Disparity Between Declining Gfr And Increasing

Most patients with diabetic renal disease display a decline in GFR that is preceded or accompanied by an increase in AER. However there is a growing body of evidence to suggest that some patients possibly follow an alternate, non-albuminuric pathway to renal impairment. The combination of impaired renal function in association with normoalbuminuria was first highlighted by Lane et al. [3] who identified eight women with type 1 diabetes who had low creatinine clearance but a normal AER. A recent study from this group has examined the clinical characteristics and renal ultrastructure in 105 normoalbuminuric type 1 diabetic patients [10]. A total of 23 (22 %) normoalbuminuric patients had a GFR < 90 ml/min/1.73 m2 and a median AER of 7.7 (range 2.0-17.6) ^g/min. These patients showed increased mesangial and mesangial matrix fractional volumes and glomerular basement membrane width when compared with age- and gender-matched controls. The glomerular lesions seen in normoalbuminuric patients with type 1 diabetes and a GFR < 90 ml/min/1.73 m2 were also more advanced than those in normoalbuminuric patients with a GFR > 90 ml/min/1.73 m2. These investigators concluded that, in type 1 diabetes, low GFR could precede increases in AER, particularly in women with longstanding diabetes associated with retinopathy and hypertension.

Studies from our group have also shown that creatinine clearance can decline in patients with type 1 or type 2 diabetes, especially females without microalbuminuria [4]. More recently, we have explored the relationship between AER and isotopically measured GFR in a larger group of patients with type 2 diabetes [93]. Thirty-four percent of participants (109/301) had a GFR < 60 ml/min/1.73 m2 (Figure 4). In patients with GFR > 60 ml/min/1.73 m2 the prevalence of normo-, micro- and macroalbuminuria was 115 (60 %), 64 (33 %) and 13 (7 %) respectively (Figure 4: zones 1, 2 and 3, respectively). For the 109 patients with a GFR < 60 ml/min/1.73 m2 the prevalence of normo-, micro-and macroalbuminuria was 43 (39 %), 38 (35 %) and 28 (26 %) respectively (Figure 4: zones 4, 5 and 6 respectively). When the 301 patients were stratified according to their AER status regardless of their GFR, 158 (52%) had normo-, 102 (34 %) had micro- and 41 (14 %) had macroalbuminuria. For these normoalbuminuric patients, 115/158 (73%) had a corresponding GFR > 60 ml/min/1.73m2 and 43/158 (27%) had a GFR < 60 ml/min/1.73m2.

The prevalence of a GFR < 60 ml/min/1.73m2 and normoalbuminuria was also calculated after excluding patients whose normoalbuminuric status was possibly altered by the use of a renin angiotensin system inhibitor. After this adjustment the prevalence of a GFR < 60 ml/min/1.73 m2 and normoalbuminuria was 20/86 (23%). Furthermore, after the additional exclusion of patients without retinopathy, the prevalence of a GFR < 60 ml/min/1.73 m2 and normoalbuminuria was not altered, i.e. 8/35 (23%). Temporal changes in GFR were also calculated in a subset of 37/109 (34%) unselected patients with impaired renal function. The mean interval between GFR measurements (years) of 4.9 ± 0.5, 5.6 ± 0.6 and 6.6 ± 0.6 years and the rate of decline in GFR (ml/min/1.73m2/year) of 5.5 ± 1.0, 2.8 ± 1.0 and 3.0 ± 07 ml/min/1.73m2/year were not significantly different for normo- (n = 15), micro- (n = 12), and macro- (n = 10) albuminuric patients respectively.

180 160 140 120 100 80 60 40 20 0

180 160 140 120 100 80 60 40 20 0

Zone 1=normal GFR +normoalbuminuria Zone 2=normal GFR +microalbuminuria Zone 3=normal GFR +macroalbuminuria Zone 4=low GFR +normoalbuminuria Zone 5=low GFR +microalbuminuria Zone 6=low GFR +macroalbuminuria

Zone 1=normal GFR +normoalbuminuria Zone 2=normal GFR +microalbuminuria Zone 3=normal GFR +macroalbuminuria Zone 4=low GFR +normoalbuminuria Zone 5=low GFR +microalbuminuria Zone 6=low GFR +macroalbuminuria

10000

Figure 4. GFR and AER in 301 patients with type 2 diabetes subdivided according to level of albuminuria and GFR > or < 60 ml/min/1.73m2.

Similar cross-sectional data were obtained using the MDRD-6 formula [26] in a survey of 820 diabetic patients from our clinic. This showed that 102

normoalbuminuric patients, representing 12% of all survey participants, had a GFR < 60 ml/min/1.73m2 [94].

Results from NHANES III suggest that the finding of non-albuminuric renal insufficiency in diabetes is not uncommon [76] (Table 1). The study included 14,622 non-institutionalised adult participants in the USA, of whom 8.3% demonstrated micro- and 1.0% macroalbuminuria. When albuminuria and renal insufficiency were considered together, 37% of participants with a low glomerular filtration rate (estimated GFR <30 ml/min/1.73 m2) demonstrated no micro- or macroalbuminuria (i.e. non-albuminuric renal insufficiency). This was most evident in the age-group of 60-79 years: 34% of diabetic and 63% of non-diabetic hypertensive patients with a GFR < 30 ml/min/1.73m2 demonstrated normoalbuminuria [76]. The prevalence of non-albuminuric renal insufficiency, when defined as a GFR < 60 ml/min/1.73m2, for subjects with diabetes in this age group was 47%. Although this may be an overestimate because of a lack of calibration of serum creatinine levels to MDRD standards [8], this study nevertheless indicates that screening tests for albuminuria and renal insufficiency identify different segments of the population. The AUSDIAB study has recently inferred a similar discordance between albuminuria and GFR in the Australian population [95].

In conclusion whilst an increase in urinary albumin excretion remains the best non-invasive indicator of a patient's risk for progressive renal disease, its absence may not predict which patients are safe from a progressive decline in GFR. Females appear to be at a particularly increased risk for this non-albuminuric pathway to impaired renal function. It has been advocated that regular measurements of GFR should be performed in long-standing normoalbuminuric patients with type 1 diabetes, especially in females who also have with retinopathy or hypertension [10]. Our studies also suggest that the above should also apply to normoalbuminuric female patients with longstanding type 2 diabetes.

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Supplements For Diabetics

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