The four-variable modification of diet in renal disease formula underestimates glomerular filtration rate in obese type 2 diabetic individuals with chronic kidney disease
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GFR is commonly estimated using the four-variable Modification of Diet in Renal Disease (MDRD) formula and this forms the basis for classification of chronic kidney disease (CKD). We investigated the effect of obesity on the estimation of glomerular filtration rate in type 2 diabetic participants with CKD.
We enrolled 111 patients with type 2 diabetes mellitus in different stages of CKD. GFR was measured using 51Cr-labelled EDTA plasma clearance and was estimated using the four-variable MDRD formula.
The bias between estimated and measured GFR was −22.4 (−33.8 to −11.0) p < 0.001 in the obese group compared with −6.04 (−17.6 to −5.5) p = 0.299 in the non-obese group. When GFR was indexed to body surface area of 1.73 m2, the bias remained significant at −9.4 (−13.4 to −5.4) p < 0.001 in the obese participants.
This study suggests that the four-variable MDRD formula significantly underestimates GFR in obese type 2 diabetic participants with CKD.
KeywordsBias Chronic kidney disease Effect of obesity on GFR Estimated GFR Glomerular filtration rate MDRD equation Type 2 diabetes mellitus
Body surface area
Chronic kidney disease
Estimated glomerular filtration rate
Modification of diet in renal disease
Nephropathy in diabetes is the leading cause of end-stage renal disease  and is associated with significantly increased cardiovascular risk [2, 3, 4]. It is important to be able to screen and accurately stage patients with diabetes and chronic kidney disease (CKD) to enable timely intervention to delay progression, as recommended by national and international guidelines [5, 6] and to ensure that medication to control vascular risks and concomitant conditions is used safely at appropriate doses. GFR is a key indicator of kidney function, but measuring it with inulin clearance or isotopic methods is time consuming, expensive and clinically inapplicable. Hence kidney function is routinely assessed and monitored using creatinine based estimated GFR (eGFR). An equation developed from the Modification of Diet in Renal Disease (MDRD) study , the four-variable MDRD formula based on serum creatinine, age, sex and race is currently widely employed . Most biochemistry laboratories now report eGFR on samples sent for measurement of renal function.
The MDRD formula has been shown to underestimate GFR in overweight and obese individuals with newly diagnosed type 2 diabetes mellitus . We speculated that this bias continues into later stages of diabetic CKD. This will have significant implications for the management of patients with type 2 diabetes mellitus, over 85% of whom are overweight or obese, where treatment choices are influenced by GFR. For example, metformin, a drug with proven cardiovascular benefits to overweight type 2 diabetic patients  may be denied owing to GFR underestimation.
The aim of the present study was to estimate the bias between isotopic GFR and eGFR in patients with type 2 diabetes mellitus, and relate it to BMI. In comparison with published studies examining this bias, our study population comprised participants with CKD stages 1 to 4, which include the particularly important category of individuals with eGFR between 30 and 60, for whom treatment decisions are often determined by an eGFR cut-off value. Also, unlike in the early CKD stages, a bias in the more advanced CKD stages will have significant clinical implications.
Indexing GFR to a body surface area (BSA) of 1.73 m2 in obese patients has been shown to significantly reduce the GFR, and some authors have suggested that unindexed GFR is preferable in routine practice and clinical studies for the obese population [11, 12, 13]. We report both GFR and GFR indexed to BSA of 1.73 m2 (indexed GFR) and also examine the difference between them in the obese and non-obese categories.
Demographics and bias between eGFR and measured GFR
BMI ≤ 30 kg/m2
BMI > 30 kg/m2
65.7 ± 10.7 (66.0 [58.0–74.0])
69.3 ± 11.2 (72 [63–77])
63.9 ± 10.0 (64.0 [57.0–73.0])
90.74 ± 22.4 (87.9 [73.9–102.8])
71.9 ± 11.5 (71.0 [63.1–80.3])
100 ± 20.6 (97.2 [86.1–112.7])
33.0 ± 7.3 (32.3 [27.7–37.5])
25.3 ± 2.8 (25.9 [23.2–27.9])
36.8 ± 5.6 (35.1 [32.3–40.3])
1.97 ± 0.25 (1.95 [1.7–2.1])
1.81 ± 0.17 (1.82 [1.6–1.9])
2.05 ± 0.24 (2.02 [1.89–2.21])
8.3 ± 1.6 (8.1 [7.1–9.4])
8.7 ± 1.7 (8.3 [7.4–9.5])
8.1 ± 1.5 (8.0 [6.8–9.3])
107.6 ± 31.8 (98.0 [87–126])
103 ± 23.3 (99.0 [87.5–113.0])
109.6 ± 35.2 (97.5 [84.5–128.0])
84.2 ± 38.9 (74.5 [55.5–106.9])
74.6 ± 24.7 (71.4 [54.9–86.9])
89.0 ± 43.7 (77.0 [57.4–110.6])
Indexed GFR (ml min−1 1.73 m−2)
73.1 ± 28.4 (72.3 [51.1–87.7])
67.3 ± 21.1 (64.3 [51.4–83.3])
76.0 ± 31.2 (74.6 [48.2–91.5])
eGFR (ml min−1 1.73 m−2)
67.2 ± 24.3 (65.8 [48.2–85.5])
68.6 ± 23.0 (69.4 [52.9–87.2])
66.6 ± 25.0 (62.8 [47.0–85.8])
Bias (95% CI)
−16.9(−8.4, −25.0) p < 0.001
−6.04 (−17.6, −5.5) p = 0.299
−22.4 (−33.8, −11) p < 0.001
Bias 1 (95% CI)
−5.82 (−9.3, −2.3) p = 0.01
1.38 (−7.7, 5.0) p = 0.66
−9.4 (−13.1, −5.4) p < 0.001
Serum creatinine assay and eGFR calculation
We used the 51Cr-labelled EDTA clearance method, which has been validated against the gold standard inulin clearance method [15, 16]. A bolus of 3.0 to 3.5 MBq 51Cr-labelled EDTA was administered to the participants intravenously at 0 min and the slope–intercept GFR was measured from three samples taken at 120, 180 and 240 min using a Cobra II Auto-Gamma Sample counter (PerkinElmer, Waltham, MA, USA). This was corrected for one-pool approximation using the quadratic Brøchner-Mortensen equation . GFR was indexed to BSA [GFRcorrected = GFRmeasured × (1.73/BSA m2)] and expressed as millilitres per minute 1.73 m−2. BSA was calculated based on the DuBois and DuBois formula: BSA (m2) = [weight (kg)0.425] × [height (cm)0.725] × 0.007184 .
Statistical analysis was carried out using SPSS (version 17.0 for Windows; SPSS, Chicago, IL, USA). The four-variable MDRD eGFR results were compared with GFR by means of two-tailed paired t tests or the Wilcoxon signed-rank test as appropriate. We defined bias as the mean of the difference between eGFR and GFR, so it was negative when eGFR underestimated GFR. Results are presented as mean ± SD unless otherwise indicated and p < 0.05 was taken to indicate statistical significance.
The bias between eGFR and GFR translates to a misclassification of study participants in the obese category into higher CKD groups. Forty per cent of participants in CKD stage 2 were misclassified into stage 3 and 54% from stage 3A to stage 3B.
Analysis of bias by sex shows a mean overall difference between women and men of −16.6 (95% CI −30.6, −2.6, p = 0.02); in the obese participants the difference was −13.7 (95% CI −32.6, 5.02, p = 0.148) and in non-obese participants the difference was −18.60 (95% CI −39.3, 2.17, p = 0.078).
It was also noted that the mean BSA increased with increasing BMI and was 2.05 ± 0.24 m2 in the obese participants. The mean difference between the GFR and the indexed GFR was 13.02 ± 53.2 (p = 0.039) in the obese participants. This discrepancy between eGFR and GFR before and after indexing to a BSA of 1.73 m2 can also be visualised from Fig. 1.
This study extends previous observations made in recently diagnosed patients with normal renal function , by demonstrating that the four-variable MDRD formula underestimates GFR in obese patients with established type 2 diabetes mellitus. Furthermore, we have found that this bias between eGFR and GFR persists into later stages of CKD. The bias was clinically significant in CKD stage 4, but not statistically so owing to the low number of participants in this group. Overall, the bias appeared to be greater in women, which could be due to the fact that women tend to have significantly higher body fat content and lower muscle mass compared with men. The difference in bias across sex was similar in magnitude, but did not reach significance in either the obese or non-obese groups analysed separately; however, the study was not powered to look at sex differences.
Underestimated GFR will have implications for the management of obese patients with type 2 diabetes mellitus, particularly as the choice of drugs, such as metformin and some of the newer glucose lowering drugs, is influenced by eGFR. More than half of our obese participants with eGFR > 45 were misclassified into a more severe CKD stage by the four-variable MDRD equation. This could lead to earlier than necessary initiation of insulin in these patients with possible adverse effects, including weight gain and hypoglycaemia. As we move away from a glucocentric approach to managing basic pathophysiology in type 2 diabetes , obese patients may be denied important therapeutic options because of an underestimated GFR.
This study also highlights the problem with indexing measured GFR as it is currently recommended in the obese population. Indexing is based on the assumption that the average BSA is 1.73 m2, but it is much higher in obese individuals. While this practice of indexing does not cause major differences in non-obese individuals, it leads to significant underestimation of measured GFR in obese individuals.
There is a need for better equations for estimating GFR in obese individuals, which are validated against the gold standard isotopic GFR in this population. Until such an equation becomes available, clinicians should consider this bias when making treatment decisions in obese patients with type 2 diabetes.
Duality of interest
The authors declare that there is no duality of interest associated with this study. No external funding was obtained for this study.
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