Normoalbuminuric Renal-InsufficientDiabetic PatientsA lower-risk group

VINCENT RIGALLEAU, MD, PHD1

CATHERINE LASSEUR, MD2

CHRISTELLE RAFFAITIN, MD1

MARIE-CHRISTINE BEAUVIEUX, PD, PHD3

NICOLE BARTHE, PD4

PHILIPPE CHAUVEAU, MD2

CHRISTIAN COMBE, MD, PHD2

HENRI GIN, MD, PHD1

OBJECTIVE — About 20% of diabetic patients with chronic kidney disease (CKD) detectedfrom the new American Diabetes Association recommendations (albumin excretion rate �30mg/24 h or estimated glomerular filtration rate [GFR] �60 ml/min per 1.73 m2) may be nor-moalbuminuric. Do the characteristics and outcome differ for subjects with and without albu-minuria?

RESEARCH DESIGN AND METHODS — A total of 89 patients with diabetes and amodification of diet in renal disease (MDRD) estimated GFR (e-GFR) �60 ml/min per 1.73 m2

underwent a 51Cr-EDTA B-isotopic GFR determination and were followed up for 38 � 11months.

RESULTS — The mean MDRD e-GFR (41.3 � 13.1 ml/min per 1.73 m2) did not significantlydiffer from the i-GFR (45.6 � 29.7). Of the subjects, 15 (17%) were normoalbuminuric. Theiri-GFR did not differ from the albuminuric rate and from their MDRD e-GFR, although theirserum creatinine was lower (122 � 27 vs. 160 � 71 �mol/l, P � 0.05): 71% would not have beendetected by measuring serum creatinine (sCr) alone. They were less affected by diabetic retinop-athy, and their HDL cholesterol and hemoglobin were higher (P � 0.05 vs. albuminuric). Noneof the CKD normoalbuminuric subjects started dialysis (microalbuminuric: 2/36, macroalbu-minuric: 10/38) or died (microalbuminuric: 3/36, macroalbuminuric: 7/38) during the fol-low-up period (log-rank test: P � 0.005 for death or dialysis), and their albumin excretion rateand sCr values were stable after 38 months, whereas the AER increased in the microalbuminuricpatients (P � 0.05), and the sCr increased in the macroalbuminuric patients (P � 0.01).

CONCLUSIONS — Although their sCr is usually normal, most of the normoalbuminuricdiabetic subjects with CKD according to an MDRD e-GFR below 60 ml/min per 1.73 m2 do reallyhave a GFR below 60 ml/min per 1.73 m2. However, as expected, because of normoalbuminuriaand other favorable characteristics, their risk for CKD progression or death is lower.

Diabetes Care 30:2034–2039, 2007

Twenty-five to forty percent of pa-tients with diabetes have kidneydamage (1), and diabetes is the first

cause of end-stage renal disease in mostcountries (2). The early detection ofchronic kidney disease (CKD) in diabetic

patients is therefore of critical impor-tance. The conventional approach forscreening is the determination of the al-bumin excretion rate (AER). However, asubstantial proportion of normoalbumin-uric diabetic patients may present with a

reduced glomerular filtration rate (GFR):their rates have been reported to be�20% based on GFR �60 ml/min per1.73 m2 in type 2 diabetes (3) and in type1 diabetes based on GFR �90 ml/min per1.73 m2 with more advanced glomerularlesions (4). In accordance with the Na-tional Kidney Foundation guidelines (5),this has led the American Diabetes Asso-ciation to recommend the screening ofCKD in diabetic patients based both onthe AER (threshold: 30 mg/24 h) and theCockcroft and Gault equation or modifi-cation of diet in renal disease (MDRD)equation estimated GFR (threshold: 60ml/min per 1.73 m2) (6).

The MDRD equation is superior tothe Cockcroft and Gault equation: it ismore accurate (7,8), more robust whenglucose control is poor (9), and not bi-ased by body weight (10), which is ofconsiderable importance because of thefrequent association of type 2 diabetes,and CKD (11), with obesity. Most of therecent reports on CKD in diabetic pa-tients rely on MDRD e-GFR (12–16).This equation may however not be idealfor screening CKD, as it is known tounderestimate normal and high GFR(17,18): some of the MDRD-based CKDdiagnosis may stem from this underes-timation (19), particularly in nor-moalbuminuric patients. Furthermore,the progressive nature of normoalbu-minuric CKD has been argued fromstudies based on measured GFR, re-ported by one group (3,20), and its as-sociation with complications relies onreports in Asian diabetic subjects, whoare known to have a high incidence ofCKD (14). Whether this applies toMDRD-diagnosed normoalbuminuricCKD in Caucasians remains to be dem-onstrated.

To evaluate the significance of nor-moalbuminuric CKD in diabetes, wecompared the isotopic GFR and serumcreatinine of normoalbuminuric versusalbuminuric diabetic patients with CKDaccording to an MDRD e-GFR �60 ml/min per 1.73 m2. The baseline character-istics of the patients, and their outcome

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

From the 1Department of Nutrition-Diabetologie, Hopital Haut-Leveque, Pessac, France; the 2Department ofNephrologie, Universite Victor Segalen-Bordeaux 2, Hopital Pellegrin, Bordeaux, France; the 3Department ofBiochimie, Hopital Haut-Leveque, Pessac, France; and the 4Department of Medecine Nucleaire, HopitalPellegrin, Bordeaux, France.

Address correspondence and reprint requests to Vincent Rigalleau, Nutrition-Diabetologie, Hopital Haut-Leveque, Avenue de Magellan, 33600 Pessac, France. E-mail: vincent.rigalleau@wanadoo.fr.

Received for publication 23 January 2007 and accepted in revised form 29 April 2007.Published ahead of print at http://care.diabetesjournals.org on 7 May 2007. DOI: 10.2337/dc07-0140.Abbreviations: AER, albumin excretion rate; CKD, chronic kidney disease; e-GFR, estimated glomerular

filtration rate; GFR, glomerular filtration rate; MDRD, modification of diet in renal disease.A table elsewhere in this issue shows conventional and Systeme International (SI) units and conversion

factors for many substances.© 2007 by the American Diabetes Association.The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby

marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

P a t h o p h y s i o l o g y / C o m p l i c a t i o n sO R I G I N A L A R T I C L E

2034 DIABETES CARE, VOLUME 30, NUMBER 8, AUGUST 2007

during a 38-month follow-up, were alsocompared.

RESEARCH DESIGN ANDMETHODS — A total of 89 patients(49 men, mean age 64 � 11 years) wererecruited from the Nutrition-Diabetologyand Nephrology departments of the Cen-tre Hospitalier Universitaire de Bordeaux.The inclusion criteria were as follows: 1)diabetes (a total of 22 patients had type 1diabetes and 67 had type 2 diabetes) and2) CKD according to an MDRD e-GFR�60 ml/min per 1.73 m2, not requiringrenal replacement therapy at inclusion.

The patients gave written informedconsent to participate in the study, whichwas approved by the ethical committee ofour institution. This study was supportedby a clinical research program in the Bor-deaux University Hospital.

Analytical methodsThe AER was determined on one 24-hurine collection during a short hospital-ization, with an immunonephelometricanalyzer (Behring Nephelometer 2) usingan appropriate kit (Nantiserum VO hu-man albumin; Dade Behring). Serum creat-inine was determined on a multiparameteranalyzer (Olympus AU 640; OlympusOptical, Tokyo, Japan), using the Jaffemethod with bichromatic measurementsaccording to the manufacturer’s specifica-tions, and daily calibration of the analyzer.This procedure did not change in our labo-ratory during the study. Clearance of theradionuclide marker was measured after in-travenous injection of 51Cr-EDTA (Cis In-dustries, Gif/Yvette, France). All patientswere studied in the morning at 9:00 A.M.,after a light breakfast. After a single bolus of100 �Ci (3.7 MBq) of 51Cr-EDTA, four ve-nous blood samples were drawn at 75, 105,135, and 165 min, and urinary sampleswere collected at 90, 120, 150, and 180min, as previously described (21). The finalresult was the mean of the four clearancevalues. If for one period, the urine flow wastoo low or if a clearance value was notwithin �20% of the mean of the three oth-ers, this value was excluded and the meanwas calculated for the other three clear-ances. Less than 5% of the values wereexcluded this way. The 51Cr-EDTA radioac-tivity was measured in a gamma counter(COBRA 2, model 05003; Packard Instru-ments, Meriden, CT).

Follow-up, care, and outcomeThis prospective study began in June2001. It was based on a cooperative fol-

low-up between diabetologists and neph-rologists with the establishment of a jointmedical file for each patient. This cooper-ative follow-up was complementary andincluded one visit with the diabetologistevery 4 months and one visit with thenephrologist every year if 40 � MDRDe-GFR �60 ml/min per 1.73 m2, every 4months if 20 � MDRD e-GFR �40 ml/min per 1.73 m2, and then one visit every1 or 2 months if MDRD e-GFR �20 ml/min per 1.73 m2. Mean duration of thefollow-up was 38 � 11 months.

The care program objectives in-cluded glycemic control according tothe French 1999 recommendations(A1C �8.0%; if possible, 6.5% withoutsevere hypoglycemia in type 2 and�7.0% in type 1 diabetes), but also con-trol of associated factors such as hyper-tension (objective: �130/80 mmHg)and dyslipidemia (objective: LDL choles-terol �1.3 g/l). We prescribed 0.8 g pro-tein � kg�1 � day�1 according to the NationalKidney Foundation recommendations(22), except for patients with clinical signsof undernutrition or who were �65 years ofage.

The primary outcome was require-ment for dialysis, or death. The secondaryoutcomes were the AER and serum creat-inine for living nondialyzed patients at theend of the follow-up.

Statistical analysisThe results are expressed as means � SD.The normoalbuminuric patients were com-pared with the albuminuric (micro- andmacroalbuminuric) patients by ANOVAand unpaired Student’s t tests for the con-tinuous variables and by �2 test for the cat-egorical variables. Similar analysis wasperformed after categorizing the subjects asnormoalbuminuric (AER �30 mg/24 h),microalbuminuric (30 � AER �300 mg/24h), and macroalbuminuric (AER �300mg/24 h), with a Bonferroni correction. Forthe primary outcome (death or dialysis),prognostic curves were obtained using theKaplan-Meier estimation method and com-pared by log-rank test; the patients who didnot present any event (death or dialysis on-set) were censored at the end of the follow-up. For the secondary outcome, thebaseline and final characteristics of the pa-tients were compared by paired Student’s ttests. All the analysis was performed usingSPSS software, version 10.0. The signifi-cance level was fixed at P � 0.05.

RESULTS

Baseline characteristicsA total of 89 patients were included. Theirmean diabetes duration was 18 � 10years, mean MDRD e-GFR was 41.3 �13.1 ml/min per 1.73 m2 (11–59.9), it didnot significantly differ from their isotopicGFR (45.6 � 29.7, P � 0.12), although15 subjects had an isotopic GFR �60 ml/min per 1.73 m2. A total of 15 subjects(17%) were normoalbuminuric. The pro-portion of subjects whose isotopic GFRwas �60 ml/min per 1.73 m2 was lowerin the normoalbuminuric group (13.3%)than the normoalbuminuric group(25.7%, NS by �2). The normoalbumin-uric subjects were less frequently affectedby diabetic retinopathy, but they hadhigher HDL cholesterol and hemoglobinlevels. For these characteristics, the differ-ence was mainly due to the macroalbu-minuric group, with intermediary valuesin the microalbuminuric group. Therewere also tendencies (P � 0.07) for morewomen, less cigarette smoking, fewer pre-vious cardiac events, a lower duration ofdiabetes, and a higher total cholesterollevel in the normoalbuminuric group.The type of diabetes, A1C, and bloodpressure did not differ (Table 1).

Most of the normoalbuminuric pa-tients (71%) had serum creatinine levelsin the normal range. Despite their lowerserum creatinine levels, their MDRD e-GFR did not significantly differ from thealbuminuric group, and the MDRD un-derestimation was not significant in eithergroup (P � 0.051 between isotopic andMDRD e-GFR in the microalbuminuricgroup). The correlation between MDRDe-GFR and the reference isotopic mea-surement was even better for the nor-moalbuminuric group, and the accuracyof the MDRD (percent estimations within�10, 30, and 50% of the isotopic GFR)tended to be better for them. The coexist-ence of normal AER and CKD couldtherefore not be attributed to the MDRDunderestimation of GFR in our patients.

OutcomePrimary outcome. Ten of the albumin-uric patients died during the follow-up,whereas all the normoalbuminuric sub-jects were alive at its end. Twelve of thealbuminuric patients required dialysisduring the follow-up (10 from the mac-roalbuminuric patients, P � 0.01 by �2),whereas none of the normoalbuminuricpatients did. Figure 1 shows the log sur-

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vival curve, with dialysis or death as theend point.Secondary outcome. The second AERand serum creatinine determination wasperformed in all the alive nondialized pa-tients. The changes in AER, serum creati-nine, and MDRD e-GFR did notsignificantly differ according to baselinenormo-, micro-, and macroalbuminuria.However, normoalbuminuria persistedduring the follow-up, and serum creati-nine did not change in the normoal-buminuric group. By contrast, AERincreased in the microalbuminuric pa-tients (P � 0.05 vs. baseline), and serumcreatinine increased in the macroalbu-minuric patients (P � 0.01 vs. baseline).The MDRD e-GFR tended to decrease inthe albuminuric patients (P � 0.05), andthe comparison between baseline and fi-nal values only involved the subjects whodid not have to start hemodialysis (12 al-buminuric patients, none normoalbu-minuric) (Table 2).

Table 1—Baseline characteristics of patients

Normoalbuminuric Albuminuric P Microalbuminuric Macroalbuminuric

n 15 74 36 38AER (mg/24 h) 20.7 � 6.2 712 � 876 0.003 123.7 � 78.7 1,270 � 922*†Serum creatinine (�mol/l) 122 � 27 160 � 71 0.04 135 � 44 183 � 84*†% Serum creatinine �120 �mol/l 71 33 0.006 35* 30*Isotopic GFR (ml/min per 1.73 m2) 47.5 � 19.9 45.2 � 31.4 0.79 51.8 � 27.4 39.0 � 33.6MDRD e-GFR (ml/min per 1.73 m2) 45.6 � 8.9 40.4 � 13.7 0.17 43.8 � 12.2 37.2 � 14.5Correlation between MDRD e-GFR and

isotopic GFRr � 0.69,P � 0.005

r � 0.45,P � 0.001

r � 0.53,P � 0.001

r � 0.34,P � 0.05

% MDRD estimations withinIsotopic GFR � 10% 26 24 0.84 22 26Isotopic GFR � 30% 73 60 0.56 61 60Isotopic GFR � 50% 86 79 0.72 83 76

Sex (% female) 66 40 0.058 52 29*Diabetes type (% type 2) 80 75 0.48 73 76Age (years) 68 � 9 64 � 12 0.17 65 � 11 62 � 13Diabetes duration (years) 14 � 5 19 � 11 0.06 19 � 12 19 � 10BMI (kg/m2) 27.0 � 4.5 26.9 � 4.3 0.89 27.1 � 4.4 26.7 � 4.3A1C (%) 9.0 � 1.3 8.5 � 1.6 0.31 8.6 � 1.3 8.5 � 2.0Cholesterol (g/l) 2.37 � 0.67 2.10 � 0.48 0.07 2.03 � 0.38 2.16 � 0.56LDL cholesterol (g/l) 1.26 � 0.46 1.19 � 0.40 0.54 1.14 � 0.32 1.25 � 0.47HDL cholesterol (g/l) 0.64 � 0.28 0.52 � 0.17 0.04 0.56 � 0.19 0.49 � 0.15*Triglycerides (g/l) 1.91 � 1.86 1.76 � 1.09 0.67 1.56 � 0.09 1.96 � 1.23Systolic blood pressure (mmHg) 143 � 16 147 � 19 0.47 145 � 19 149 � 19Diastolic blood pressure (mmHg) 79 � 8 81 � 10 0.56 79 � 9 83 � 10Number of antihypertensive drugs 2.5 � 1.8 2.4 � 1.2 0.68 2.2 � 1.0 2.5 � 1.3% on ACE inhibitors 40 59 0.25 69 50% on angiotensin 2 receptor inhibitors 20 16 0.71 16 17Hemoglobin level (g/dl) 13.3 � 1.4 12.3 � 1.4 0.01 12.6 � 1.3 12.0 � 1.4*% With previous cardiac event 13 38 0.058 31 46% With diabetic retinopathy 26 66 0.01 61* 71*% Cigarette smoking 20 52 0.054 41 63*

Data are means � SD unless otherwise indicated. *Means P � 0.05 vs. the normoalbuminuric group; †means P � 0.05 vs. the microalbuminuric group. The mediumcolumn gives the significance for the difference between the normoalbuminuric group and the other patients (n � 74).

Figure 1—Log survival plot (end point: death or dialysis).

Normoalbuminuric chronic kidney disease in diabetes

2036 DIABETES CARE, VOLUME 30, NUMBER 8, AUGUST 2007

CONCLUSIONS — Our first objec-tive was to find out whether normoalbu-minuric diabetic patients might representan artificial group, stemming from over-diagnosed CKD due to the underestima-tion of high GFR by the MDRD equation.The isotopic determination of GFR in ourpatients argues against this hypothesis: al-though the MDRD underestimated theirGFR, the difference was slight and not sig-nificant. The proportion of subjects forwhich isotopic GFR was �60 ml/min per1.73 m2 was indeed lower in the nor-moalbuminuric group (13.3%) than inthe normoalbuminuric group (25.7%, NSby �2), and the correlation between esti-mated and measured GFR was better inthe normoalbuminuric group. Most ofthese patients, therefore, really had a GFR�60 ml/min per 1.73 m2, which wouldhave been missed for 71% of them if theirrenal function had been assessed solely bya serum creatinine level �120 �mol/l.Despite its underestimation of GFR,mainly for GFR �60 ml/min per 1.73 m2

(18,23), and the increase in the number ofdetected CKD (12,24), the use of theMDRD equation as recommended by theAmerican Diabetes Association is of inter-est, especially when AER is normal.

Apart from their relatively low creat-inine levels, our normoalbuminuric CKDpatients displayed a number of specificcharacteristics: a higher proportion ofwomen, a lower duration of diabetes, alow prevalence of retinopathy (3,4), fewersmokers (25), higher hemoglobin levels(26,27), and higher HDL cholesterol(28,29) are consistent with previous re-ports on the characteristics associatedwith the presence of an abnormal AER. Asour normoalbuminuric patients weremainly women and slightly older, theirlow MDRD e-GFR was not unexpected:

increasing age and female sex both reducethe MDRD estimation. Only a minority ofthese patients had diabetic retinopathy,suggesting that their renal impairmentmay not be due to diabetic nephropathy.However, around one-third of type 2 di-abetic patients with renal biopsy–demonstrated diabetic glomerulopathydo not have retinopathy (30). Becauseblood pressure levels did not differ be-tween the two groups, it seems unlikelythat the low GFR of normoalbuminuricpatients was due to nephroangiosclerosis;these patients were also less affected byprevious cardiovascular events. However,they required as much antihypertensivetherapy as did the albuminuric patients,which suggests that their renal impair-ment was not without consequence.

Although 17 is similar to the 20 nor-moalbuminuric patients studied by Ma-cIsaac et al. (3), the small sample size is alimitation of our study, which probablyexplains why the differences betweenAER and e-GFR changes did not reach sig-nificance. Formulae estimations areknown to underestimate the decline inGFR in diabetic patients (31). None of thenormoalbuminuric patients died orstarted dialysis, and their stable AER andserum creatinine, whereas AER increasedin microalbuminuric, and creatinine in-creased in the macroalbuminuric, bothsignificantly, are however strong indica-tions for a better outcome in the nor-moalbuminuric group. It must be noticedthat most of the clinical events occurredin CKD patients with macroalbuminuria.The different characteristics we foundmay have contributed to this better out-come: male sex (32), a longer duration ofdiabetes (33), the presence of retinopathy(34), a lower hemoglobin level (32,35),and smoking (36) have all been reported

to be associated with the progression ofnephropathy in diabetes. However, themost probable is the persisting absence ofalbuminuria by itself: numerous reportshave emphasized its importance for CKDprogression (30,33–35,37,38) and coro-nary heart disease (39) in diabetes.

Some other limitations should benoted. As reflected by the scatter of theisotopic GFR in the albuminuric group(Table 1), their proportion of stages 4–5CKD was higher (26/74 vs. 3/15 nor-moalbuminuric), which can explain thatall the subjects who had to start dialysiswere albuminuric. We feel nonethelessthat the few severe and terminal CKDcases in the normoalbuminuric group is areflection that it is, on the whole, a ratherstable condition. Silveiro et al. (40)studied the evolution over 5 years of51Cr-EDTA–determined GFR in 32 nor-moalbuminuric type 2 diabetic subjects:their GFR decline (�0.18 ml/min permonth) did not differ from normal sub-jects (�0.14), except for 13 subjects whowere hyperfiltering at baseline (�0.61).Nine of our normoalbuminuric patientswere treated by ACE inhibitors or angio-tensin receptor blockers. Although theirproportion did not differ from the albu-minuric group, these treatments mayhave contributed to their good outcome,but we cannot be sure of this because wedo not know whether they had abnormalAER before the initiation of these medica-tions. Finally, because no renal biopsywas performed in our patients, their renalimpairment may not have been due to di-abetic nephropathy, which would ac-count for their better outcome (30).However, we feel that whether our pa-tients actually had diabetic nephropathyis not the issue: our purpose was to deter-mine the outcomes in patients with dia-betes and a reduced estimated GFR,classified as presenting CKD according tothe new recommendations. Of such pa-tients, 17% were normoalbuminuric inour study. Our isotopic determination ofGFR confirmed that they really had GFRbelow 60 ml/min per 1.73 m2, althoughmost of them would have not been de-tected on the sole basis of their serum cre-atinine level. But they did not progress,and the necessity to measure estimatedGFR by MDRD, and label these patients ashaving CKD, may result in adverse emo-tional and financial consequences. Fur-ther s tudies on the outcome ofnormoalbuminuric CKD in diabetes arerequired to demonstrate that the aware-ness of this condition is a benefit.

Table 2—Outcome characteristics of patients at the end of follow-up

Normoalbuminuric Microalbuminuric Macroalbuminuric

n 15 36 38Follow-up duration

(months)40 � 8 (23–54) 38 � 11 (17–54) 37 � 13 (2–59)

AER (mg/24 h) 18.0 � 9.0 271.1 � 342.2* 1,508.3 � 417.4Serum creatinine

(�mol/l)123 � 25 142 � 44 265 � 167†

MDRD e-GFR (ml/minper 1.73 m2)

45.8 � 8.5 43.0 � 12.8 29.5 � 21.1

Dialysis onset 0 2 10‡Death 0 3 7

Data are n, means � SD (range), or means � SD. *P � 0.05 and †P � 0.01 vs. the result at the inclusion(shown in the Table 1). ‡P � 0.01 by �2 test.

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Acknowledgments— This study was sup-ported by a grant from the Programme Hospi-talier de Recherche Clinique 2001.

We would like to thank Dr. Simon Jarmanfor revision of the English manuscript.

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