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Diabetic Nephropathy

Early Glomerular Filtration Rate Loss as a Marker of Diabetic Nephropathy George Jerums,1

Elif Ekinci,2 Sianna Panagiotopoulos3 and Richard J MacIsaac4

1. Professor, Endocrine Centre, Austin Health and University of Melbourne, Heidelberg Repatriation Hospital; 2. Endocrinologist, Endocrine Centre, Austin Health and University of Melbourne, Heidelberg Repatriation Hospital; 3. Manager, Office for Research, Endocrine Centre, Austin Health and University of Melbourne, Heidelberg Repatriation Hospital; 4. Professor, St Vincent’s Hospital and University of Melbourne


In the early 1980s, studies in type 1 diabetes suggested that glomerular filtration rate (GFR) loss begins with the onset of macroalbuminuria. However, recent evidence indicates that up to one-quarter of subjects with diabetes reach a GFR of less than 60 ml/min/1.73 m2 (chronic kidney disease [CKD] stage 3) before developing micro- or macroalbuminuria. Furthermore, the prospective loss of GFR can be detected in early diabetic nephropathy (DN) well before CKD stage 3. Early GFR loss usually reflects DN in type 1 diabetes but, in older patients with type 2 diabetes, the assessment of early GFR loss needs to take into account the effects of ageing. The assessment of GFR is now feasible at clinical level, using formulas based on serum creatinine, age, gender and ethnicity. Overall, the estimation of early GFR loss is more accurate with the Chronic Kidney Disease Epidemiology (CKD–EPI) formula than with the Modification of Diet in Renal Disease (MDRD) study formula, but there is some evidence that the CKD-EPI formula does not exhibit better performance than the MDRD formula for estimating GFR in diabetes. Both formulas underestimate GFR in the hyperfiltration range. Formulas based on the reciprocal of cystatin C can also be used to estimate GFR, but their cost and lack of assay standardisation have delayed their use at clinical level. In summary, early GFR loss is an important marker of DN as well as a potentially reversible target for interventions in DN.

Keywords Early glomerular filtration rate loss, hyperfiltration, normoalbuminuric renal insufficiency, Modification of Diet in Renal Disease (MDRD)

Disclosure: The authors have no conflicts of interest to declare. Received: 21 December 2011 Accepted: 19 January 2012 Citation: European Endocrinology, 2012;8(1):27–31 Correspondence: George Jerums, Endocrine Centre, Austin Health and University of Melbourne, Heidelberg Repatriation Hospital, PO Box 5444, Heidelberg West, Victoria, 3081, Australia. E:

Since the early 1980s, the clinical diagnosis of diabetic nephropathy (DN) has been based on the progression of albuminuria. Albumin excretion rate (AER) was categorised as normo-, micro- or macroalbuminuria based on retrospective studies of AER in type 1 diabetes prior to the introduction of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Microalbuminuria (or dipstick-negative albuminuria) predicted macroalbuminuria (or dipstick-positive albuminuria – i.e., overt nephropathy) in 60–80 % of patients with type 1 diabetes over intervals of 6–14 years. However, recent studies have shown that the predictive value of microalbuminuria is of the order of 30–50 % and spontaneous remission of microalbuminuria occurs in over 50 % of patients.1,2

A decline in glomerular filtration rate (GFR) was initially considered to occur only in patients with macroalbuminuria.3

Subsequent experience

has shown that GFR may start to decline in subjects with type 1 diabetes at the stage of microalbuminuria.4

Using serial measurements of Furthermore, progressive

decline in GFR has also been described in normoalbuminuric subjects with type 1 or type 2 diabetes.5

creatinine clearance, it was shown that approximately one-third of subjects with either type 1 or type 2 diabetes developed a decline in renal function without a corresponding increase in AER. Subsequent studies in type 2 diabetes using isotopic GFR showed that approximately one-quarter of subjects developed non-albuminuric renal insufficiency (GFR <60 ml/min/1.73 m2), after exclusion of


patients treated with renin-angiotensin system (RAS) inhibitors.6 Although these studies have shown that early GFR loss is not confined to macroalbuminuric subjects, the rate of progression of GFR loss is usually more rapid in subjects with macroalbuminuria.

Using this definition, the first Joslin Kidney Study monitored trends in renal function over four years in 279 type 1 diabetes patients with new-onset microalbuminuria.3

Studies in type 1 diabetes have defined early decline in renal function as a loss of GFR of >3.3 % per year, corresponding to the 97.5th percentile of the decline in creatinine clearance in non-diabetic normotensive Caucasians in the Baltimore Longitudinal Study of Aging.7

The reciprocal of serum cystatin C

was used to compare the annual percentage change in GFR in this cohort (mean baseline GFR 155 ml/min/1.73 m2) with a control group of normoalbuminuric patients (mean baseline GFR 143 ml/min/1.73 m2). Early renal function decline occurred in 31 % of microalbuminuric and 9 % of normoalbuminuric patients (p<0.001). Furthermore, the frequency of early renal function decline was related to the course of AER over a four-year period. A higher frequency of early GFR loss (67.7 %) occurred in subjects whose AER doubled during the study, compared with subjects who had stable microalbuminuria (32.2 %) and subjects whose microalbuminuria was halved (16.2 %). These findings suggest that early GFR and AER trajectories are separate processes during the early stages, but become more closely coupled during the later stages of DN.3


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