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Diabetes Care 29:142-144, 2006
DOI: 10.2337/diacare.29.01.06.dc05-1063
© 2006 by the American Diabetes Association
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Pathophysiology/Complications
Brief Report

Increased Urinary Excretions of Immunoglobulin G, Ceruloplasmin, and Transferrin Predict Development of Microalbuminuria in Patients With Type 2 Diabetes

Takuma Narita, MD, Mihoko Hosoba, MD, Masafumi Kakei, MD and Seiki Ito, MD

From the Department of Endocrinology, Diabetes, and Geriatric Medicine, Akita University School of Medicine, Akita, Japan

Address correspondence and reprint requests to Takuma Narita, The Department of Endocrinology, Diabetes, and Geriatric Medicine, Akita University School of Medicine, Hondo, Akita 010-8543, Japan. E-mail: narita{at}med.akita-u.ac.jp

Abbreviations: Cr, creatinine • CRL, ceruloplasmin • IgG, immunoglobin G • NAG, N-acetylglucosaminidase • Tf, transferrin


   INTRODUCTION
TOP
 INTRODUCTION
RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
Microalbuminuria is generally considered as the best available noninvasive predictor of diabetic nephropathy. However, several studies have shown that increases in certain urinary proteins (immunoglobin G [IgG] [1–3], transferrin [Tf] [4–7], and ceruloplasmin [CRL] [3,8]) were found in normoalbuminuric diabetic patients. Recently, we reported that in normoalbuminuric diabetic patients, there was a strong linear correlation among these urinary proteins (9). To assess whether increased urinary excretions of IgG, CRL, and Tf can predict development of microalbuminuria, we conducted a 5-year follow-up study of type 2 diabetic patients with normoalbuminuria at baseline.


   RESEARCH DESIGN AND METHODS
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
RESULTS
 CONCLUSIONS
 References
 
In 1998 and 1999, we recruited 140 type 2 diabetic patients with normoalbuminuria from outpatients. Normoalbuminuria was defined as a urinary albumin-to-creatinine ratio <30 mg/gCr in all of three serial spot urine samples. No subjects had a history of disease other than diabetes, hypertension, or dyslipidemia.

Since urinary IgG, CRL, and Tf can be easily affected by meal protein (10,11), timed overnight urine samples were collected on three different days within 2 or 3 months for analyses of these urinary proteins and N-acetylglucosaminidase (NAG) (3,8–13). Geometric means of the results expressed as protein-to-creatinine (Cr) ratios including albumin (U-Alb/Cr, U-IgG/Cr, U-CRL/Cr, U-Tf/Cr, and U-NAG/Cr, respectively) were calculated. Increases in these parameters at baseline were defined as exceeding the upper limits of healthy control subjects (Table 1). Means of HbA1c (A1C) and serum lipids were calculated from data in three blood samples taken in the morning after the urine collections.


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  		Table 1— Clinical characteristics of 117 normoalbuminuric type 2 diabetic patients

 
These patients were followed at our outpatients’ clinic once a month. The development of microalbuminuria was defined as two consecutive U-Alb–to–Cr ratios of spot urines ≥30 mg/gCr. During 5-year follow-up, 3 patients died and 20 patients discontinued their visits to our clinic. Finally, 117 patients (83.6%) were available for analysis of the development of microalbuminuria.

All participants in this study gave their consent after being fully informed of the study protocol.


   RESULTS
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
CONCLUSIONS
 References
 
Of 117 patients, 17 (14.5%) progressed to microalbuminuria. Baseline A1C, mean A1C during the follow-up, and rates of retinopathy and use of insulin at baseline were significantly higher in progressors than in nonprogressors. Blood pressure levels during the follow-up were slightly higher in progressors than in nonprogressors (not statistically significant). Other parameters exhibited no difference between progressors and nonprogressors (Table 1) (Mann-Whitney U test or Pearson’s {chi}2 test).

At baseline, U-IgG/Cr, U-CRL/Cr, and U-Tf/Cr of progressors were significantly higher than those of nonprogressors, but there was no difference in U-NAG/Cr. The rate of progression to microalbuminuria was significantly higher in patients with increased U-IgG/Cr (8 of 17, 47.1%) than in patients without increased U-IgG/Cr (9 of 100, 9%) (P = 0.0003; odds ratio [OR] 8.99 [95%CI 3.16–25.6]). Similar results were also obtained for U-CRL/Cr and U-Tf/Cr but not for U-NAG/Cr (Table 1).

In a multiple logistic regression analysis, the model included the clinical parameters at baseline and during the follow-up (Table 1) as variables. Increased U-IgG/Cr was selected as a representative of urinary proteins for multicollinearity among U-IgG/Cr, U-CRL/Cr, and U-Tf/Cr. In the model, use of insulin and retinopathy at baseline, high diastolic blood pressure during the follow-up, and increased U-IgG/Cr at baseline were independent variables for development of microalbuminuria (P = 0.049, 0.039, 0.031, and 0.0098, respectively; OR 7.03 [95% CI 1.01–48.84], 7.57 [1.10–51.96], 3.12 [1.10–8.80 per 5 mmHg], and 10.87 [1.78–66.5], respectively).


   CONCLUSIONS
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
References
 
Increased urinary excretions of IgG, CRL, and Tf had equal predictive value for development of microalbuminuria in normoalbuminuric type 2 diabetic patients. Kazumi et al. reported that increased urinary Tf excretion could predict development of microalbuminuria in normoalbuminuric type 2 diabetic patients (14). We confirmed their result and found that increased urinary IgG and CRL can also predict development of microalbuminuria.

Our previous study showed that transiently enhanced glomerular filtration rate in response to acute protein loading did not cause an increase in urinary albumin excretion but parallel increases in urinary excretions of IgG, CRL, and Tf in healthy volunteers (10,11). Our findings suggest that these urinary proteins reflect changes in renal hemodynamics more sensitively than albumin. Parallel increases in these urinary proteins in timed overnight urine samples were found in patients with impaired glucose tolerance (15) and in type 2 diabetic patients with normoalbuminuria (3,9). Furthermore, strict glycemic control reversed increases in these urinary proteins without change in albuminuria (3). Given the finding that hyperglycemia induces an increase in intraglomerular hydraulic pressure (16–18) in early stages of diabetic nephropathy, parallel increases in these urinary proteins likely reflect increased intraglomerular hydraulic pressure, and increased intraglomerular hydraulic pressure does not produce increase in albuminuria. Accordingly, the present results are consistent with the animal studies that increased intraglomerular hydraulic pressure plays a pivotal role in development of diabetic glomerulosclerosis (16–18).

Although A1C levels at baseline and during the follow-up were higher in progressors than in nonprogressors, multiple logistic regression analysis did not indicate that the glycemic control level was an independent predictor of development of microalbuminuria. Several landmark studies of type 2 diabetes showed that poor glycemic control is a risk factor for development of microalbuminuria (19,20). Our negative finding may be explained by the relatively small differences in A1C between progressors and nonprogressors and the relatively lower levels of A1C compared with those in such studies (19,20). Considering that insulin use and retinopathy at baseline were indicated as independent predictors of development of microalbuminuria in the present study, progressed state of microangiopathy at baseline may be a more powerful predictor than the glycemic control level during 5-year follow-up.

Diastolic blood pressure level during follow-up was shown to be an independent predictor of development of microalbuminuria by multiple logistic regression analysis. This result was consistent with that of U.K. Prospective Diabetes Study (21). The higher reading of diastolic blood pressure correlates with progressors and the lower with nonprogressors.

In conclusion, we found that increases in urinary IgG, CRL, and Tf had equal predictive value for development of microalbuminuria in normoalbuminuric diabetic patients. Increases in these urinary proteins appear to be more sensitive indicators of renal hemodynamic changes, such as enhanced intraglomerular hydraulic pressure, than urinary excretion of albumin.


   Footnotes
 
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

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.

Received for publication June 10, 2005. Accepted for publication September 29, 2005.


   References
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 

  1. Deckert T, Feldt-Rasmussen B, Djurup R, Deckert M: Glomerular size and charge selectivity in insulin-dependent diabetes mellitus. Kidney Int 33:100–106, 1988[Medline]
  2. Jerums G, Allen TJ, Cooper ME: Triphasic changes in selectivity with increasing proteinuria in type 1 and type 2 diabetes. Diabet Med 6:772–779, 1989[Medline]
  3. Narita T, Fujita H, Koshimura J, Meguro H, Kiatazto H, Shimotomai T, Kagaya E, Suzuki K, Murata M, Usami A, Ito S: Glycemic control reverses increases in urinary excretions of immunoglobulin G and ceruloplasmin in type 2 diabetic patients with normoalbuminuria. Horm Metab Res 33:370–378, 2001[Medline]
  4. O’Donnel MJ, Martin P, Florkowski CM, Toop MJ, Chapman C, Holder R: Urinary excretion of transferrin excretion in type I (insulin-dependent) diabetes mellitus. Diabet Med 8:657–661, 1991[Medline]
  5. Cheung CK, Cockram CS, Yeung VFT, Schwaminathan R: Urinary excretion of transferrin in non-insulin-dependent diabetics: a marker for early complications. Clin Chem 35:1672–1674, 1989[Abstract/Free Full Text]
  6. McCormick CP, Konen JC, Shihabi ZK: Microtransferrinuria and microalbuminuria. I. In the diabetic human. Clin Physiol Biochem 8:53–58, 1990[Medline]
  7. Bernard AM, Ouled Amor AA, Goemaere-Vanneste J, Antonie JL, Lauwerys RR, Lambert A, Vandeleene B: Microtransferrinuria is a more sensitive indicator of early glomerular damage in diabetes than microalbuminuria. Clin Chem 34:1920–1921, 1988[Free Full Text]
  8. Yamazaki M, Ito S, Usami A, Tani N, Hanyu O, Nakagawa O, Nakamura H, Shibata A: Urinary excretion rate of ceruloplasmin in non-insulin dependent diabetic patients with different stage of nephropathy. Eur J Endocrinol 132:681–687, 1995[Abstract]
  9. Narita T, Sasaki H, Hosoba M, Miura T, Yoshioka N, Morii T, Shimotomai T, Koshimura J, Fujita H, Kakei M, Ito S: Parallel increase in urinary excretion rates of immunoglobulin G, ceruloplasmin, transferrin, and orosomucoid in normoalbuminuric type 2 diabetic patients. Diabetes Care 27:1176–1181, 2004[Abstract/Free Full Text]
  10. Narita T, Kitazato H, Koshimura J, Suzuki K, Murata M, Ito S: Effects of protein meals on the urinary excretion of various plasma proteins in healthy subjects. Nephron 81:398–405, 1999[Medline]
  11. Koshimura J, Narita T, Sasaki H, Hosoba M, Yoshioka N, Shimotomai T, Fujita H, Kakei M, Ito S: Urinary excretions of transferrin and orosomucoid are increased after acute protein loading in healthy subjects. Nephron Clin Pract 100:c33–c37, 2005[Medline]
  12. Brodows RG, Nichols D, Shaker G, Kubasik NP: Evaluation of a new radioimmunoassay for urinary albumin. Diabetes Care 9:189–193, 1986[Abstract]
  13. Narita T, Koshimura J, Suzuki K, Murata M, Meguro H, Fujita H, Kitazato H, Ito S: Effects of short-term glycemic control, low protein diet and administration of enalapril on renal hemodynamics and protein permselectivity in type 2 diabetic patients with microalbuminuria. Tohoku J Exp Med 189:117–133, 1999[Medline]
  14. Kazumi T, Hozumi T, Ishida Y, Ikeda Y, Kishi K, Hayakawa M, Yoshino G: Increased urinary transferrin excretion predicts microalbuminuria in patients with type 2 diabetes. Diabetes Care 22:1176–1180, 1999[Abstract/Free Full Text]
  15. Fujita H, Narita T, Ito S: Abnormality in urinary protein excretion in Japanese men with impaired glucose tolerance. Diabetes Care 22:823–826, 1999[Abstract/Free Full Text]
  16. Hostetter TH, Rennke HG, Brenner BM: The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies. Am J Med 72:375–380, 1982[Medline]
  17. Zatz R, Meyer TW, Rennke HG, Brenner BM: Predominance of hemodynamic rather than metabolic factors in the pathogenesis of diabetic glomerulopathy. Proc Natl Acad Sci U S A 82:5963–5967, 1985[Abstract/Free Full Text]
  18. Anderson S, Brenner BM: Pathogenesis of diabetic nephropathy: Hemodynamic considerations. Diabetes Metab Rev 4:163–177, 1988[Medline]
  19. UK Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853, 1998[Medline]
  20. Okubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 28:103–117, 1995[Medline]
  21. UK Prospective Diabetes Study Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 317:703–713, 1998[Abstract/Free Full Text]

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