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Risk factors for development of incipient and overt diabetic nephropathy in patients with non-insulin dependent diabetes mellitus: prospective, observational study

^a Steno Diabetes Center DK 2820 Gentofte Denmark, ^b Centre of Preventive Medicine Glostrup University Hospital DK 2600 Glostrup Denmark, ^c Statistics Novo Nordisk DK 2880 Bagsvaerd Denmark

Correspondence to: Dr Gall

	Abstract

Top Abstract Introduction Patients and methods Results Discussion References

Objective: To evaluate putative risk factors for the development of incipient diabetic nephropathy (persistent microalbuminuria) and overt diabetic nephropathy (persistent macroalbuminuria) in patients with non-insulin dependent diabetes.
Design: Prospective, observational study of a cohort of white, non-insulin dependent diabetic patients followed for a median period of 5.8 years.
Setting: Outpatient clinic in tertiary referral centre.
Subjects: 191 patients aged under 66 years with non-insulin dependent diabetes and normoalbuminuria (urinary albumin excretion rate<30 mg/24 h) who attended the clinic during 1987.
Main outcome measures: Incipient and overt diabetic nephropathy.
Results: Fifteen patients were lost to follow up. Thirty six of the 176 remaining developed persistent microalbuminuria (30-299 mg/24 h in two out of three consecutive 24 hour urine collections) and five developed persistent macroalbuminuria (300 mg/24 h in two out of three consecutive collections) during follow up. The five year cumulative incidence of incipient diabetic nephropathy was 23% (95% confidence interval 17% to 30%). Cox's multiple stepwise regression analysis revealed the following risk factors for the development of incipient or overt diabetic nephropathy: increased baseline log urinary albumin excretion rate (relative risk 11.1 (3.4 to 35.9); P<0.0001); male sex (2.6 (1.2 to 5.4); P<0.02); presence of retinopathy (2.4 (1.3 to 4.7); P<0.01); increased serum cholesterol concentration (1.4 (1.1 to 1.7); P<0.01); haemoglobin A1c concentration (1.2 (1.0 to 1.4); P<0.05); and age (1.07 (1.02 to 1.12); P<0.01). Known duration of diabetes, body mass index, arterial blood pressure, serum creatinine concentration, pre-existing coronary heart disease, and history of smoking were not risk factors.
Conclusion: Several potentially modifiable risk factors predict the development of incipient and overt diabetic nephropathy in normoalbuminuric patients with non-insulin dependent diabetes.

	Introduction

Top Abstract Introduction Patients and methods Results Discussion References

Insulin dependent and non-insulin dependent diabetic patients with so called microalbuminuria (urinary albumin excretion rate between 30 and 299 mg/24 h) have an increased risk of developing diabetic microangiopathy and macroangiopathy, and in addition they suffer from premature death compared with normoalbuminuric diabetic patients, as reviewed by Parving et al.¹ Diabetic patients with persistent microalbuminuria–incipient diabetic nephropathy² –have about 20 times the risk of developing diabetic nephropathy.^{1 2 3 4 5 6} Prospective observational studies, conducted mainly in patients with insulin dependent diabetes, have identified several modifiable risk factors for the development of microalbuminuria and for progression of microalbuminuria to overt diabetic nephropathy, such as poor glycaemic control, slightly increased blood pressure, smoking, and hyperlipidaemia.^{7 8 9 10 11} Most but not all studies in insulin dependent diabetic patients have revealed a beneficial effect of strict glycaemic control on progression of incipient to overt diabetic nephropathy.^{12 13 14} Such data are lacking for patients with non-insulin dependent diabetes. All studies dealing with angiotensin converting enzyme inhibition in insulin dependent^{15 16 17} and in non-insulin dependent diabetic patients¹¹ have reported a beneficial effect on progression of incipient to overt diabetic nephropathy (secondary prevention). Primary prevention of incipient and overt nephropathy is feasible only if the risk factors initiating the process can be identified. Unfortunately, only scant information is available about white patients with non-insulin dependent diabetes.¹⁸

Our prospective study lasting nearly six years was conducted to elucidate putative risk factors for the development of incipient and overt diabetic nephropathy in a cohort of normoalbuminuric white patients with non-insulin dependent diabetes.

	Patients and methods

Top Abstract Introduction Patients and methods Results Discussion References

Patients
The study population was based on all 363 patients aged under 66 years with non-insulin dependent diabetes who attended the Hvidöre Hospital between 1 January and 31 December 1987. All patients were asked to collect a 24 hour urine sample for analysis of albumin excretion. We excluded 172 patients: 31 were not white, four lacked baseline urine collections, and 137 had microalbuminuria or macroalbuminuria at baseline (see fig 1). This left 191 patients who fulfilled the inclusion criteria of being white and having normoalbuminuria (urinary albumin excretion rate<30 mg/24 h) in 1987. All 191 patients were traced through the national register at the beginning of 1993. If a subject had died before 1 January 1993, the date of death was recorded and information on the cause of death was obtained from death certificates. All death certificates were reviewed independently by at least two observers, and the primary cause of death was recorded. The observation period was defined as the number of days from the date of examination in 1987 to the date of death or 1 January 1993. We also excluded 15 patients in whom only the baseline urinary albumin excretion rate was available because of loss to follow up. Thus the 176 remaining patients who formed the cohort in the present study had a mean of six (range 2-15) urine collections performed during follow up. These 176 patients had similar clinical baseline characteristics to those 15 patients who were lost to follow up: sex ratio (men:women) 1.3 v 2.0, median (range) age 55 (20-65) v 54 (34-64) years, known duration of diabetes 6 (1-34) v 5 (1-39) years, and geometric mean (range) urinary albumin excretion rate 8 (1-29) v 10 (3-29) mg/24 hours.

View larger version (20K): [in this window] [in a new window]   Fig 1 Flow chart of progress of all non-insulin dependent diabetic patients below 66 years of age attending Hvidöre Hospital in 1987

Non-insulin dependence was defined as follows: treatment by diet alone or diet combined with oral hypoglycaemic agents; insulin treatment and onset of diabetes after the age of 40 years and a body mass index above normal (25 kg/m² in women, 27 kg/m² in men) at the time of diagnosis; or insulin treatment, normal weight, and a glucagon stimulated C peptide value 0.60 pmol/ml.¹⁹ A glucagon test was performed whenever the body mass index was<25 kg/m² in women and<27 kg/m² in men at the time of diagnosis.²⁰

Arterial blood pressure was measured twice in the right arm after 10 minutes' rest while the patient was in the supine position by using a Hawksley random zero sphygmomanometer (Hawksley, Sussex), recording phase I (systolic) and phase V (diastolic). All blood pressure readings were performed by one observer (MG). Arterial hypertension was defined according to the World Health Organisation criteria: systolic blood pressure 160 mm Hg or diastolic blood pressure 95 mm Hg, or both, or if antihypertensive treatment was being prescribed.

A 12 lead resting electrocardiogram was coded by using the Minnesota codes,²¹ and coronary heart disease was defined as probable myocardial infarction (code 1.1-1.2) or possible myocardial ischaemia (code 1.3, 4.1-4.4, 5.1-5.3, or 7.1). Retinopathy was assessed by direct ophthalmoscopy after pupillary dilatation by one senior registrar trained in diabetes. On the basis of the description the degree of retinopathy was classified into: none, background, or proliferative. Body mass index (kg/m²) was calculated. Present medication and history of smoking were recorded. Current smokers were defined as subjects smoking one or more cigarette, cigar, or pipe a day. Former smokers were defined as subjects who reported having stopped smoking before the baseline examination. Non-smokers were patients who described themselves as never having smoked. A positive history of smoking included current and former smokers.

Approval for the study was obtained from the ethics committee of Copenhagen county.

Laboratory measurements
Urine collection was carried out during unrestricted daily activity. If bacterial growth was found, urine collection was repeated after treatment. The urinary albumin concentration was determined by radioimmunoassay.²² Persistent microalbuminuria was defined as a urinary albumin excretion rate of 30-299 mg/24 hours in two out of three consecutive 24 hour collections and persistent macroalbuminuria as a urinary albumin excretion rate of 300 mg/24 hours in two out of three consecutive collections.² The time of transition was defined as the time when the second among three measurements was above the limit.

Haemoglobin A1c concentration (normal range 4.1-6.1%)²³ and serum concentrations of creatinine,²⁴ total cholesterol,²⁵ and high density lipoprotein cholesterol²⁶ were measured in peripheral blood.

Statistical analysis
Values are given as means (SD), medians (ranges), or percentages (95% confidence intervals). We used the unpaired t test to compare cross classified continuous variables and the ² test to evaluate proportions when we compared baseline data in the group of patients who developed incipient or overt diabetic nephropathy with the group of patients who remained normoalbuminuric. The urinary albumin excretion rate was logarithmically transformed before statistical analysis and is presented as geometric mean and range because of its positively skewed frequency distribution. All tests were two sided.

Cox's proportional hazards multiple regression analyses^{26 27} were used to examine the baseline variables predictive of progression to incipient or overt diabetic nephropathy. Results are described as relative risk (hazard ratio). The models used included those baseline variables that were found to be significantly different when we compared the two groups or that were a priori considered to be potentially important predictors of increased urinary albumin excretion rate–that is, sex, age, known duration of diabetes, body mass index, retinopathy, arterial blood pressure, hypertension, log urinary albumin excretion rate, haemoglobin A1c, serum cholesterol concentration, pre-existing coronary heart disease, and smoking–and stepwise backward selection was used. Baseline urinary albumin excretion rate was logarithmically transformed because of the skewed distribution. Relative risk thus corresponds to a 10-fold increase in urinary albumin excretion rate. Confidence intervals were based on the normal approximation on the logarithmic scale. A P value of less than 0.05 was regarded as significant.

	Results

Top Abstract Introduction Patients and methods Results Discussion References

We followed up 176 normoalbuminuric patients with non-insulin dependent diabetes for a median (range) of 5.8 (1.5-6.0) years. Thirty six (26 men) patients (20%; 95% confidence interval 15% to 27%) developed incipient diabetic nephropathy, five (three men) patients (3%; 1% to 7%) developed overt diabetic nephropathy, and 135 patients remained normoalbuminuric (fig 1). The five year cumulative incidence of incipient diabetic nephropathy was 23% (17% to 30%) (fig 2).

View larger version (11K): [in this window] [in a new window]   Fig 2 Cumulative incidence of incipient diabetic nephropathy according to duration of follow up in 176 non-insulin dependent diabetic patients with normoalbuminuria at baseline

Sixteen patients had died: eight who remained normoalbuminuric, one who had progressed to incipient nephropathy, two who had progressed to overt nephropathy, and five who were lost to follow up (fig 1). Cardiovascular disease was the prevailing cause of death in nine patients while the seven others died from infection (such as pneumonia) or unknown causes. Renal disease was not recorded as either an underlying or contributory cause of death in any of the patients.

Table 1) shows clinical characteristics of the patients who developed raised urinary albumin excretion and those who remained normoalbuminuric. Patients who progressed to incipient or overt diabetic nephropathy were older men with poor long term glycaemic control and increased systolic blood pressure who suffered from diabetic retinopathy. Seventy six percent of patients (31/41) who progressed had retinopathy at the time of transition to microalbuminuria. The five patients who developed persistent macroalbuminuria all suffered from diabetic retinopathy at the time of transition to macroalbuminuria. The baseline urinary albumin excretion rate was significantly higher among those who progressed compared with those who remained normoalbuminuric (14 v 7 mg/24 h). The rate of urinary albumin excretion and concentration of haemoglobin A1c were also significantly higher in the group who progressed when we adjusted for the difference in age found between the two groups. The systolic blood pressure was not significantly different between the groups when we adjusted for age. It is well known, however, that the systolic blood pressure increases with age. Forty one per cent of the patients who progressed received antihypertensive treatment, mostly a diuretic or a ß blocker alone or in combination, compared with 25% of the patients who remained normoalbuminuric (P=0.07). Serum total cholesterol concentration tended to be higher (P=0.06) in the patients who later developed incipient or overt nephropathy. A higher prevalence of pre-existing coronary heart disease was also observed among those patients who developed incipient or overt nephropathy. Patients who progressed were comparable with respect to antidiabetic treatment, known duration of diabetes, body mass index, serum concentration of creatinine, diastolic blood pressure, prevalence of hypertension, concentration of high density lipoprotein cholesterol, and history of smoking compared with patients who remained normoalbuminuric.

The possible risk factors for development of abnormally increased urinary albumin excretion rate (>30 mg/24 h) were examined in backward stepwise Cox's multiple regression analysis. Log10 urinary albumin excretion rate, male sex, presence of retinopathy, serum cholesterol concentration, haemoglobin A1c concentration, and age were significantly associated with development of abnormally increased urinary albumin excretion (table 2). A 10-fold increase in urinary albumin excretion rate was associated with a relative risk of 11.1 (95% confidence interval 3.4 to 35.9). A similar analysis was performed without the baseline urinary albumin excretion rate in the stepwise procedure. Again male sex, presence of retinopathy, serum cholesterol concentration, haemoglobin A1c concentration, and age appeared as the only significant determinants of abnormally increased urinary albumin excretion rate. The effect of baseline urinary albumin excretion rate was also analysed separately in Cox's multiple regression analysis without stepwise selection and including only the recognised risk factors–that is, sex, arterial blood pressure, haemoglobin A1c, known duration of diabetes, and urinary albumin excretion rate. A 10-fold increase in baseline urinary albumin excretion rate was associated with a relative risk of 11.3 (3.3 to 38.2; P<0.0005). Figure 3) indicates the relative importance of sex on the cumulative incidence of incipient diabetic nephropathy. The relative importance of systolic blood pressure and haemoglobin A1c concentration on the cumulative incidence of incipient diabetic nephropathy were calculated according to the median of the systolic blood pressure (143.5 mm Hg) (fig 4) and haemoglobin A1c (7.55%) (fig 5).

View larger version (15K): [in this window] [in a new window]   Fig 3 Cumulative incidence of incipient diabetic nephropathy with respect to sex and according to duration of follow up in 176 non-insulin dependent diabetic patients with normoalbuminuria at baseline (P<0.05)

View larger version (14K): [in this window] [in a new window]   Fig 4 Cumulative incidence of incipient diabetic nephropathy with respect to median systolic blood pressure and according to duration of follow up in 176 non-insulin dependent diabetic patients with normoalbuminuria at baseline (P=0.06)

View larger version (14K): [in this window] [in a new window]   Fig 5 Cumulative incidence of incipient diabetic nephropathy with respect to median haemoglobin A1c concentration and according to duration of follow up in 176 non-insulin dependent diabetic patients with normoalbuminuria at baseline (P=0.10)

Fourteen patients started antihypertensive treatment during the course of the study. Five patients were treated with angiotensin converting enzyme inhibitors, the remaining nine patients with alternative treatment. In eight of the patients we could compare the rate of change in urinary albumin excretion rate before and after the start of antihypertensive treatment; the urinary albumin excretion rate showed an average increase of 67% a year before and an average decrease of 7.7% a year after the start of antihypertensive treatment in these patients.

	Discussion

Top Abstract Introduction Patients and methods Results Discussion References

Our prospective study of a cohort of normoalbuminuric white patients with non-insulin dependent diabetes revealed that 36 out of 176 developed incipient diabetic nephropathy (persistent microalbuminuria) and five overt diabetic nephropathy (persistent macroalbuminuria) during a median follow up period of 5.8 years. The five year cumulative incidence of incipient diabetic nephropathy was 23%. The major determinants of progression to incipient or overt diabetic nephropathy were identified as minimal increase of urinary albumin excretion within the normal range, poor long term glycaemic control, increased concentrations of serum cholesterol, presence of retinopathy, male sex, and older age.

We have confirmed and extended previous findings regarding the cumulative incidence of microalbuminuria in white¹⁸ and Asian²⁸ non-insulin dependent patients. Normoalbuminuric Pima Indians with non-insulin dependent diabetes, however, are at an even higher risk of developing abnormally increased urinary albumin excretion (albumin:creatinine ratio 30 mg/g) as the incidence of microalbuminuria was found to be 37% during a median follow up period of 4.7 years.²⁹

Given the fluctuating nature of urinary albumin excretion, the use of only a single urine collection at baseline for the classification of patients as being normoalbuminuric, microalbuminuric, or macroalbuminuric may have introduced misclassification of the patients. Only eight (6%) among the 137 patients who were excluded from the study because of the presence of microalbuminuria or macroalbuminuria at baseline, however, had reverted to persistent normoalbuminuria on basis of multiple testing during follow up.

The range of urine collections during follow up varied from two to 15. The low number of urine collections observed in some patients was mainly because of patients leaving the study early (death or moving away). The mean (SD) total number of urine collections in the 24 patients followed for under five years was 3.0 (2.4) compared with an average of 6.3 (2.0) collections in the 152 patients followed for more than five years.

A high rate of urinary albumin excretion within the normal range was found to be the most important risk factor for later development of incipient and overt nephropathy; this agrees with previous findings in non-insulin dependent^{18 28} and insulin dependent diabetic patients.^{7 8 9} This may suggest that even very low rates of urinary albumin excretion reflect the pathological process leading to diabetic nephropathy.

We found male sex to be significantly related to abnormally increased albumin excretion rates during follow up, in contrast with results from earlier studies of patients of different ethnic origin with non-insulin dependent diabetes.^{18 28 29} Furthermore, the present result supports the suggestion of a more rapid progression to nephropathy in white men than in white women on the basis of our earlier observations of male predominance among macroalbuminuric patients with non-insulin dependent diabetes.^{30 31}

Impact of metabolic control
Long term glycaemic control has been shown to be important with regard to the development of microvascular complications in both types of diabetes. We found that poor long term glycaemic control, indicated by the concentration of glycated haemoglobin, was an important predictor of the development of abnormally increased urinary albumin excretion, confirming data from the prospective studies in non-insulin dependent^{18 29} and insulin dependent diabetic subjects.^{8 9} In the study by John et al glycaemic control did not appear as a risk factor, but only the fasting blood glucose concentration was measured.²⁸ Several but not all studies in insulin dependent diabetic patients have shown beneficial effects of long term strict glycaemic control on the start and progression of microalbuminuria.^{12 13 14 32} These findings have recently been confirmed in a selected group of insulin treated Japanese patients with non-insulin dependent diabetes.³³

Many of the changes in plasma lipoproteins associated with renal disease are believed to be caused by renal dysfunction; hyperlipidaemia, however, may be associated with development of glomerular injury.³⁴ Ravid et al found that the concentration of cholesterol, both initially and during a five year follow up period, was positively related with the subsequent increase in urinary albumin excretion in microalbuminuric patients with non-insulin dependent diabetes.³⁵ In the present study the concentration of serum cholesterol was associated with an increased risk of developing incipient or overt nephropathy. Furthermore, serum cholesterol concentration was found to be related to the development of abnormally increased urinary albumin excretion rates in Pima Indians who had had diabetes for more than 10 years.²⁹

Schmitz and coworkers showed systolic blood pressure to be an independent risk factor for the relative rate of increase of the urinary albumin concentration "slope."¹⁸ A higher mean arterial blood pressure was also a risk factor for development of an abnormally increased rate of urinary albumin excretion in the Pima Indians.²⁹ The same group has also reported that high blood pressure before the development of diabetes predicts microalbuminuria after the onset of non-insulin-dependent diabetes in Pima Indians.³⁶ Systolic blood pressure was significantly higher in those who progressed to incipient and overt diabetic nephropathy in our study. It did not, however, appear as an independent predictor of progression in the multiple Cox's regression analysis. Many patients received treatment for hypertension, potentially obscuring any role of blood pressure in the development of diabetic kidney disease. A small number of patients (five) progressed to diabetic nephropathy in the present study. We have previously demonstrated the impact of systolic blood pressure on progression of diabetic nephropathy in non-insulin dependent diabetic patients.³⁷ The influence of arterial blood pressure on the development of microalbuminuria in insulin dependent diabetic patients has also yielded conflicting results.^{7 8 9}

Diabetic retinopathy supporting the diagnosis of diabetic nephropathy
The presence of diabetic retinopathy strongly suggests that diabetic nephropathy is the cause of persistent macroalbuminuria in non-insulin dependent diabetic patients.³⁸ In the present study patients who developed abnormally high urinary albumin excretion were significantly more likely to have retinal lesions at baseline than those who remained normoalbuminuric. Furthermore, 76% of the patients who progressed had diabetic retinopathy at the time of transition to microalbuminuria, and the five patients who developed persistent macroalbuminuria all suffered from diabetic retinopathy at the time of transition to macroalbuminuria, supporting the diagnosis of diabetic nephropathy. A close relation between the presence of diabetic retinopathy and risk of developing an abnormally high urinary albumin excretion rate has also been reported by other workers.^{7 29}

Conclusion
We have found that several potentially modifiable risk factors, such as urinary albumin excretion rate, long term poor glycaemic control, and hypercholesterolaemia predict the development of incipient and overt diabetic nephropathy in normoalbuminuric patients with non-insulin dependent diabetes.

	Acknowledgements

We thank Mrs A Fentz, Mrs S Damm, Mrs E Lassen, and the staff at Steno Diabetes Center for their assistance; Mrs A Josephsen and the late Mrs V Rosenkrantz, National Board of Health, for their help with the death certificates; and Mrs M Appleyard, Mrs I Eefsen, and Mrs C Haugaard for coding the electrocardiograms.

Funding: No external funding.

Conflict of interest: None.

	References

Top Abstract Introduction Patients and methods Results Discussion References

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