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Diabetic Nephropathy

Formulas for estimating eGFR based on the reciprocal of plasma cystatin C levels have the advantage of accuracy at higher GFR levels. However, cystatin C measurements are more expensive than plasma creatinine measurements. The lack of standardisation of assays is another factor delaying the use of this analyte as a marker of GFR at clinical level.31,32

Formulas for estimating GFR combining cystatin C and creatinine have been developed, but have not yet been shown to improve the precision of monitoring early GFR decline in diabetics.33

Interpreting GFR slopes in subjects with type 2 diabetes is more complex than in younger subjects with type 1 diabetes because of the effect of age-related decline in GFR. The mean rate of age-related GFR decline is approximately 1 ml/min/year after the age of 40 years.7 It follows that, if a subject aged 60 years with type 2 diabetes has a rate of GFR loss of 2.0 ml/min/year and this is reduced to 1.5 ml/min/year by aggressive antihypertensive therapy, then the diabetes-related component of GFR loss (1.0 versus 0.5 ml/min/year) has been halved.

Competing risks create a further difficulty in assessing GFR loss in type 2 diabetes. For instance, cardiovascular deaths occurred in less than 1 % of type 1 diabetes patients in the DCCT-EDIC study, compared with 25 % of type 2 diabetes patients in the long-term UKPDS follow-up study.24


Hyperfiltration (HF; i.e., GFR >130 ml/min/1.73 m2) is a common finding in type 1 diabetes with poor glucose control. In most subjects, it responds to improvement in glucose control. However, in a proportion of subjects, HF persists for several years. A recent meta-analysis of 12 early studies (six prospective, six retrospective) of type 1 diabetes patients with HF concluded that HF predisposes to the development of micro- or macroalbuminuria, with a hazard ratio of 2.3 when compared with a concurrent (normoalbuminuric) control group.34

However, there is so far no evidence that HF predicts a decline in GFR to subnormal levels (see Figure 3).35

Further long-term

studies of GFR gradients are therefore required to establish whether HF ultimately leads to renal impairment, after adjustment for glycaemic control and other confounding factors. In contrast to the meta-analysis mentioned above, a recent single centre study from

1. Macisaac RJ, Jerums G, Diabetic kidney disease with and without albuminuria, Curr Opin Nephrol Hypertens, 2011;20:246–57.

2. Perkins BA, Ficociello LH, Silva KH, et al., Regression of microalbuminuria in type 1 diabetes, N Engl J Med, 2003;348:2285–93.

3. Mogensen CE, Christensen CK, Predicting diabetic nephropathy in insulin-dependent patients, N Engl J Med, 1984;311:89–93.

4. Perkins BA, Ficociello LH, Ostrander BE, et al., Microalbuminuria and the risk for early progressive renal function decline in type 1 diabetes, J Am Soc Nephrol, 2007;18:1353–61.

5. Tsalamandris C, Allen TJ, Gilbert RE, et al., Progressive decline in renal function in diabetic patients with and without albuminuria, Diabetes, 1994;43:649–55.

6. MacIsaac RJ, Tsalamandris C, Panagiotopoulos S, et al., Nonalbuminuric renal insufficiency in type 2 diabetes, Diabetes Care, 2004;27:195–200.

7. Lindeman RD, Tobin J, Shock NW, Longitudinal studies on the rate of decline in renal function with age, J Am Geriatr Soc, 1985;33:278–85.

8. Molitch ME, Steffes M, Sun W, et al., Development and progression of renal insufficiency with and without albuminuria in adults with type 1 diabetes in the diabetes control and complications trial and the epidemiology of diabetes interventions and complications study, Diabetes Care, 2010;33:1536–43.

9. Pavkov ME, Knowler WC, Lemley KV, et al., Early renal function decline in type 2 diabetes, Clin J Am Soc Nephrol, 2012;7;78–84.

10. Babazono T, Nyumura I, Toya K, et al., Higher levels of urinary albumin excretion within the normal range predict

the Joslin Clinic found no evidence that HF estimated by cystatin C predisposes to the development of microalbuminuria in type 1 diabetes.36

The exact reasons for these disparate findings are not known. However, it is possible that a ‘calendar’ effect may explain the negative findings in the Joslin Clinic study. That is, improvements in the control of glucose, blood pressure and dyslipidaemia over the past 20 years may have diminished the role of HF as a predictor of microalbuminuria. Whether HF results in faster early GFR loss and ultimately leads to impaired GFR awaits further long-term study.

Studies of HF in type 2 diabetes are more difficult to interpret than in type 1 diabetes because of the effects of age and obesity on GFR. A correction for age-related loss of GFR can be made by subtracting 1 ml/min/1.73 m2 per year after 40 years of age.37

In obese subjects

with type 2 diabetes, there is a continuing debate on whether GFR should be indexed for body surface area.38

In the previously mentioned study in Pima Indians with type 2 diabetes with average age below 50 years, early GFR loss (≥3.3 % per year) occurred over four years in 88 subjects and renal function remained stable in 107 subjects.9

Hyperfiltration at baseline, defined

as a GFR ≥154 ml/min, was present in 53 % of subjects with early GFR loss and a similar proportion of subjects with stable renal function (48 %). Therefore, this study does not support the concept that HF predisposes to early GFR decline. However, it should be noted that mean body mass index was over 30 kg/m2 in both study groups. Therefore, if GFR were expressed per body surface area, most of these subjects would not be classified as having HF.


Early GFR loss is increasingly recognised as a marker of DN. Loss of GFR commonly occurs before the onset of macroalbuminuria and is even seen in normoalbuminuric subjects. However, early GFR decline and progression to ESRD are still strongly influenced by the progression of albuminuria. The optimal method for accurately estimating an early decline in GFR, from normal to subnormal levels, is yet to be defined. Markers of increased risk for the development of early GFR loss, apart from albuminuria, are currently being investigated. n

faster decline in glomerular filtration rate in diabetic patients, Diabetes Care, 2009;32:1518–20.

11. Gaede P, Vedel P, Larsen N, et al., Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes, N Engl J Med, 2003;348:383–93.

12. Rossing P, Hommel E, Smidt UM, et al., Reduction in albuminuria predicts a beneficial effect on diminishing the progression of human diabetic nephropathy during antihypertensive treatment, Diabetologia, 1994;37:511–6.

13. Jerums G, Panagiotopoulos S, Premaratne E, et al., Lowering of proteinuria in response to antihypertensive therapy predicts improved renal function in late but not in early diabetic nephropathy: a pooled analysis, Am J Nephrol, 2008;28:614–27.

14. Gaede P, Tarnow L, Vedel P, et al., Remission to normoalbuminuria during multifactorial treatment preserves kidney function in patients with type 2 diabetes and microalbuminuria, Nephrol Dial Transplant, 2004;19:2784–8.

15. Parving HH, Andersen AR, Smidt UM, et al., Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy, Lancet, 1983;1:1175–9.

16. Bakris GL, Weir MR, Angiotensin-converting enzyme inhibitor- associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med, 2000;160:685–93.

17. Colhoun HM, Betteridge DJ, Durrington PN, et al., Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS), Am J Kidney Dis, 2009;54:810–9.

18. Davis TM, Ting R, Best JD, et al., Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes

(FIELD) Study, Diabetologia, 2011;54:280–90.

19. Patel A, ADVANCE Collaborative Group, MacMahon S, et al., Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial, Lancet, 2007;370:829–40.

20. Zoungas S, de Galan BE, Ninomiya T, et al., Combined effects of routine blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with type 2 diabetes, Diabetes Care, 2009;32:2068–74.

21. Ismail-Beigi F, Craven T, Banerji MA, et al., Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial, Lancet, 2010;376:419–30.

22. Holman RR, Paul SK, Bethel MA, et al., 10-year follow-up of intensive glucose control in type 2 diabetes, N Engl J Med, 2008;359:1577–89.

23. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group, N Engl J Med, 1993;329:977–86.

24. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study, JAMA, 2003;290:2159–67.

25. DCCT/EDIC Research Group, de Boer IH, Sun W, Cleary PA, et al., Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes, N Engl J Med, 2011;365:2366–76.

26. Levey AS, Stevens LA, Schmid CH, et al., A new equation to estimate glomerular filtration rate, Ann Intern Med, 2009;150:604–12.



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