clssicl pthologic fetures to tht described in other popultions [18]. It frequently results in end-stge renl disese, which develops in nerly 15 per cent of dibetic Pim Indins by 2 yers durtion of dibetes [19]. The purposes of the present study were: (I) to investigte the incidence of nephropthy s reflected by the presence of hevy proteinuri in popultion with high prevlence nd reltively erly ge of onset of type 2 dibetes; (2) to compre the incidence of proteinuri in type 2 dibetes with tht reported in type 1 dibetes; nd (3) to identify possible risk fctors for the development of proteinuri in subjects with dibetes. Methods Since 1965, ll Pim Indins t lest five yers of ge living in defined re of the Gil River Indin Community in Arizon hve been sked to prticipte in systemtic biennil reserch exmintions. These exmintions included modified orl glucose tolernce test, mesurements of height, weight, nd blood pressure, nd collection of urine. After voiding, the ptients were given 75 g orl crbohydrte lod (Glucol, Ames Division of Miles Lbortory Inc., Elkhrt, Indin or Dexcol, Custom Lbortories Inc., Bltimore, Mrylnd, USA). Two hours lter, venous blood ws drwn for plsm glucose nd serum cretinine determintions, nd urine specimen ws collected nd screened for protein with bromphenol strips (Lbstix, Miles Lbortory Inc.). Protein concentrtion ws determined by the Shevky-Stfford procedure [2] on ll specimens showing trce or more of protein; the concentrtion of cretinine in the sme urine specimen ws determined; nd the protein (g/liter) to cretinine (glliter) rtio ws clculted. Hevy proteinuri ws defined by P/C rtio 1. (or 113 mg protein/mmol cretinine). This rtio is equivlent to totl protein excretion rte of bout 1 g per dy [21, 22]. No other mens of quntifying proteinuri, such s by repeted

2 682 Kunzelmn et!: Incidence of proteinuri in type 2 dibetes Age yers Sexb Tble 1. Incidence of hevy proteinuri (P/C 1.) Nondibetic Dibetic Person-yers Cses Incidence Person-yers Cses Incidence 5 24 M ,3 F I M F M F M F Totl Age-sex djusted incidence % confidence intervl ( ) ( ) Cses/l person-yers t risk b M = mle, F = femle mesurements over severl months or by 24-hour urine collections, ws routinely vilble in this lrge popultion study. Dibetes ws dignosed t the first biennil exmintion t which the two-hour post-lod plsm glucose ws 2 mg/dl (11.1 mmol/liter) [23], or when the Indin Helth Service Hospitl serving the community found post-prndil or twohour post-lod glucose concentrtion of 2 mg/dl (11.1 mmol/liter) [15]. Renl insufficiency ws defined by serum cretinine concentrtion 2. mg/dl (177 j.mol/liter). Blood pressure ws mesured with mercury sphygmomnometer with the subject resting supine. Systolic nd distolic pressures were tken by usculttion of the brchil rtery. Incidence, the rte t which persons t risk develop proteinuri, ws expressed s the number of new cses of proteinuri per 1 person-yers t risk. Cumultive incidence rtes of proteinuri in dibetic Pims nd in subjects from two other longitudinl studies of dibetic nephropthy were compred [13, 14]. Cumultive incidence rtes were presented in the studies or derived from incidence rtes [24] strtified by durtion of dibetes. The cumultive incidence estimtes the probbility tht proteinuri will develop by certin durtion of dibetes conditionl on survivl to tht point. Sex, obesity, two-hour plsm glucose concentrtion t dignosis, blood pressure, type of tretment, cigrette smoking, nd ge t dignosis of dibetes were exmined s risk fctors for proteinuri. The effects of vribles which chnge over time, such s ge, durtion of dibetes, blood pressure, nd type of tretment, were ssessed by strtifiction of person-yers t risk of proteinuri. Age ws ctegorized nd chnged t ech subject's 5th, 25th, 45th, or 65th birthdy (tht is, t 2 yer intervls strting t ge 5 yers, the erliest possible entry in the study); five-yer dibetes durtion ctegories were used strting t the dte of dignosis nd chnging t the 5-, 1- nd 15-yer nniversries of tht dte; nd vribles such s blood pressure or type of tretment for dibetes, tht were ssessed t biennil exmintions, were chnged t ech subsequent exmintion. Blood pressure mesurements were ctegorized ccording to the observed vlues whether or not ntihypertensive drugs were tken. Subjects were lso strtified by fctors which did not chnge with time, such s sex nd ge nd plsm glucose t the time of dignosis. The incidence of renl insufficiency ws computed by similr methods. New cses of renl insufficiency were defined by the first occurrence of serum cretinine concentrtion 2. mg/ dl (177.tmol/liter) t biennil exmintion mong persons with t lest one previous biennil exmintion t which the serum cretinine concentrtion ws below this level. Person-yers t risk were strtified by durtion of dibetes s described bove nd by the presence of hevy proteinuri. Proteinuri ws clssified s bsent or present t ech biennil exmintion ccording to whether the P/C rtio ws < 1. or 1., nd the person-yers t risk of renl filure were ccumulted for tht ctegory until the next biennil exmintion. Incidence rtes were ge-sex djusted by the direct method using the 198 U.S. census popultion s stndrd, s previously described [15]. Age-sex djusted rtes were clculted in ctegories of durtion of dibetes nd hd to be restricted to subjects 25 yers of ge s the longer durtion ctegories were not represented mong younger subjects. Incidence rte rtios, djusted for ge, sex, nd durtion of dibetes, were computed by the Mntel nd Henszel procedure [25]; tests of liner ssocition were computed by the Mntel extension test [261. These nlyses were modified for person-time denomintors s suggested by Rothmn nd Boice [271. Results Among the dibetic subjects, 18 of the 48 persons t risk developed hevy proteinuri during 7,878 person-yers of follow-up, nd mong nondibetic subjects, 49 of 4,171 developed hevy proteinuri during 35,21 person-yers of follow-up (Tble 1). The ge-sex-djusted incidence of hevy proteinuri ws 9.7 times s high in dibetic s in nondibetic subjects (95% confidence intervl = 6.1 to 15.3). In dibetic subjects, the incidence of hevy proteinuri incresed with incresing ge until ges 45 to 64 yers in mles nd 65 yers in femles. Among dibetic subjects, the incidence rte ws similr in men nd women fter djustment for ge nd durtion of dibetes (incidence rte rtio, men compred with women, 1., 95% confidence intervl =.7 to 1.4). Among subjects 25 yers of ge with dibetes, the ge-sex djusted incidence rte incresed from 4 cses per 1, person-yers in those with less thn 5 yers durtion to 16 cses per 1, person-yers in those with 15 yers durtion (Fig. 1). Among ll dibetic subjects, the

3 Kunzelmn et!: Incidence of proteinuri in type 2 dibetes C ạ 8 (-) Durtion of dibetes, yers Fig. 1. Incidence rtes (nd 95% confidence intervls) of hevy proteinuri by durtion of dibetes. Age-sex djusted in subjects 25 yers old. 5 4 C 3 E Durtion of dibetes, yers Fig. 2. Cumultive incidence of hevy proteinuri in dibetic Pim Indins. cumultive incidence of hevy proteinuri s function of durtion of dibetes ws 5% fter 2 yers (Fig. 2). Tble 2 shows the incidence rtes of hevy proteinuri in dibetic subjects 25 yersof ge strtified by ge nd durtion of dibetes. The incidence rtes clerly incresed with longer durtion of dibetes in ech ge group, wheres within ctegoties of durtion of dibetes, the differences between ge groups were smll. After controlling for durtion of dibetes there ws no significnt effect of ge; wheres fter controlling for ge, the effect of durtion ws highly significnt (P <.1). Tble 3 shows the incidence of renl insufficiency in dibetic subjects 25 yers of ge ccording to durtion of dibetes nd presence or bsence of hevy proteinuri t the previous biennil exmintion. The ge-sex-durtion-djusted incidence of renl insufficiency mong dibetic subjects ws 42 times s high in those with proteinuri s in those without (95% confidence intervl = 24 to 75). Sex hd no significnt effect on the Age yers Tble 2. Incidence of hevy proteinuri Durtion of dibetes yers > Incidence in cses/1 person-yers, both sexes combined, in subjects 25 yers old. incidence of renl insufficiency fter controlling for presence of proteinuri, ge, nd durtion of dibetes (incidence rte rtio, men compred with women, =1.1, 95% confidence intervl =.6 to 1.9). Figure 3 shows the incidence of proteinuri ccording to the durtion of dibetes in reltion to severl risk fctors: ) ge t dignosis, b) two-hour post-lod plsm glucose t dignosis, c) type of tretment, nd d) blood pressure. Subjects with younger ge t dignosis of dibetes tended to hve higher incidence rte (Fig. 3A), but the differences mong the groups shown were not sttisticlly significnt. There ws strong ssocition between the severity of hyperglycemi t the time of dignosis of dibetes nd the incidence of proteinuri, (P <.1, controlling for ge, sex, nd durtion of dibetes, Fig. 3B). In ech durtion group, subjects with the highest two-hour post-lod plsm glucose t dignosis ( 45 mgldl) hd the highest incidence of proteinuri. Figure 3C shows the incidence of proteinuri ccording to the type of tretment: insulin, orl hypoglycemic gents, or no drug. The incidence rte ws highest in subjects who were being treted with insulin, intermedite in those treted with orl gents, nd lowest in those treted without drugs (P <.1, controlling for ge, sex, nd durtion of dibetes). The incidence of proteinuri ws significntly relted to systolic blood pressure (P <.1, controlling for ge, sex, nd durtion of dibetes, Fig. 3D) nd to distolic blood pressure (dt not shown). The reltionship with systolic blood pressure persisted fter strtifiction by the simultneous two-hour post-lod plsm glucose concentrtion (P <.1, controlling for ge, sex, durtion of dibetes, nd two-hour glucose). Neither obesity, s mesured by body mss index, nor cigrette smoking ws ssocited with n incresed rte of proteinuri (not shown). Discussion Becuse of the high frequency nd reltively erly ge of onset of type 2 dibetes in Pim Indins [151, it hs been possible to exmine the incidence of proteinuri with fewer problems thn encountered in mny studies of type 2 dibetes in older subjects. One of these problems is the high mortlity from other cuses tht is encountered in mny studies even t reltively short durtions of dibetes. Becuse of the frequent onset of dibetes t n erly ge, mny dibetic Pim Indins survive long enough fter dignosis to llow proteinuri to develop. Among the Pims, it hs been possible to estimte the onset of dibetes with resonble ccurcy becuse glucose tolernce testing hs been performed t pproximtely two-yer intervls since Estimting disese onset in other popultions is usully difficult in type 2 dibetes, s subjects my remin

4 684 Kunzelmn et!: Incidence of proteinuri in type 2 dibetes Tble 3. Incidence of renl insufficiency (serum cretinine 2.O mg/dl or 177 Lmol/liter) by durtion proteinun t the previous biennil exmintion Durtion of dibetes yers Without proteinuri of dibetes nd presence of hevy With proteinuri Person-yr Cses Incidence Person-yr Cses Incidence Age-sex djusted cses/l person-yers in subjects 25 yers old I A 2 i 15 1 Age t Dx <25 A D 55 2-hr gluc. t Dx o o <25 Cl) >, C 2 I I I I D -I Tretment o Insulin A Orl o No drug Systolic B.P. o 16 A o < I I Durtion of dibetes, yers Fig. 3. Incidence of hevy proteinuri in dibetic Pim Indins ccording to: (A) ge t dignosis (yrs.); (B) 2-hr post-lod plsm glucose t dignosis (mgldl); (C) type of tretment for dibetes (insulin, orl hypoglycemic gent, or no hypoglycemic drugs); nd (D) systolic blood pressure (mm Hg). symptomtic for mny yers prior to recognition of their disese, Furthermore, s nerly ll eligible Pims hve received systemtic exmintions [15], it hs been possible to void the problems ssocited with the selective referrl of ptients with complictions to centers specilizing in dibetes cre. Hevy proteinuri in this study ws defined by urine protein (g/liter) to urine cretinine (g/liter) rtio of 1., which corresponds to protein excretion rte of bout 1 g/dy [21, 22]. Persistent proteinuri, s detected by conventionl clinicl methods nd used s n index of nephropthy in mny studies of nephropthy in type 1 dibetes, is lmost invribly present t this level. Moreover, the reltive frequency of proteinuri s defined by P/C rtio of 1. mong dibetic compred with nondibetic subjects indictes its specificity in dibetic subjects s n index of dibetes-relted kidney disese. The overll impct of renl disese ssocited with dibetes mong the Pims is considerble. Proteinuri predicts the development of renl insufficiency. Furthermore, end-stge renl disese, or deth from renl disese, occurs 62 times s frequently mong dibetic s mong nondibetic Pims nd occurs in nerly 15 per cent of Pims fter 2 yers of dibetes [191. Other cuses of renl disese mong dibetic subjects cnnot be ruled out in ll cses. However, given the present knowledge of the reltive frequency of proteinuri, renl insufficiency, end-stge renl disese [19], nd postmortem ppernce of the kidneys in dibetic Pims (181, it ppers tht proteinuri s defined in this study is, in most instnces, ttributble primrily to dibetic nephropthy. In the present study the cumultive incidence of proteinuri in reltion to durtion of type 2 dibetes in Pim Indins ws s

5 C., C V C > E Fig. 4. Cumultive incidence of hevy proteinuri mong dibetic subjects by durtion of dibetes in three longitudinl studies: type 2 dibetic Pims (); type I dibetic subjects, Steno Memoril Hospitl, Denmrk (s); nd type I dibetic subjects, Joslin Clinic, USA (J). high s tht reported in type 1 dibetes. The present findings were compred with results of two other studies (Fig. 4). In one of these, 97 type I dibetic ptients dignosed before the ge of 31 yers were followed for up to 4 yers t the Steno Memoril Hospitl in Denmrk [13], nd proteinuri ws defined by protein excretion >5 mg/24 hr in t lest four successive urine smples t lest one month prt. In the other study, type 1 dibetic ptients dignosed before the ge of 21 yers were followed for up to 4 yers t the Joslin Clinic in Boston, Msschusetts, USA [14], nd proteinuri ws defined by urine protein concentrtion of 3 mgldl in three or more successive urine collections or 1. g protein in 24-hour urine collection. The cumultive incidence of nephropthy in type 1 dibetes in these studies ws quite similr. In contrst, in the Pims with type 2 dibetes, the cumultive incidence up to 2 yers fter the dignosis of dibetes ws even higher, reching pproximtely 5% fter 2 yers. These findings contrst with the common teching tht dibetic nephropthy is more common in type 1 thn in type 2 dibetes [3, 4], belief pprently derived from studies tht show renl filure to be more common cuse of deth in type 1 thn in type 2 dibetes. For exmple, mong ll deths of Joslin Clinic dibetic ptients through 1968, the proportion scribed to renl disese rnged from 46% in ptients who hd been dignosed before 2 yers of ge (presumbly with type 1 dibetes) to only 3% in those dignosed t ge 6 yers or older (presumbly with type 2 dibetes) [28]. As type 2 dibetes tends to occur t older ges, ptients with type 2 dibetes re t higher risk of deth from other cuses nd re, therefore, less likely to survive long enough to develop dibetic nephropthy nd die s result of it. While renl filure s cuse of deth my be more frequent in type 1 thn in type 2 dibetes, one cnnot conclude tht the risk of developing nephropthy in dibetes of given durtion is higher in type 1 dibetes. Indeed, the present dt (Fig. 4) suggest tht, s function of the durtion of dibetes, the incidence of nephropthy is t lest s high in type 2 s in type 1 dibetes. Thus, the greter likelihood tht deth in subjects with type 1 dibetes will be ttributed to renl disese ppers to be due to their younger ge, longer survivl time, Kunzelmn et!: Incidence of proteinuri in type 2 dibetes Durtion of dibetes, yers nd lower risk of deth from other cuses rther thn to the type of dibetes per Se. Whether the rte of proteinuri mong Pim Indins is typicl of tht of ptients of other ethnic origins with type 2 dibetes is unknown. Creful interpopultion studies of durtion-specific incidence rtes of dibetic nephropthy re necessry to resolve this question. In contrst to results reported from Rochester, Minnesot [291, in this study n older ge t dignosis of dibetes ws not ssocited with higher durtion-specific incidence of proteinuri. Severl other risk fctors did, howeyer, predict the development of proteinuri mong dibetic Pim Indins. A higher two-hour post-lod plsm glucose t the time of the dignosis of dibetes predicted higher incidence of proteinuri, not only in the erly yers, but even fter 15 to 2 yers durtion. These findings re in ccord with other studies, both longitudinl nd cross-sectionl, which show n impressive reltionship between nephropthy nd the degree of hyperglycemi [3 32]. Whether the level of hyperglycemi per se is cuslly relted to the development of nephropthy, or whether it is n indictor of the severity of more bsic metbolic defect relted to dibetes, cnnot be determined from the vilble dt. The severity of dibetes s judged by the type of tretment ws lso n importnt determinnt of the risk of developing proteinuri in type 2 dibetes mong the Pims, similr to the previously reported ssocition with the development of retinopthy [33]. Such n ssocition might rise becuse ptients with more severe hyperglycemi or with other complictions might be more likely to receive insulin tretment. It seems unlikely tht insulin is custive fctor for nephropthy, but, becuse tretment ws not rndomly ssigned, the present dt do not permit evlution of this hypothesis. Blood pressure ws risk fctor for proteinuri in the present study nd my be cuslly relted to its development. Blood pressure ws risk fctor for nephropthy in type 1 dibetes [34], nd tretment of hypertension reduced the rte of progression of nephropthy in type I dibetes [35] nd decresed lbumin excretion rtes in group of ptients including both types of dibetes [36]. The present finding tht blood pressure predicts the development of proteinuri hs severl possible interprettions. Blood pressure my hve incresed s result of renl disese of lesser severity thn detected by the present definition of proteinuri, nd the pprent predictive vlue of blood pressure for the development of hevy proteinuri my simply reflect n effect of progression of such renl disese. Alterntively, elevted blood pressure my result in incresed susceptibility of the kidney to dibetes-relted dmge. Proteinuri my be the result of the combined insult, nd blood pressure, therefore, my be cuslly relted to the development of hevy proteinuri. This concept is consistent with evidence in type 1 dibetes tht prentl blood pressure is predictive of proteinuri in the offspring [37, 38] nd tht proteinuri is relted to incresed lithium-sodium countertrnsport velocity in red cells, which is thought to be mrker for idiopthic hypertension [38, 39]. It is lso consistent with the finding in the Pim Indins tht blood pressure mesured prior to the development of dibetes predicts bnorml lbuminuri fter the development of dibetes [4]. Such reltionship might lso ccount for the fmilil ggregtion of proteinuri nd renl

6 686 Kunzelmn et!: Incidence of proteinuri in type 2 dibetes insufficiency mong dibetic Pims [41]. Whether hypertension is consequence of erly nephropthy, t stge not detected in the present study, or whether it is custive fctor nd present before ny renl dmge hs occurred, remins to be determined. Nevertheless, the possibility tht the tretment of hypertension my influence the risk nd progression of nephropthy in type 2 dibetes, s it ppers to do in type 1, clerly wrrnts investigtion. The incidence of proteinuri in type 2 dibetes mong the Pim Indins is t lest s high s tht reported in type 1 dibetes. Furthermore, some of the risk fctors for proteinuri identified in the present study, such s the durtion of dibetes, the degree of hyperglycemi, nd hypertension, pper to predict nephropthy in both types of dibetes. Whether the incidence of nephropthy in type 2 dibetes vries between popultions is unknown, but s type 2 dibetes is by fr the most common type of dibetes nd is frequently the underlying cuse of end-stge renl disese in the generl popultion, the nturl history nd determinnts of nephropthy in type 2 dibetes require further elucidtion. The finding tht, s function of the durtion of dibetes, the incidence of proteinun in type 2 dibetes is t lest s high s in type 1 dibetes is ominous in view of the much greter frequency nd pprently incresing incidence of type 2 dibetes worldwide. If, in the future, more persons develop type 2 dibetes t younger ges, nd mortlity rtes from other cuses such s ischemic hert disese decline, the burden of dibetesrelted renl disese my increse drmticlly. However, interventions, such s reduction of blood pressure, hyperglycemi, or perhps, protein intke, which my be effective in meliorting the course of renl disese in type 1 dibetes [42], my lso ffect the course of nephropthy of type 2 dibetes. Acknowledgments We thnk the members of the Gil River Indin Community for their coopertion nd prticiption in this study; the technicl, clericl nd physicin stff of the Dibetes nd Arthritis Epidemiology Section, NIDDK, for conducting the exmintions nd processing the dt; nd Ms. Chrlene Gishie for her secretril support. Reprint requests to Dr. Willim C. Knowler, 155 Est Indin School Rod, Phoenix, Arizon 8514, USA. References 1. MARKS HH: Longevity nd mortlity of dibetics, Am J Pub Helth 55: , LIEF PD: Renl impirment in dibetes mellitus, in Dibetes Mellitus, edited by RIFKIN H, RASKIN P. New York, Americn Dibetes Assocition, 1981, vol. V. p MAUER SM, BLANCE MS: A comprison of kidney disese in type I nd II dibetes. 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