A review on the role of Renal Functional Reserve as an assessment tool of renal insufficiency in the early stages of Diabetes

Objectives: Early detection before renal impairment takes place is an understated important goal. This goal is made more challenging when most renal structural injuries tend to take place in absolute clinical silence. The measurement of renal functional reserve (RFR) in diabetic patients is challenging since the presence of high glucose levels stimulate hyperfiltration and it is necessary to dissociate both effects. In the early stages of diabetes, RFR with maintained filtration capacity has been found to be diminished. Various studies have since shown that insulin-dependent diabetic mellitus (IDDM) is associated with hyperfiltration in the early stages of the disease. The response to an acute protein load in hyperfiltrating diabetic patients is that of a fall in GFR while renal blood flow remains constant. The association of early hyperfiltration and late diabetic nephropathy (DN) has also been observed. Although it has been widely accepted that hyperfiltration is associated with RFR loss, the value of RFR in diabetes has not been constantly assessed.

Methods: A review on study designs such as diagnostic cross sectional studies and cohort studies on diabetes and renal diseases were carried out. Randomised studies of RFR measurement with glomerular filtration rate (GFR) were also reviewed.

Results: RFR of diabetic patients were compared with normal healthy subjects in 6 studies. Type 1 diabetes patients were studied in 4 RFR investigations^1,2,3,4. 3 studies looked into RFR of Type 2 diabetes mellitus patients^4,5,6. 2 studies specifically looked into RFR of IDDM patients^{2, 7}. RFR values were calculated as the difference between stimulated and baseline GFR values. There were certain evidences of absent or diminished response of renal reserve among the 6 studies. Control group subjects and patients without microalbuminuria showed retained RFR functions while patients with micoralbuminuria demonstrated the loss of the function.

Conclusions: At current, the presence of microalbuminuria is the strongest available and non-invasive risk predictor of developing DN. However, various studies have indicated that the risks of developing DN exist even when urinary albumin excretion (UAE) values are normal⁸. In some type 1 and type 2 diabetic patients, decreased GFR values were found even when UAE appears within normoalbunimuria⁹ , demonstrating that normoalbuminuria does not necessarily equate to normal GFR in both type 1 and type 2 diabetic patients. At the same time, some patients with microalbuminuria may revert to normoalbuminuria. Even so, a significant proportion of normoalbuminuric diabetic patients have been found with well established DN lesions. In fact, there is now accumulating evidence pointing out that the risk of DN progression starts when UAE are still within normoalbuminuria^{7, 9}. Microalbuminuria is uncommon within the first 10 years of type 1 diabetes and first screening has been recommended at 5 years after diagnosis¹⁰. Keeping in mind that normoalbuminuria does not necessarily rule out DN, earlier than 5 years screening for microalbuminuria may then not be the answer to early detection of DN, and the role of microalbuminuria may be more of a marker than an early predictor of DN. New innovative tests need to be investigated and validated for their efficacies in providing better predictions of the risk of DN before renal implications are established, and one of the possibilities could be the evaluation of RFR through a stress GFR test. From the literatures reviewed, RFR has performed well in its indicative role in detecting glomerular changes in established diabetic patients. However, with the wide spectrum of conditions in diabetes, current evidence is not yet conclusive regarding RFR’s potential predictive role in the early stages of diabetes, especially in pre-diabetes (of both type 1 and 2 diabetes mellitus).