Curr Diab Rep (2014) 14:529 DOI 10.1007/s11892-014-0529-6
INVITED COMMENTARY
Non-Proteinuric Diabetic Nephropathy Varun Chawla & Bijan Roshan
Published online: 21 August 2014 # Springer Science+Business Media New York 2014
Keywords Non-proteinuric diabetic nephropathy . Diabetes . Chronic kidney disease . Albuminuria
Diabetes is the leading cause of end-stage renal disease (ESRD) in the USA [1]. The prevalence of diabetic kidney disease has increased steadily in proportion to the prevalence of diabetes [2]. Most patients with advanced diabetic kidney disease are overtly proteinuric. Still, clinicians are encountering diabetic patients without proteinuria, and at times even without microalbuminuria, who suffer from advanced chronic kidney disease (CKD) that seems out of proportion to nondiabetic patients with similar co-morbidities.
Albuminuria and Diabetic Nephropathy In 1980s, Mogensen et al. devised a staging classification for diabetic nephropathy (DN) that became the widely accepted clinical-pathologic classification for DN [3]. In this classification, stage 1 is characterized by glomerular hyperfiltration and an increase in glomerular filtration rate (GFR) and kidney size. In stage 2, thickening of glomerular capillary basement membrane occurs and can be only detected histologically. Stage 3 is characterized by microalbuminuria, and GFR, still normal or high, starts to decline. Stage 4 is overt diabetic
V. Chawla Chabot Nephrology Medical Group, Fremont, CA, USA e-mail: [email protected] B. Roshan (*) Division of Renal Diseases and Hypertension, University of Colorado Denver, 12700 East 19th Ave., Room 7015, Aurora, CO 80045, USA e-mail: [email protected]
nephropathy with macroalbuminuria in which we see a further drop in GFR. Stage 5 is ESRD with uremia due to DN. Microalbuminuria since then become a hallmark of DN and considered as the first clinical sign of DN. It was even thought that without albuminuria, CKD cannot be ascribed to DN, as before microalbuminuria, the GFR is normal or even i n c r e a s e d i n M o g e n s e n ’s s t a g e s 1 o r 2 . T h u s , microalbuminuria is commonly used for the screening of DN. There are however a few problems with the traditional model of the first development of microalbuminuria, then progression to macroalbuminuria accompanied by renal dysfunction, and finally ESRD. First, there is frequent regression of microalbuminuria in patients with type 1 diabetes. In fact, microalbuminuria regresses to normoalbuminuria in a large number of patients [4–6]. The other problem with this model is that non-proteinuric kidney disease is quite prevalent in patients with diabetes [7–9]. Initially, the source of albuminuria in DN was thought to be solely of glomerular origin. However, much of filtered albumin can be reabsorbed by renal tubular cells and it is possible to have lower levels of albuminuria even with tubular disease [10, 11]. Natau et al. studied markers of tubular and glomerular injury in diabetic patients with and without albuminuria and in normal controls [12]. They found that both glomerular and tubular markers are associated with albuminuria, independently of GFR, suggesting that albuminuria reflects both glomerular and tubulointerstitial damage.
Non-albuminuric Diabetic Nephropathy In the United Kingdom Prospective Diabetes study (UKPDS) group, 4,006 participants with type 2 diabetes and normoalbuminuria and normal creatinine were followed for a median of 15 years: of these, 1,132 (28 %) developed renal impairment. Of those, 575 (51 %) did not have preceding
529, Page 2 of 3
albuminuria and 39 % did not develop albuminuria during the study follow-up [7]. In the DEMAND (Developing Education on Microalbuminuria for Awareness of Renal and Cardiovascular Risk in Diabetes) study, a global, cross-sectional analysis of 11,315 participants with diabetes and an estimated GFR of
INVITED COMMENTARY
Non-Proteinuric Diabetic Nephropathy Varun Chawla & Bijan Roshan
Published online: 21 August 2014 # Springer Science+Business Media New York 2014
Keywords Non-proteinuric diabetic nephropathy . Diabetes . Chronic kidney disease . Albuminuria
Diabetes is the leading cause of end-stage renal disease (ESRD) in the USA [1]. The prevalence of diabetic kidney disease has increased steadily in proportion to the prevalence of diabetes [2]. Most patients with advanced diabetic kidney disease are overtly proteinuric. Still, clinicians are encountering diabetic patients without proteinuria, and at times even without microalbuminuria, who suffer from advanced chronic kidney disease (CKD) that seems out of proportion to nondiabetic patients with similar co-morbidities.
Albuminuria and Diabetic Nephropathy In 1980s, Mogensen et al. devised a staging classification for diabetic nephropathy (DN) that became the widely accepted clinical-pathologic classification for DN [3]. In this classification, stage 1 is characterized by glomerular hyperfiltration and an increase in glomerular filtration rate (GFR) and kidney size. In stage 2, thickening of glomerular capillary basement membrane occurs and can be only detected histologically. Stage 3 is characterized by microalbuminuria, and GFR, still normal or high, starts to decline. Stage 4 is overt diabetic
V. Chawla Chabot Nephrology Medical Group, Fremont, CA, USA e-mail: [email protected] B. Roshan (*) Division of Renal Diseases and Hypertension, University of Colorado Denver, 12700 East 19th Ave., Room 7015, Aurora, CO 80045, USA e-mail: [email protected]
nephropathy with macroalbuminuria in which we see a further drop in GFR. Stage 5 is ESRD with uremia due to DN. Microalbuminuria since then become a hallmark of DN and considered as the first clinical sign of DN. It was even thought that without albuminuria, CKD cannot be ascribed to DN, as before microalbuminuria, the GFR is normal or even i n c r e a s e d i n M o g e n s e n ’s s t a g e s 1 o r 2 . T h u s , microalbuminuria is commonly used for the screening of DN. There are however a few problems with the traditional model of the first development of microalbuminuria, then progression to macroalbuminuria accompanied by renal dysfunction, and finally ESRD. First, there is frequent regression of microalbuminuria in patients with type 1 diabetes. In fact, microalbuminuria regresses to normoalbuminuria in a large number of patients [4–6]. The other problem with this model is that non-proteinuric kidney disease is quite prevalent in patients with diabetes [7–9]. Initially, the source of albuminuria in DN was thought to be solely of glomerular origin. However, much of filtered albumin can be reabsorbed by renal tubular cells and it is possible to have lower levels of albuminuria even with tubular disease [10, 11]. Natau et al. studied markers of tubular and glomerular injury in diabetic patients with and without albuminuria and in normal controls [12]. They found that both glomerular and tubular markers are associated with albuminuria, independently of GFR, suggesting that albuminuria reflects both glomerular and tubulointerstitial damage.
Non-albuminuric Diabetic Nephropathy In the United Kingdom Prospective Diabetes study (UKPDS) group, 4,006 participants with type 2 diabetes and normoalbuminuria and normal creatinine were followed for a median of 15 years: of these, 1,132 (28 %) developed renal impairment. Of those, 575 (51 %) did not have preceding
529, Page 2 of 3
albuminuria and 39 % did not develop albuminuria during the study follow-up [7]. In the DEMAND (Developing Education on Microalbuminuria for Awareness of Renal and Cardiovascular Risk in Diabetes) study, a global, cross-sectional analysis of 11,315 participants with diabetes and an estimated GFR of
