Nephropathy risk in...

[left.htm]

Nephropathy risk in type 1 diabetes

Original article:
Risk factors for development of incipient and overt diabetic nephropathy in type 1 diabetic patients: a 10-year prospective observational study. Rossing P, Hougaard P, Parving H-H. Diabetes Care 2002; 25(5): 859–64.

Summary
A group of 537 type 1 normoalbuminuric (urinary albumin excretion rate [UAER] £30 mg/24 h) diabetic patients aged >18 years, with diabetes duration ³5 years and not taking any antihypertensive medication, were followed for a median period of 9 years in order to evaluate prospectively the putative risk factors for development of micro- and macroalbuminuria.
Of the 537 patients, 403 remained free of any diabetic nephropathy, whereas 134 (25%) developed incipient (100) or overt (34) nephropathy. The baseline variables and risk factors of the two groups showed a significant difference in HbA1c, presence of retinopathy, UAER at study entry and smoking habits (Table I).

Table I: Baseline variables and risk factors in 537 type 1 diabetic patients according to development of incipient/overt diabetic nephropathy.

There were no significant differences with respect to sex, age, duration of diabetes, blood pressure or serum creatinine.
Cox’s proportional hazards multiple regression analyses were used to examine the baseline variables predictive of progression to microalbuminuria or macroalbuminuria.

Table II: Risk factors for progression to incipient or overt diabetic nephropathy in 537 type 1 diabetic patients followed for 10 years, by means of Cox’s multiple regression analysis.

As shown in Table II, the same variables and risk factors were significantly correlated with the risk of developing diabetic nephropathy: log10 UAER, HbA1c, retinopathy and smoking. The other variables and risk factors (sex, duration of diabetes, arterial blood pressure, serum creatinine, height and social class) were not significantly correlated with risk.
To illustrate the impact of the risk markers and their combination, the authors arbitrarily chose baseline values above the median for HbA1c (8.6%) and UAER (10 mg/24 h) as risk markers for progression to microalbuminuria in addition to the presence/absence of smoking and diabetic retinopathy.
The individual risk for development of microalbuminuria during 10 years of follow-up was estimated from a Cox’s regression model using the four binary risk markers (Fig. 1).

Fig. 1: Individual risks of progression to microalbuminuria during 10 years of follow-up in type 1 diabetic patients with normoalbuminuria. Based on the presence or absence of HbA1c >8.6%, UAER >10 mg/24 h, smoking and retinopathy.

Thus, a type 1, non-smoking, diabetic patient without retinopathy and with HbA1c <8.6% and UAER <10 mg/24 h had a 10% risk of developing diabetic nephropathy over a 10-year period, whereas a type 1 diabetic patient who smoked and presented with retinopathy, HbA1c >8.6% and UAER >10 mg/24 h had a 70% risk of developing the complication over the same period.
The authors conclude that their study demonstrates that several potentially modifiable risk factors, such as smoking, poor glycemic control and UAER, predict the development of incipient and overt diabetic nephropathy in so-called normoalbuminuric type 1 diabetic patients.

Comment
The presence of microalbuminuria is an established predictor of the development of overt diabetic nephropathy in both type 1 and type 2
diabetes [1–4]. Some 30% of type 1 diabetic patients develop diabetic nephropathy within 25 years of diabetes onset [5]. Microalbuminuria is also a risk marker for increased morbidity and premature death from cardiovascular diseases [6]. However, the primary prevention of diabetic nephropathy is only feasible if modifiable risk factors are known. Published data have demonstrated the beneficial effect of lowering blood pressure, UAER and HbA1c [7–10].
Our group carried out an analysis of the factors predicting nephropathy in type 1 diabetic patients participating in the Diabetes Control and Complications Trial who had either poor or good metabolic control [11]. The analysis demonstrated the beneficial effect of good metabolic control, lower UAER at entry and shorter duration of diabetes.
The present article by Rossing et al. reinforces, in a prospective observational study, the major benefit of good metabolic control, low UAER and absence of smoking and diabetic retinopathy. A type 1 diabetic patient meeting all those favourable conditions has a low (10%) risk of developing diabetic nephropathy, whereas a type 1 diabetic patient with none of those variables has a high (70%) risk of developing the complication. These figures reinforce the absolute need for early and optimal metabolic control. However, they also show that despite optimal conditions 10% of type 1 diabetic patients will develop nephropathy, whereas despite very poor conditions 30% will not.
We must therefore continue the search for all variables and risk factors that could discourage or promote the development of diabetic nephropathy. Until these are found, we believe that the cut-off value of normal versus abnormal UAER should be lowered and our patients should be urged to achieve long-lasting optimal metabolic control.

References
1. Parving H-H, Oxenboll B, Svendsen PA et al. Early detection of patients at risk of developing diabetic nephropathy. Acta Endocrinol 1982; 100: 550–5.
2. Viberti GC, Hill RD, Jarrett RJ et al. Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet 1982; 1: 1430–2.
3. Mogensen CE, Christensen CK. Predicting diabetic nephropathy in insulin-dependent patients. N Engl J Med 1984; 311: 89–93.
4. Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity onset diabetes. N Engl J Med 1984; 310: 356–60.
5. Andersen AR, Christiansen JS, Andersen JK et al. Diabetic nephropathy in Type 1 (insulin-dependent) diabetes: an epidemiological study. Diabetologia 1983; 25: 496–501.
6. Rossing P, Hougaard P, Borch-Johnsen K, Parving H-H. Predictors of mortality in insulin dependent diabetes: 10 year observational follow-up study. Br Med J 1996; 313: 779–84.
7. Mathiesen ER, Ronn B, Jensen T et al. Relationship between blood pressure and urinary albumin excretion in development of microalbuminuria. Diabetes 1990; 39: 245–9.
8. Microalbuminuria Collaborative Study Group UK. Predictors of the development of microalbuminuria in patients with type 1 diabetes mellitus: a seven year prospective study. Diabetic Med 1999; 16: 918–25.
9. The Diabetes Control and Complications Trial Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int 1995; 47: 1703–20.
10. Royal College of Physicians of Edinburgh Diabetes Register Group. Near-normal urinary albumin concentrations predict progression to diabetic nephropathy in Type 1 diabetes mellitus. Diabetic Med 2000; 17: 782–91.
11. Zhang L, Krzentowski G, Albert A, Lefèbvre PJ. Factors predictive of nephropathy in DCCT type 1 diabetic patients with good or poor metabolic control. Diabetic Med. In press.

Summary and Comment:
Georges Krzentowski, Charleroi, Belgium