Diabetic nephropathy: a serious complication of diabetes mellitus

K K L Ho 何繼良

HK Pract 2001;23:548-553

Summary

Diabetic nephropathy is a serious complication of diabetes mellitus. It accounts for the most common cause of renal failure in patients on renal replacement therapy. The long-term prognosis of diabetic patients with renal failure on dialysis is poor. Family physicians have more opportunities than specialists to screen for the development of diabetic nephropathy by testing urine microalbumin. Early initiation of treatment with tight control of glycaemia and high systemic blood pressure are most important. Development of complications in other systems in diabetes are common. Morbidity and mortality in diabetic patients with nephropathy due to cardiovascular diseases are common.

摘要

腎病是糖尿病的嚴重併發症，也是因腎衰竭而接 受透析治療的最常見原因，長期預後較差。家庭醫生較專科醫生有更多機會利用微蛋白尿的檢查來篩選可 能發生糖尿病腎病的病人。盡早嚴格控制血糖及高血壓對病情至為重要。糖尿病也常引起腎病以外的合併 症，糖尿病罹患心血管病也頗為普遍。

Introduction

Proteinuria due to diabetic nephropathy has been demonstrated in diabetic patients since the 18th century.¹ Bright, in 1836, postulated that the presence of albuminuria could reflect a serious renal complication in diabetic patients.² Kimmelstiel and Wilson, a hundred years later, described the presence of nodular glomerular intercapillary lesions in diabetic patients suffering from the clinical syndrome of heavy proteinuria, renal impairment and hypertension.³ Nowadays, diabetic nephropathy, mostly due to non-insulin dependent diabetes mellitus (NIDDM), is the most common single cause of end-stage renal failure (ESRF) in the Western world. It is the cause of renal failure in 40% to 45% of those entering renal replacement therapy programs.⁴

Diabetic nephropathy can be diagnosed clinically in both insulin dependent diabetes mellitus (IDDM) and NIDDM when the following criteria exists: persistent albuminuria >300mg/24h, presence of diabetic retinopathy, and no clinical or laboratory evidence of kidney or urinary tract disease other than diabetic nephrosclerosis.^5-7 The presence of microalbuminuria strongly predicts the development of diabetic nephropathy in both IDDM^8,9 and NIDDM.^10,11 The definition of microalbuminuria is urinary albumin excretion greater than 30mg/24h (20mg/min) and less than or equal to 300mg/24h (200mg/min).¹² However, the usual urine dipsticks available at our clinics are unable to detect albuminuria below 300mg/24h. Therefore, the presence of microalbuminuria can be missed by the usual dipstick urinalysis. A 24-hour urine collection for laboratory analysis is the standard method for quantification of microalbuminuria.

Diabetic patients are not protected from other kidney diseases. The presence of other renal diseases in diabetic patients with diabetic nephropathy is not uncommon. It should be thought of especially in those with an atypical clinical course e.g. the rapid development of proteinuria and/or the presence of haematuria.^13,14 Thus the presence of proteinuria may not reflect the presence of advanced diabetic nephropathy but may be due to the co-existence of other types of nephropathy in the diabetic patient. Renal biopsy may be necessary to clarify the histological diagnosis of kidney pathology in diabetic patients with atypical clinical course of the disease.

Clinical presentation and course

Elevated glomerular filtration rate (GFR) or hyperfiltration is a frequent finding in newly diagnosed diabetic patients and during the intervals of poor glycaemic control proceeding the subsequent development of albuminuria.¹⁵ Diabetic patients develop nephropathy through different stages in sequence from normoalbuminuria to microalbuminuria and finally proteinuria. Albuminuria is the first clinical sign to be detected. Fluid retention with peripheral oedema is the first symptom which usually occurs early in the course of the disease. Plasma albumin may be slightly reduced.¹⁶ Kidney function in patients with diabetic nephropathy is usually well preserved in the early stage of the disease. However, the GFR usually shows a linear but highly variable rate of decline ranging from 2 to 20ml/min/year with a mean of 12ml/min/year.¹⁷ Renal papillary necrosis should be suspected in diabetic patients who develop recurrent episodes of urinary tract infection, renal colic, haematuria or acute renal failure due to obstructive uropathy.

Diabetic nephropathy is a clinical syndrome with persistent albuminuria (>300mg/24h), raised arterial blood pressure, and progressive decline in renal function.⁵ The time course for the development of these different stages of proteinuria varies between different patients. The development of diabetic nephropathy in patients with less than 10 years' duration of diabetes mellitus is uncommon. The incidence usually peaks between 10 to 20 years of diabetes then declines progressively afterward.¹⁸

Who is at risk of developing nephropathy and renal impairment

The diabetic subpopulation with microalbuminuria is at risk of developing diabetic nephropathy.^8-10 Other well recognised risk factors include male sex,⁵ familial clustering of diabetic nephropathy,¹⁹ systemic hypertension,²⁰ poor glycaemic control,^21,22 cigarette smoking,^23,24 onset of IDDM before 20 years of age,²⁵ and increased sodium-lithium countertransport.²⁶ Several of these factors are also implicated in the progression of nephropathy from microalbuminuria to overt proteinuria and to end-stage renal failure (ESRF): systemic hypertension, albuminuria, poor glycaemic control, hyperlipidaemia, and increased GFR.^27,28 The effects of dietary protein intake on renal function are not clearly demonstrated.²⁹

Extrarenal involvement

End stage renal failure is the major cause of morbidity and mortality in diabetic patients. However, the excessive mortality in diabetic patients with nephropathy comes from cardiovascular disease.^30-32 Diastolic dysfunction and cardiac hypertrophy are common findings in diabetic patients. The presence of left ventricular hypertrophy predisposes diabetic patients to ischaemic heart disease, heart failure, ventricular arrhythmia, and sudden death. Microalbuminuria not only predicts the development of nephropathy but also cardiovascular morbidity and all cause mortality in diabetes mellitus.³² Microalbuminuria is known to be associated with several cardiovascular risk factors: hypertension,³³ hyperlipidaemia,³⁴ increased platelet aggregability,³⁵ insulin resistance and hyperinsulinaemia,³⁶ and endothelial dysfunction.³⁷ However, the mechanism of the link between microalbuminuria and cardiovascular causes of death is unclear.

Other extrarenal involvement in patients with diabetic nephropathy are also common. Diabetic retinopathy is present in nearly all IDDM patients with nephropathy.³⁸ Only 50-60% of NIDDM patients with nephropathy have retinopathy.³⁹ The absence of retinopathy in proteinuric diabetic patients should be investigated for other glomerulonephropathies especially when haematuria is also present. Macroangiopathy leading to cerebral vascular accident, carotid artery stenosis, peripheral vascular disease, and coronary artery disease is common in nephropathic patients.³⁹ Peripheral neuropathy is also a common finding in patients with advanced nephropathy. Foot ulcers with superimposed infection and digital gangrene requiring amputation are not uncommon. Symptomatic autonomic neuropathy with abnormal cardiovascular reflexes, postural hypotension, impotence, diarrhoea, and delay and gastric emptying are frequent problems in these patients.⁴⁰

Treatment

The current available treatments for end stage renal failure include haemodialysis, peritoneal dialysis, and renal transplantation. The long-term survival with these treatment modalities is still disappointing for those with diabetic nephropathy in comparison to other causes of renal failure. Five-year survival in diabetic patients with renal failure on dialysis is only 25-40%.⁴¹ Previous study has shown screening and early intervention in diabetic patients with microalbuminuria are likely to have life-saving effects.⁴² Therefore, regular screening and early initiation of preventive measures for the development of diabetic nephropathy and associated complications are important and should be the future direction in the management of the disease.

Treatment and prevention strategies depend on the stage of the disease. Primary prevention includes educating diabetic patients and the medical community, addressing the importance of glycaemic control, blood pressure control, and stopping cigarette smoking. Secondary prevention includes angiotensin-converting enzyme inhibitors, cholesterol lowering agents, and perhaps restriction of dietary protein. Tertiary care including dialysis or transplantation is generally managed by nephrologists whereas family physicians continue to play an important role in the general care of these patients. Both specialists and family physicians are needed to focus efforts on the primary and secondary prevention strategies to reduce end-stage diabetic nephropathy and its complications.

Glycaemic Control

Over the last few years, the role of hyperglycaemia has emerged as critical in mediating progressive renal damage in diabetes. Patients with a lesser degree of glycaemic control are more likely to develop nephropathy and retinopathy⁴³ especially when the haemoglobin A_1c (HbA_1c) concentration is above 8.5%.^44,45 The prospective Diabetes Control and Complications Trial (DCCT) has shown that the chance of developing microalbuminuria can be lowered with better control of blood glucose.46 Better glycaemic control also reduces the progression of microalbuminuria to overt proteinuria, and the development of diabetic retinopathy and neuropathy. Good control of glycaemia is important in all stages of diabetes.

Blood pressure control and dietary protein restriction

Higher systemic blood pressure, particularly in the hypertensive range, has been shown to be associated with subsequent development of nephropathy.⁴⁴ Patients with hypertension and relatively poor glycaemic control are at even greater risk of overt nephropathy. The development of nephropathy can only be delayed, by controlling the glycaemia alone, without also lowering the systemic blood pressure.

Antihypertensive drugs of different classes lower protein excretion in patients with diabetic nephropathy by lowering systemic blood pressure.⁴⁷ Meta-analysis has documented ACE inhibitors have greater anti-proteinuric effect and reduction of the rate of decline in renal function than calcium channel blockers, beta-blockers, and diuretics.^48-50 ACE inhibition reduces the incidence of nephropathy both in hypertensive and normotensive diabetic patients.^51-53 The administration of an ACEI to normotensive NIDDM patients with microalbuminuria decreased both albumin excretion and progression to overt diabetic nephropathy compared to patients treated with placebo.⁵⁴

Protein restriction also seems to be able to lower protein excretion in diabetic patients with nephropathy and slow the rate of decline in renal function.^55,56 However, diabetics are at increased risk of protein malnutrition because the reduction in protein intake may be associated with enhanced protein breakdown induced by insulin deficiency.⁵⁷ The control of cholesterol levels in diabetes is important. Evidence suggests that hypercholesterolaemia in addition to hypertension is a risk factor for progressive renal failure.⁵⁸

Recommendations

Patients with diabetes mellitus should be screened yearly for the presence of microalbuminuria and complications of other systems. It seems reasonable to initiate therapy with an ACE inhibitor in diabetic patients with microalbuminuria even when normotensive. Calcium channel blockers can be used when ACE inhibitors cause side effects of hyperkalaemia or persistent dry cough. Data from previous studies suggest that combinations of non-dihydropyridine calcium channel blockers and ACE inhibitors have advantages over conventional antihypertensive agents with regard to having more favourable side effect profiles and improving renal and overall survival. Therefore, combination therapy with these agents may be valuable, especially in diabetic patients with renal impairment in whom the control of blood pressure is inadequate with ACE inhibitor alone.^59,60 The general aim is to reduce the diastolic pressure to between 80 to 85mmHg.^61,62 The control of hypercholesterolaemia is also important. However, the role of dietary protein restriction is uncertain because of the possibility of under nutrition with simultaneous restriction of fat and carbohydrate in diabetic patients.

Both primary care physicians and specialists have an important role in managing these patients at different stages of the disease. Primary care physicians have the most frequent contact and therefore have the greatest opportunity to screen the patients at risk. Initiation of treatment and education can be given at an early stage to achieve more favourable outcomes in the clinical course of these patients. Patients at greater risks of developing complications can be referred to specialists when their hyperglycaemia and systemic hypertension are difficult to control, or, when having increasing micro-albuminuria and advancing renal failure.

Conclusion

Diabetes is the most common cause of end-stage renal failure in many developed countries. Both the incidence of diabetes and its renal complications are increasing. Primary care physicians have the most frequent contact with these patients and therefore will have the greatest potential to make their clinical course more favourable. Early prevention and therapeutic interventions of diabetic nephropathy are the most effective measures.