SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES 18 develop microvascular complications even as late as 30–40 years after the onset of the disease. On the other hand, a small minority may have severe retinopathy after only 5–7 years. Clustering of nephropathy, for example, has been observed in some families and the history of essential hypertension in a first-degree relative is associated with an increased risk of nephropathy in the family member with type 1 diabetes. In WESDR there were no obvi- ous differences between people with type 1 and type 2 diabetes in the inci- dence of microvascular complications in relation to rising HbA1 C . In the UKPDS the risk of each of the microvascular and macrovascular complications of type 2 diabetes was strongly associated with hyperglycaemia, as measured by HbA1 C . There was no evidence of a threshold and there was a threefold increase over the range of <6% to > 10% (Fig. 2.6). Despite all these studies demonstrating a clear relationship between hyper- glycaemia, HbA1 C and the development of microvascular complications, the reasons remain obscure. Although glycosylated haemoglobin reflects ‘recent’ Fig. 2.6 Estimated hazard ratios for significant risk factors for coronary artery disease occurring in 335 out of 3,055 diabetic patients. BMJ 1998; 316: 823–828, with permission. 3 1 0.4 40 45 50 55 60 7065 2.5 3.0 3.5 4.0 4.5 5.0 1.00.9 1.1 Age (years) High density lipoprotein cholesterol (mmol/l) Low density lipoprotein cholesterol (mmol/l) 1.2 1.3 40 45 50 55 60 7065 2.5 3.0 3.5 4.0 4.5 5.0 1.00.9 1.1 Haemoglobulin A1 c (%) never smokers ex- smokers current smokers Systolic blood pressure (mmHg) 1.2 1.3 3 1 0.4 Estimated hazard ratios (95% Cl)Estimated hazard ratios (95% Cl) CHAPTER 2 • RISK FACTORS glycaemic control, there are inevitably differences between individuals regarding the rates of formation and breakdown of glycated haemoglobin and no clear answers about how these may relate to risk of microvascular compli- cations. A single HbA1 C must be interpreted with caution since recent studies have shown that in an individual with stable glycaemic control the 95% con- fidence limits for an HbA1 C of 7.0% are between 6.1 and 7.9%. The DCCT study data revealed that past glycaemia over 3–4 months contribute only 10% to the current HbA1 C and the most recent 30 days contribute 50%. Monozygotic twin studies have shown that 62% of the population variance in HbA1 C is genetically determined. Put simply, an HbA1 C of 8.0% in a person with diabetes whose pre-diabetic HbA1 C was 3.5% may represent a complete- ly different risk of developing microvascular complications than a similar patient with the same HbA1 C , whose prediabetic HbA1 C was 5.8%. HYPERTENSION, HYPERLIPIDAEMIA AND SMOKING Hypertension exacerbates the micro- and macrovascular complications of diabetes (Fig. 2.7) but it is important to differentiate between the hyperten- sion associated with the two main types of diabetes. People with type 1 dia- betes at diagnosis have similar blood pressures to those without diabetes and the development of hypertension increases with diabetes duration and is associated with the development of nephropathy. Microalbuminuria and proteinuria are manifestations of renal involvement. Untreated, the hyper- tension worsens, protein excretion rates increase and glomerular filtration rates fall. Clustering of nephropathy in families suggests that there may be a genetic predisposition to nephropathy and hypertension in some individuals with type 1 diabetes. Hypertension in people with type 2 diabetes, however, is much more com- mon, may precede the diagnosis, and is present in between 30 and 50% at diagnosis. It is a major component of the metabolic syndrome that consti- tutes type 2 diabetes and appears to reflect insulin resistance. The effects on the cardiovascular system are more profound than similar blood pressure lev- els in a person without diabetes. For example, in the MRFIT study, rising sys- tolic blood pressure was associated with increasing 10-year CHD mortality which was 3–5 times greater in those with diabetes. Epidemiological studies have demonstrated the continuous relationship between serum cholesterol and risk of atherosclerotic vascular disease, par- ticularly CHD. This was confirmed by the Framingham study and, in the MRFIT study when over 300,000 men aged 35–57 years were screened, the relationship between cholesterol and death from CHD was independent of smoking and hypertension and continuous across the age range. There was also a strong relationship between CHD and cholesterol level in people with diabetes. 19 SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES 20 The lipid abnormalities associated with diabetes are both qualitative and quantitative. There are no quantitative differences between patients with type 1 diabetes and those without diabetes, though abnormalities may appear with the development of nephropathy or if glycaemic control is poor. HDL levels are often in the normal range but sub-fractions of HDL show significant differences from the normal population. For example, HDL 2 levels have a strong negative correlation with CHD and in type 1 diabetes levels of this subfraction are low, in favour of HDL 3 , which does not have the same cardioprotective properties. In type 2 diabetes the spectrum of lipid abnormalities is broader and an essential element of the metabolic syndrome. HDL levels are low, and associ- ated with hypertriglyceridaemia. Total and LDL-cholesterol levels are similar to non-diabetic levels, but again qualitative differences exist. LDL particles are small and dense and thought to be more atherogenic. Nevertheless, LDL levels correlate with the presence of clinical macrovascular disease in both type 1 and type 2 diabetes. Hypertriglyceridaemia as a risk factor CHD Fig. 2.7 Incidence rates (95% confidence interval) of myocardial infarction and micro- vascular end points by category of updated mean systolic blood pressure, adjusted for age, sex and ethnic group expressed for white men aged 50–54 years at diagnosis and mean duration of diabetes 10 years. BMJ 2000; 321: 412–419, with permission. 50 40 30 Adjusted incidence per 1000 person years (%) Systolic BP 20 10 0 110 120 130 140 Myocardial infarction Microvascular end points 150 160 170 CHAPTER 2 • RISK FACTORS remains controversial, but accounts for some of the other lipid changes such as low HDL and the formation of small dense LDL. There are also correla- tions with plasminogen activator inhibitor I (PAI-I). Smoking is an independent risk factor for macrovascular disease and in the MRFIT study increased the 10-year risk of dying from CHD by 2.4 times in non-diabetics (from 10.1 to 23.9 per 1,000) and by 1.6 times in those with dia- betes (from 44.5 to 68.7 per 1,000). Smoking has also been implicated in the progression of microvascular and other diabetic complications including retinopathy, nephropathy and necrobiosis lipoidica. Analysis of the MRFIT data suggested that stopping smoking was one of the most effective interven- tions at reducing mortality from macrovascular disease. ETHNICITY There appear to be definite ethnic variations in the prevalence of complica- tions of type 2 diabetes. Compared to the WESDR population of non- Hispanic whites, retinopathy is much more common in the Pima Indians of Arizona and the Mexican-Americans in San Antonio, Texas. Nephropathy and CHD is more common in indigenous peoples such as the Maori in New Zealand (Fig. 2.8) and South Asians, occurring a decade or so earlier, than Europeans. On the other hand, CHD is less frequent in the Pima Indians with type 2 diabetes than many non-diabetic white populations in the US. 21 Fig. 2.8 Risk of recorded death with nephropathy by Cox’s proportional hazards regression model after accounting for age, sex, and source of patient. Shown are Europeans with type 2 diabetes ( ■ ): Maori with type 2 diabetes ( ◆ ): and Pacific Islands people with type 2 diabetes ( ▲ ). Rate of death from nephropathy 0.00 102345 Time (years) 67 0.02 0.04 0.06 0.08 SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES 22 CONCLUSION Risk factors for the micro- and macrovascular complications of diabetes are similar in both type 1 and type 2 diabetes but significant differences exist in the prevalence and role of hypertension and hyperlipidaemia. Duration of dia- betes is significantly correlated with complications in type 1 diabetes. An essen- tial part of diabetes care is an annual structured risk assessment so that indi- vidual management plans can be developed to target these increased risks. FURTHER READING Kannel WB, McGee DL. Diabetes and glucose tolerance as risk factors for cardiovascular dis- ease: The Framingham Study. Diabetes Care 1979; 2: 120–6. Stamler J, Vaccaro O, Neaton JD, Wentworth D. for the Multiple Risk Factor Intervention Trial Research Group. Diabetes, other risk factors and 12 year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993; 16: 434–44. Yudkin JS. How can we best prolong life? Benefits of coronary risk factor reduction in non- diabetic and diabetic subjects. BMJ 1993; 306: 1313–18. CHAPTER 3 DIABETIC NEPHROPATHY Adrian R. Scott MD, FRCP 23 INTRODUCTION Diabetes is now the commonest cause of end-stage renal failure (ESRF) in Europe and North America. This is mainly because of the increasing preva- lence of diabetes and because people with diabetes are now accepted more readily onto renal replacement programs, having been excluded in the past. In Scandinavia and the USA, 30% of people requiring dialysis or transplantation have diabetes though there are significant variations across Europe. Between 20–30% of people with type 1 or type 2 diabetes will develop nephropathy but only a small percentage of people with type 2 dia- betes will progress to ESRF, most dying of cardiovascular disease long before the need for renal dialysis. Nevertheless, the much higher preva- lence of type 2 diabetes means that up to 50% of patients with diabetes requiring dialysis are from this group. There are considerable ethnic variations in the prevalence of nephropathy. For example, in the UK Anglo-Asians and Afro-Caribbeans have a much higher prevalence of nephropathy. In the USA Pima Indians with type 2 dia- betes are particularly at risk, as are Maori in New Zealand. CLINICAL PRESENTATION The earliest clinical manifestation of diabetic renal disease is the finding of small quantities of albuminuria (30–300mg/24 h or 20–200 μg/min), often within 5–10 years of diagnosis, which increases progressively over a number of years. In cross-sectional studies, microalbuminuria is present in approximately 20–30% of insulin-treated adults and 10–30% of Caucasian adults with type 2 diabetes, and there is a clear relationship with glycaemic control (Fig. 3.1). The progression of nephropathy is best documented in type 1 diabetes (Fig. 3.2). A history of hypertension in a first-degree relative and differences in Na + –Li + counter-transport suggest there is a component related to genet- ic predisposition. Poor glycaemic control may initiate functional changes within a year or two of the diagnosis of diabetes, including renal hypertro- phy and hyperfiltration with an increase in renal blood flow and glomerular filtration rate (GFR). These changes are reversible and metabolically dependent. Recent studies suggest that even levels of albumin excretion rate above 10μg/min are highly predictive of future microalbuminuria. Blood pressure rises progressively in parallel with increasing albuminuria and sec- ondary lipid abnormalities also occur. The glomerular barrier loses its size selectivity and as macroproteinuria is reached GFR has already started to decline. Occasionally, nephrotic syndrome may result. Vascular Complications of Diabetes: Current Issues in Pathogenesis and Treatment, Second Edition Edited by Richard Donnelly, Edward Horton Copyright © 2005 by Blackwell Publishing Ltd The rate of decline of renal function is linear but the time to ESRF varies considerably between individuals (Fig. 3.3). Albuminuria is a manifestation of a generalized vasculopathy and a high proportion of patients with nephro- pathy develop symptomatic coronary heart disease (CHD) in the early course of their renal disease. The associated anaemia and hypertension lead to left ventricular hypertrophy (LVH) and heart failure. Death from stroke, myocar- dial infarction or peripheral gangrene occurs in nearly 75% of patients, either before or during renal replacement therapy, and 50% of type 1 diabetics are dead within 10 years of the onset of proteinuria. KEY DIAGNOSTIC FEATURES Although the diagnosis of nephropathy is based on the finding of Albustix positive albuminuria (equivalent to a urinary albumin excretion rate of more than 300mg/day), it is important to remember that the renal disease is already well established at the stage of overt proteinuria with irreversible structural changes having occurred in the glomeruli. In type 1 diabetes, SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES 24 Fig. 3.1 Relation between mean hemoglobin A 1 : values and the risk of microalbuminuria in patients with IDDM. N Engl J Med 1995; 332: 1251–1255. 12 10 8 Odds ration 6 4 2 0 7 8 9 10 12 Hemoglobin A 1 (%) 14 16 18 20 CHAPTER 3 • DIABETIC NEPHROPATHY patients over 12 years of age should be screened annually for microalbu- minuria using the albumin/creatinine ratio (ACR) on the first morning urine sample (Fig. 3.4). Type 2 patients should be routinely screened for albuminuria and, if Albustix negative, annual screening undertaken for microalbuminuria, particularly if a positive result would alter or intensify their management. Classically, the finding of Albustix positive proteinuria on more than two occasions in a person with established diabetes (having first ruled out uri- nary tract infection) is indicative of diabetic nephropathy. Hypertension is 25 Fig. 3.2 Natural history of diabetic nephropathy: Oxford Textbook of Medicine 3 rd edn. Oxford University Press, 1996. Normal <20 μg/min Stable 1% decline pa >40 years Stable: higher in those progressing to incipient nephropathy Large kidneys Tubular hypertrophy/ hyperplasia Glomerular enlargement Normal ultrastructure GBM thickening 20 nm pa Incipient nephropathy >20 <200 μg/min (increase 20% pa) Age related changes; more rapid loss when UAER approaches 200 μg /min or if blood pressure increases Initially stable, but higher than normal UAER controls Increases with increasing UAER Kidneys remain large GBM thickening 54 nm pa Mesangial expansion ~ 4% pa Clinical nephropathy <200 μg/min Decline 10 ml/min/y (hypertensive), 1–4 ml/min/y (normotensive) Most patients hypertensive (>140/85 mmHg) Increases with declining GFR Kidneys shrink GBM 2–3 times normal, stable Nodules Global glomerulosclerosis Mesangial expansion ~ 7% pa UAER GFR Blood pressure Pathology 1%–2% per annum 3%–4% per annum pa = per anum; GBM = glomerular basement membrane SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES 26 commonly associated (Fig. 3.5) and the absence of retinopathy should prompt consideration of an alternative diagnosis in a patient with type 1 dia- betes. However, in type 2 diabetic patients only about 50% of those with nephropathy have associated retinopathy. Renal ultrasound can be helpful in excluding unrelated structural abnor- malities such as hydronephrosis or polycystic kidneys, but asymetrical kid- neys may be indicative of renal artery stenosis (RAS), especially in patients with peripheral vascular or aortic aneurysm disease. If renal artery dopplers are suggestive of RAS, arteriography or CT-angiography is justified but the contrast media used for these investigations can precipitate renal failure. Adequate hydration with intravenous saline is important, but early sugges- tions that oral treatment with acetylcysteine reduced the incidence of con- trast-induced renal complications has not been confirmed by subsequent studies. Metformin should be stopped two days before the investigation because of the small risk of lactic acidosis. Haematuria is an unusual feature in diabetic nephropathy and these patients may have co-existent renal disease unrelated to their diabetes. Renal biopsy is rarely necessary but should be considered in these patients, since it may occasionally reveal potentially treatable glomerular disease, e.g. IgA nephropathy. The morphological changes seen in the diabetic kidney, e.g. dif- fuse and nodular glomerulosclerosis and arteriolohyalinosis (Kimmelstiel- Wilson kidney), which may be present in over 90% of kidneys after 10 years of Fig. 3.3 Decline of renal function in 16 patients with nephropathy. ABC of Diabetes 1982; 285: 627–629. 5 4 3 2 1 0 01020 Months 30 40 1 Creatinine x 10 3 CHAPTER 3 • DIABETIC NEPHROPATHY 27 Fig. 3.4 Screening strategy and monitoring programme for microalbuminuria in type 1 diabetes. St Vincent Joint Force for Diabetes Report of the Renal Disease Subgroup, 1994, 2 nd edn. First morning urine sample Normal No timed urine Retest in 1 year Retest to confirm if still abnormal Timed urine sample* AER > 20 μg/min (30 mg/24 h) Two other timed urine samples within 6–12 weeks AER ≥ 20 μg/min (30 mg/24 h) in at least one sample - Monitor as often as required -Monitor HbA1 c , blood pressure, lipids, creatinine -Test for retinopathy, CHD, CVD, PVD, neuropathy -Commence ACE-inhibitor AER = albumin excretion rate CHD = coronary heart disease CVD = cerebral vascular disease HBA1 c = glycated haemoglobin PVD = peripheral vascular disease * If timed urine sample difficult to obtain, monitoring should continue with the use of albumin/creatinine (A/C) ratio. No prospective study has however so far evaluated the validity of A/C ratio as a monitoring index AER < 20 μg/min Albumin concentration <20 mg/l and or Albumin: creatinine < 2.5 mg/mmol in men < 3.5 mg/mmol in women Albumin concentration ≥20 mg/l and or Albumin: creatinine ≥2.5 mg/mmol in men ≥ 3.5 mg/mmol in women [...]... the increased risk of CHD is present from diagnosis and one cohort study found a history of MI in 16.5% of males and 9.7% of females at the time of diagnosis of diabetes During a 10-year follow-up the age-adjusted incidence of first MI was 1.5-fold higher in diabetic men and up to 8.1-fold higher in diabetic women compared to age-matched non-diabetics In the Framingham study, 3,000 non-diabetic women... treatment for patients with diabetes mellitus: meta-analysis of controlled double-blind randomised trials Diabetic Medicine 20 04; 21 : 18 25 Viberti GC, Jarrett RJ, Mahmud U, Hill RD, Argyropoulos A, Keen H Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus Lancet 19 82; i: 1430–14 32 Vascular Complications of Diabetes: Current Issues in Pathogenesis and Treatment,...SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES 60 Cumulative incidence (%) 28 Hypertension Proteinuria 50 40 30 20 10 0 15 20 25 30 35 40 Age (years) 45 50 55 Fig 3.5 Cumulative incidence of hypertension and persistent proteinuria in type 1 diabetes: Handbook of Diabetes, 2nd edn From Williams G & Pickup JC, Blackwell Science, 1999 type 1 diabetes, are not synonymous with... mortality, rates of Albuminuria (mg/min) Glomerular filtration rate (ml/min/1.73m2) Mean arterial blood pressure (mmHg) Start of antihypertensive treatment 125 115 105 95 ΔGFR = 0.94 (ml/min/mo) 105 95 ΔGFR = 0 .29 (ml/min/mo) 85 75 ΔGFR = 0.10 (ml/min/mo) 65 55 125 0 750 25 0 -2 6 -1 0 1 2 Years 3 4 5 Fig 3.6 Effect of blood pressure control on progression of renal disease in 11 patients with type 1 diabetes. .. patients with type 1 diabetes Parving H-H et al BMJ 1987; 29 4: 1443–1447 6 29 SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES 40 Less tight control (n = 390→161) Tight control (n = 758→ 325 ) Patients with events (%) 30 30 20 10 32% reduction in risk for diabetes related mortality P = 0.019 0 0 1 2 3 4 5 6 Years from randomization 7 8 9 Fig 3.7 UK Prospective Diabetes Study Group (UKPDS): blood... is some evidence of a cardiomyopathy associated with diabetes which could predispose to a worse outcome post-MI A raised admission blood glucose in patients with acute coronary syndrome is predictive of both in-patient and long-term mortality A meta-analysis of 15 previous studies 37 SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES 50 Cumulative mortality (%) 38 40 30 20 10 Women with... cerebrovascular events The fascination of doctors with unusual patterns of small vessel disease has meant that for many decades the true impact of vascular disease in people with diabetes has received less attention than it deserves Both types of diabetes are associated with a many-fold increase in the risk of macrovascular disease, particularly coronary heart disease (CHD), stroke (CVA) and peripheral vascular. .. without MI Non-DM with MI DM with MI 40 0 1 2 3 4 Years 5 6 7 8 Fig 4.4 Probability of death in 1,059 subjects with type 2 diabetes and 1,378 non-diabetic subjects with and without prior MI Haffner S et al N Engl J Med 1998; 339: 22 9–34 39 40 SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES regimen for at least three months and this was associated with a 29 % reduction in mortality The group... duration of diabetes and the presence of nephropathy Many older studies failed to distinguish between the two major types of diabetes but the recent British Diabetic Association (BDA) cohort study followed insulin-treated patients diagnosed before the age of 30 years, and found an excess of deaths at all ages Vascular disease was implicated from the third decade onwards (Fig 4.1) With type 2 diabetes. .. 120 0 1000 800 600 400 20 0 0 0 20 40 60 80 GFR (51Cr EDTA) 100 120 Fig 3.8 Relationship between glomerular filtration rate (GFR) measured using chromium-51 edetic acid (51Cr EDTA GFR) and serum creatinine, in patients being investigated for renal disease Values are means and ranges (unpublished data from Roberts B, Gabriel R, 1975 BMJ 1986; 29 3: 1119–1 120 ) 31 32 SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS . MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES 22 CONCLUSION Risk factors for the micro- and macrovascular complications of diabetes are similar in both type 1 and type 2 diabetes but significant. 1986; 29 3: 1119–1 120 ). Serum creatinine (μmol/l) 400 600 800 1000 120 0 1400 1600 20 0 0 020 4060 GFR ( 51 Cr EDTA) 80 100 120 SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES 32 After. (Kimmelstiel- Wilson kidney), which may be present in over 90% of kidneys after 10 years of Fig. 3.3 Decline of renal function in 16 patients with nephropathy. ABC of Diabetes 19 82; 28 5: 627 – 629 . 5 4 3 2 1 0 01 020 Months 30