Diabetes mellitus and the kidney

Diabetic nephropathy is kidney damage resulting from longstanding or poorly controlled diabetes mellitus. The disorder includes damage to capillaries (tiny blood vessels) in the kidneys and hardening of the tissues. As a result, the kidneys become less able to filter the blood efficiently. Protein may escape into the urine, depleting the body’s supplies (nephrotic syndrome). In severe cases, chronic kidney failure may develop. Many affected people have hypertension (high blood pressure), which may also cause damage to the blood vessels. People with diabetes should have regular check-ups so any kidney problems can be treated as soon as possible. Checks may include urine tests for protein, as well as kidney function tests.

Essentials

Diabetic nephropathy is the commonest cause of endstage renal disease in the developed world, causing 44% of incident cases requiring renal replacement therapy in the United States of America and 24% in the United Kingdom in 2008 Most of these have type 2 diabetes, and in some countries the proportion of patients with endstage renal disease who have type 1 diabetes is falling.

Aetiology and pathology—causation is related to glycaemic control (e.g. glycation of proteins, oxidative stress, sorbitol overproduction, alteration in growth factors), hypertension, genetic factors, and dietary and other environmental factors. Pathological hallmarks are thickening of the glomerular basement membrane and mesangial expansion, with or without nodule formation, secondary to an accumulation of extracellular matrix.

Staging and natural history—is classically described in terms of urinary albumin excretion rate (UAER): (1) normoalbuminuria—UAER less than 20 µg/min, albumin/creatinine ratio (ACR) less than 2.5 mg/mmol (men), less than 3.5 mg/mmol (women); (2) microalbuminuria (also called incipient nephropathy)—UAER 20 to 200 µg/min, ACR 2.5 to 30 mg/mmol (men), 3.5 to 30 mg/mmol (women); and (3) clinical proteinuria (sometimes called clinical nephropathy or overt nephropathy)—UAER greater than 200 µg/min, ACR greater than 30 mg/mmol. This staging does not map well onto that for chronic kidney disease based upon estimated glomerular filtration rate (eGFR) (see Chapters 21.4 and 21.6).

Clinical features—most patients (>60%) will have a normal UAER throughout their diabetic life, but 1 to 2% of the remainder develop persistent microalbuminuria each year. Once UAER exceeds 200 µg/min, there tends to be a relentless increase in proteinuria, occasionally into the nephrotic range, and GFR declines progressively at a rate that largely depends on blood pressure control.

Prevention—in both type 1 and type 2 diabetes, tight glycaemic control can prevent microalbuminuria.Whether intensive blood pressure control using angiotensin converting enzyme (ACE) inhibitors can prevent microalbuminuria is controversial. In both type 1 and type 2 diabetes, intensive blood pressure control using ACE inhibitors or angiotensin II receptor blockers (ARBs) slows progression from microalbuminuria to clinical proteinuria and slows the rate of decline in GFR (more so in type 1 than type 2).

Management—aims for: (1) good control of glycaemia (typical recommendations are for HbA1c level <7.5% (58 mmol/mol) (NICE) and <7.0% (53 mmol/mol) (American Diabetes Association) in type 1 and 6.5–7.5% (48 – 58 mmol/mol) in type 2); (2) good control of hypertension (<130/80 mmHg, with even lower targets recommended in those with heavy proteinuria) using an ACE inhibitor and/or an ARB; and (3) other interventions, including some or all of serum lipid lowering, low-dose aspirin, smoking cessation and reduction of dietary protein and salt.

Prognosis—mortality is higher for people with diabetes and increased albuminuria compared to those with normoalbuminuria. In type 2 diabetes, the annual mortality is almost 5% for patients with clinical proteinuria, and almost 20% for those with a serum creatinine greater than 175 µmol/litre or in endstage renal disease. Survival on dialysis remains worse for patients with diabetes compared to those without: 1 year survival was 83% in the UK in 2008 compared to 88% for the non-diabetic population. Cardiovascular disease is the commonest cause of death, and multifactorial cardiovascular risk-factor intervention has been shown to reduce mortality and morbidity in type 2 diabetes, and is mandatory for all patients with diabetic nephropathy.

Diabetes mellitus and the kidney - in detail - technical article

Introduction

Diabetic nephropathy is the commonest single cause of endstage renal disease requiring renal replacement therapy in the United Kingdom and the United States of America, and the second most common cause in mainland Europe and Japan. Around 40% of patients with type 1 and 20% of those with type 2 diabetes develop nephropathy (although these rates are time and duration of diabetes dependent) and consequently are at high risk of endstage renal disease. The incidence of diabetes worldwide is increasing, with an estimated prevalence of 380 million by 2025, hence the future personal and health economic burdens of diabetic endstage renal disease pose serious problems for health care providers.

Historical perspective

Proteinuria had been described in patients with diabetes in the 19th century, but its significance was only appreciated after the description of nodular glomerulosclerosis in the kidneys of diabetic patients by Kimmelstiel and Wilson in 1936. The specificity of these lesions for diabetes and the description of a more generalized accumulation of extracellular matrix material in the mesangium and glomerular basement membrane confirmed the pathological basis for proteinuria.

Lundbaek developed the concept of microangiopathy, linking the pathological features of retinal and glomerular lesions, and Root in 1953 coined the term triopathy to include retinopathy, nephropathy, and neuropathy. Microangiopathy is almost completely specific to diabetes and its presence has been used to define the blood glucose levels that diagnose diabetes. In the 1960s, the mean time from onset of proteinuria to endstage renal disease was 7 years; it is now closer to 20 years. However, diabetic patients with nephropathy continue to have a greatly increased mortality from cardiovascular disease. The multifactorial aetiopathogenesis of nephropathy offers opportunities for treatment but also poses major problems for prevention.

Aetiology

Hyperglycaemia

Observational studies have shown that sustained poor glycaemic control is associated with a greater risk for the development of nephropathy in both type 1 and type 2 diabetes. There are several potential mechanisms by which hyperglycaemia may cause nephropathy. These are common to all the microvascular complications of diabetes and are listed in Bullet list 1 (see also ‘Glycaemic control’ below).

Bullet list 1 Aetiopathological factors for nephropathy

  • Glycaemia related:
    • • Glycation of proteins—formation of advanced glycation end products
    • • Polyol pathway—sorbitol overproduction
    • • Protein kinase C β activation
    • • Altered glomerular haemodynamics
    • • Increased production of growth factors/cytokines such as TGFβ, CTGF, NF-κβ, VEGF, PDGF, IGF-1, angiotensin II, and prostanoids
  • Systemic hypertension
  • Genetic factors
  • Mechanical/structural factors
  • Fetal programming
  • Dietary factors, such as high protein intake and salt
  • Smoking, other environmental factors

CTGF, connective tissue growth factor; IGF-1, insulin-like growth factor-1; PDGF, platelet-derived growth factor; TGFβ, transforming growth factor β; VEGF, vascular endothelial growth factor.

Blood pressure

Systemic blood pressure is higher in patients with type 1 diabetes who subsequently develop microalbuminuria. One study has also found a stronger family history of hypertension in type 1 patients with diabetic nephropathy compared to those without.

In type 2 diabetes, a prediabetic mean arterial pressure higher than 97 mmHg (130/70 mmHg) strongly predicts the development of proteinuria in Japanese people and Pima Indians. Cohorts of normotensive (<140/90 mmHg) type 2 patients with microalbuminuria from Israel, Japan, and India showed little change in blood pressure over 7, 4, and 5 years, respectively, despite an increase in their urinary albumin excretion rate (UAER) over this time. The situation in Europid type 2 diabetes may be different. In the United Kingdom Prospective Diabetes Study (UKPDS), hypertension (defined as >160/90 mmHg or >150/85 mmHg on treatment) was present in over 30% of newly diagnosed patients. Only one-third of these had an increased urinary albumin concentration.

The observed changes in blood pressure may therefore initiate the nephropathic process in type 2 diabetes but occur as a result of it in type 1, although this distinction is not absolute. What is certain is that progression of nephropathy is much faster in patients with higher systemic blood pressure.

Haemodynamic factors

Glomerular filtration rate (GFR) is increased in newly diagnosed type 1 and type 2 diabetic patients. This phenomenon has been termed hyperfiltration and is thought to be due to a relative vasodilatation of the afferent glomerular arteriole, which leads to an increase in intraglomerular capillary pressure  and thereby glomerulosclerosis. Hyperfiltration and raised intraglomerular capillary pressure are thought to be caused by activation of the local renin–angiotensin system, leading to an excess production of angiotensin II and thereby relative vasoconstriction of the efferent glomerular arteriole.

The evidence in humans is conflicting and not helped by differing definitions of an abnormally high GFR and the difficulty of obtaining an estimate of intraglomerular capillary pressure. It appears that the rate of decline of GFR in hyperfiltering type 1 patients with a normal UAER is greater than that seen in age-matched and duration-matched controls. A meta-analysis has demonstrated a link between hyperfiltration and subsequent development of microalbuminuira in type 1 diabetes but could not exclude a confounding effect of hyperglycaemia. Recent data suggest that there is a link between hyperfiltration and later development of microalbuminuria in adolescents, and a positive relationship between GFR and glomerular basement membrane thickening in younger adults. Pima Indians show an increase in GFR at or shortly after the development of type 2 diabetes, but their baseline values are not linked to the subsequent development of nephropathy.

Growth factors

In experimental animals an initial increase in kidney size observed in diabetes is preceded by an increase in renal production of insulin-like growth factor-1, and there are reports of increased circulating and urinary levels in people with diabetes. Other growth factors listed in Bullet list 1 have been linked to matrix accumulation and development of proteinuria in experimental diabetes.

Increased whole kidney volume is also a feature of newly diagnosed type 1 diabetes in humans, but there is no conclusive link to subsequent development of nephropathy. Several of the growth factors listed in Bullet list 1 have been found to have an increased production or gene expression in biopsies from patients with diabetes compared to those from nondiabetic patients. It is unclear whether these changes are causative.

Mechanical and structural factors

Along with whole kidney volume, glomerular size is also increased at diagnosis of type 1 diabetes and is a feature of established clinical proteinuria in both type 1 and type 2 disease. These changes may be secondary to haemodynamic alterations in early disease or represent an adaptive response to loss of filtration surface in established diabetic nephropathy. A link between glomerular size and subsequent progression to sclerosis has been described in patients with minimal-change nephropathy, but the connection in diabetes is not proven.

Reductions of heparan sulphate proteoglycan in the extracellular matrix of diabetic patients and the glomerular basement membrane of those with microalbuminuria and clinical proteinuria have been reported. This finding has formed the basis of the so-called Steno hypothesis, which proposes that these alterations underpin the pathophysiology of nephropathy.

In vitro studies of mechanical stretch on cultured human mesangial cells and podocytes has demonstrated increased production of cytokines and growth factors associated with extracellular matrix accumulation. These studies provide a plausible mechanism whereby changes in intraglomerular capillary pressure may lead to glomerulosclerosis.

The discovery of glomerular epithelial cells (podocytes) in the urine of patients with proteinuria has led to extensive research into their possible role in progressive nephropathies, including diabetes. Reduced numbers of podocytes have been found in human diabetic glomeruli from patients with diabetic nephropathy, but it remains unclear whether these changes precede or result from developing glomerulopathy. There is a significant negative relationship between the numbers of podocytes per glomerulus and increasing proteinuria in patients with established diabetic nephropathy.

Fetal programming

The low birth weight–thrifty phenotype hypothesis proposes intrauterine malnutrition as a possible cause of adult hypertension and diabetes, perhaps mediated by reduced numbers of renal glomeruli or islets of Langerhans, respectively. Studies have failed to confirm lower glomerular numbers in white diabetic patients with nephropathy compared to those without, and no consistent relationship between birth weight and adult glomerular number has been demonstrated. A post mortem study of victims of road traffic accidents in Germany found a link between low glomerular number and hypertension in life in non-diabetic individuals, thus providing a potential mechanism of risk of fewer glomeruli at birth for subsequent kidney disease.

Other factors

Smoking rates are higher in diabetic patients with nephropathy, although a plausible mechanism of effect has yet to be defined. A link between raised blood lipids and the causation and progression of renal disease is still hotly debated. Both cross-sectional and prospective studies have shown an association between plasma total cholesterol and triglyceride levels and UAER and change in GFR, but the effects of therapy are inconsistent.

In experimental diabetes, dietary protein restriction can prevent glomerulosclerosis. Cross-sectional studies of patients with type 1 diabetes found that UAER increased in patients with a protein intake of more than 20% of their total food energy, while in type 2 diabetic and normal subjects, a 0.1g/kg body weight per day increase in protein intake was associated with a greater risk of developing microalbuminuria.

Abnormalities of endothelial function assessed by increases in plasma von Willebrand factor and homocysteine levels have been described in diabetic patients with normoalbuminuria who go on to develop microalbuminuria, and also in those with a persistently increased UAER at baseline. The EURODIAB investigators suggest that endothelial dysfunction provides a unifying hypothesis for the causation of microvascular and macrovascular disease in diabetes.

Genetics

There is a greater than 80% concordance for nephropathy and a more than 73% concordance for normoalbuminuria in diabetic siblings of probands with type 1 diabetes. In Pima Indians, the prevalence of diabetic nephropathy is 14% in the offspring of parents neither of whom have nephropathy, compared to 46% of offspring when both parents have the condition. These observations have led to many studies looking for a possible genetic cause of nephropathy, most of which have used the candidate gene approach with largely disappointing results. The most intensively studied genetic abnormality has been the insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE) gene, but the results are inconsistent. A genome-wide scan has identified a possible locus on chromosomes 7 and 20 in the Pima Indians, and other loci have been described in different populations. Although some workers have suggested that the family observations are consistent with a major gene effect, none has yet been confirmed. It is very likely that genetics play a role, but this is almost certainly a polygenic rather than a monogenic effect.

Pathology and pathogenesis

Patients with newly diagnosed type 1 diabetes have large kidneys, and studies in experimental animals suggest that this enlargement is due to tubular hypertrophy and hyperplasia, together with an expansion of the tubulointerstitium. Proximal tubular cells appear loaded with glycogen (the Armanni–Ebstein lesion). These changes are probably a response to the increased filtration of glucose at the glomerulus and can be reversed in animals by glycaemic correction. Glomerular and tubular structure is otherwise normal at diagnosis in human type 1 diabetes.

The pathological hallmarks of diabetic nephropathy are thickening of the glomerular basement membrane and mesangial expansion, with or without nodule formation, secondary to an accumulation of extracellular matrix (mostly type IV collagen). This accumulation results from a combination of increased production and decreased breakdown of matrix proteins. Glomerular basement membrane thickening can be detected in nearly all patients with diabetes of more than 10 years’ duration, irrespective of UAER. Those with clinical proteinuria almost invariably have glomerular basement membrane widths 2 to 3 times the upper limit of normal (350 nm). Mesangial volumes remain in the normal range in patients who have a normal UAER. Nodule formation, although virtually pathognomonic, is not invariable. A combination of mesangial expansion encroaching on the available filtration surface area and afferent arteriolar hyalinosis leading to glomerular ischaemia leads to eventual total glomerulosclerosis and permanent loss of filtration capacity, ultimately resulting in endstage renal disease.

Patients with type 2 diabetes have been less well studied, but the pathological appearances of subjects with established diabetic nephropathy are very similar to those with type 1. However, pathological changes in patients with microalbuminuria are more heterogeneous, and a significant prevalence of nondiabetic pathology (c.10%) has been reported.

Latterly, changes to the podocyte including foot process effacement, podocyte loss, and subsequent adhesion of the glomerular basement membrane to Bowman’s capsule have been linked to increasing UAER and are the subject of intensive research. Tubulointerstitial expansion with fibrosis and tubular atrophy are also well described in patients with clinical proteinuria.

Epidemiology

Reported incidence and prevalence rates of nephropathy are heavily dependent on the diagnostic criteria (see below) and the population under study. Classically, nephropathy has been classified based on UAER into normoalbuminuria, microalbuminuria, and clinical proteinuria (Table 1 below). Selecting only population-based cohorts with good patient ascertainment gives prevalence rates for microalbuminuria of between 5 and 21% for type 1 and 11 to 42% for type 2 diabetes. Reported annual incidence rates are around 2% for type 1 patients (Table 2 below). For clinical proteinuria, the prevalence is 6.4% in type 1 patients in the United Kingdom, with a range from 5 to 33% worldwide for type 2. A cumulative incidence of approximately 20% after 20 years’ duration was found in type 1 diabetic cohorts of the Steno Hospital in Denmark and Joslin Clinic in the United States of America, and similar figures have been reported for patients with type 2 diabetes in the United States (25%) and Germany (27%).

Table 21.10.1.1 Levels of proteinuria, albuminuria, and albumin/creatinine ratio (ACR) that define normal, microalbuminuria, and clinical proteinuria. Borderline results should be repeated on early morning samples or confirmed by a timed collection

 

  24h urine Timed overnight ‘Spot’ samplea,b
Total protein (g/day) Albumin (mg/day) Albumin (µg/min) Albumin concentration (mg/litre) ACR (mg/mmol) ACR (mg/g)
Normal <0.15 <30 <20 <20
  • <2.5 male
  • <3.5 female
  • <20 male
  • <40 female
Microalbuminuria   30–300 20–200 50–300
  • 2.5–30 male
  • 3.5–30 female
  • 20–300 male
  • 40–300 femalec
Clinical proteinuria >0.5 >300 >200 >300 >30 >300

a False-positive results with diurnal variation, exercise, urine infection, other renal disease, haematuria, heart failure.

b False-negative results with dilution, diuresis.

c American Diabetes Association uses a definition of 30–300 mg/g for both males and females.

Table 21.10.1.2 Natural history of nephropathy in type 1 diabetesa

 

  Normal Microalbuminuria Clinical proteinuria
UAER <20 µg/min 1–2% p.a progress to microalbuminuria 20–200 µg/min (increasing by 20% p.a) (up to 25% type 1 revert to normal) 1–4% p.a progress to clinical nephropathy >200 µg/min
GFR Stable: declines at 1 ml/min per year from over 40 years of age   Age-related changes until UAER approaches 200 µg/min or if blood pressure increases   Declines at 10 ml/min per year (hypertensive), 4 ml/min per year (normotensive)
Blood pressure Stable: significantly higher in those progressing to microalbuminuria   Initially stable, but higher than normal controls. Tends to increase with increasing UAER  
  • Most patients hypertensive (>140/90 mmHg).
  • Increases with declining GFR
Pathology
  • Large kidneys
  • Tubular hypertrophy/hyperplasia
  • Glomerular enlargement—normal ultrastructure, but glomerular basement membrane thickening 20 nm p.a.
 
  • Kidneys can remain large
  • Glomerular basement membrane thickening 54 nm p.a.
  • Mesangial expansion 4% p.a.
 
  • Kidneys tend to shrink
  • Glomerular basement membrane 2–3 times normal thickness, but stable
  • Nodule formation
  • Global glomerulosclerosis
  • Mesangial expansion c.7% p.a.

GFR, glomerular filtration rate; p.a., per annum; UAER, urinary albumin excretion rate.

a Fewer data in type 2 patients, many of whom are hypertensive at diagnosis.

More recent data from patients prospectively studied from diagnosis of type 1 diabetes in Scandinavia have revealed lower cumulative incidences of 15% after 20 years (Denmark) and 11% after 30 years (Sweden). There have also been reductions in the numbers of patients with type 1 diabetes entering renal replacement therapy programmes in the United States of America (incident rate in 1995–1999 was 7.1% vs 3.9% in 2000–2004); and the cumulative incidence of endstage renal disease secondary to type 1 diabetes in Finland is only 7.8% after 30 years.

The situation for type 2 diabetes is less clear as far as microalbuminuria and clinical proteinuria are concerned, although the transition rates are similar to type 1 at 1 to 2% per year. A population-based study in the United States of America has suggested that fewer patients with type 2 diabetes presented with clinical proteinuria at diagnosis in the 1990s compared to 30 years previously. Recent analysis of the UKPDS cohort has suggested a cumulative incidence of a urinary albumin concentration between 50 and 299 mg/litre (microalbuminuria) of 42% at 20 years and of clinical proteinuria of 20% after 20 years. Endstage renal disease rates for type 2 diabetes continue to increase in Europe but have reached a plateau in the United States of America at around 50% incidence and 35% prevalence. Incidence rates are now declining in the Pima Indians but are continuing to increase in the United Kingdom and Europe.

There is a dramatic difference in the risk of microalbuminuria, clinical proteinuria, and endstage renal disease in ethnic subgroups. In the United States of America there is a fourfold increased prevalence of African American and native American patients on renal replacement therapy compared to white patients. The increase is threefold for those of Hispanic origin. A similar increased risk has been reported for South Asian populations in the United Kingdom.

Many countries have registers of patients entering renal replacement therapy and in 2008 Malaysia had the highest incident rate of patients with diabetes entering renal replacement therapy at over 55%. Close behind was New Zealand at 45.5%, but there were lower numbers in Australia (34%), almost certainly due to the differing ethnic mix. Pacific islanders and Maori people are much more prone to renal disease and diabetes than those of European extraction. The reasons for the excess risk of endstage renal disease in these groups is unclear but may be genetic, related to increased rates of hypertension, or the result of fetal programming. There are intriguing data suggesting that the number and size of glomeruli is different in Australian aborigines compared to white Europid patients.

Prevention

Glycaemic control

The association of glycaemia and development of nephropathy has led to numerous studies exploring the potential of glycaemic control in the prevention of increases in UAER. The two largest studies were the Diabetes Control and Complications Trial (DCCT) in type 1 and the UKPDS in type 2 (Table 3 below). Both compared the intensive management of hyperglycaemia using multiple injections of insulin in type 1 and early use of insulin in type 2 against more conventional control. Those in the intensively treated groups also had more frequent contact with health care professionals. The DCCT cohort was invited to continue surveillance for a further 8 years as part of the Epidemiology of Diabetes Interventions and Complications (EDIC) study. More recently the ACCORD (Action to Control CardiOvascular Risk in Diabetes) study of intensive glycaemic control in patients with type 2 diabetes at high cardiovascular risk has reported.

Table 21.10.1.3 Comparison of intensive vs conventional therapy in the prevention of microalbuminuria in type 1 (DCCT + EDIC) and newly diagnosed type 2 (UKPDS) patients

 

Study Number Ethnicity Duration of study (years) Achieved HbA1c Microalbuminuria
Intensive (%) Conventional (%) Intensive (%) Conventional (%) RRR (%)
DCCT   European (96%) 9 7.2 (normal <6.05) 9.1 (UAER >40 mg/day)    
 No retinopathy 726         15 27 44
 Retinopathy 715         27 42 35
EDIC 1112   8 8.0 8.2 6.8 15.8 57
UKPDS 3867
  • European 81%
  • Indian Asian 10%
  • Afro-Caribbean 8%
9 7.0 (normal 6.2) 7.9 19.2 (UAC >50 mg/litre) 25.4 24

DCCT, Diabetes Control and Complications Trial; EDIC, Epidemiology of Diabetes Interventions and Complications Study; RRR, relative risk reduction; UAC, urinary albumin concentration, annual; UAER, urinary albumin excretion rate, annual 4-h collections (biannual for EDIC); UKPDS, United Kingdom Prospective Diabetes Study.

Both DCCT and UKPDS demonstrated a significant reduction in numbers developing microalbuminuria, although there was still a substantial incidence of 15 and 19.2%, respectively, in the intensively treated cohorts (Table 3 above). Interestingly, the benefit of intensive treatment continued in the EDIC follow-up, despite a deterioration in HbA1c to levels close to those seen in the conventional group at 8.2%. Thus a prolonged period of good glycaemic control appears to confer benefit in terms of prevention of complications in the kidney (and the retina) for many years. Moreover, the intensive cohort who were normotensive at the beginning of the EDIC study showed a 32% reduction in the risk of developing hypertension (blood pressure >140/90 mmHg) compared to the conventional group. The ACCORD Study, however, failed to demonstrate a benefit in terms of prevention of microalbuminuria, but the study was closed early because of excess cardiac deaths and it was not powered for microvascular end points.

There is continuing controversy as to whether intensive glycaemic control alone can prevent the progression of microalbuminuria to clinical proteinuria. Careful analysis of the DCCT cohort failed to show an impact. It is likely that other factors such as blood pressure control are of more importance for progression once UAER exceeds 30 to 40 mg/day. There are no conclusive data on the impact of improved glycaemic control on the development of endstage renal disease, decline in GFR, or death in patients with type 1 diabetes. The UKPDS showed a positive benefit of intensive therapy on the rate of doubling of serum creatinine at 12 years (0.91% vs 3.52%, P <0.003) in patients with type 2 diabetes, but the numbers were very small. Pancreas transplantation in type 1 patients has demonstrated that long-term (10 years) complete glycaemic normalization can reverse established pathological changes in native (nontransplanted) glomeruli. Thus glomerulopathy may take as long to reverse as it does to develop, and studies to date may have been of too short a duration and glycaemic correction inadequate.

Blood pressure control

There have been many studies of antihypertensive therapy in diabetic nephropathy. For clarity these will be dealt with under three headings: primary prevention (of microalbuminuria), secondary prevention (of clinical proteinuria), and tertiary prevention (of endstage renal disease and death).

Primary prevention

The EURODIAB Controlled Trial of Lisinopril in Insulin-dependent Diabetes (EUCLID) studied normotensive type 1 diabetic patients with a UAER between 5 and 20 µg/min and demonstrated a significant reduction in albuminuria after 2 years, but no significant impact on the numbers developing microalbuminuria. This finding has been confirmed recently by the Diabetic retinopathy Candesartan Trials (DIRECT) and RASS (Renin-Angiotensin System Study) studies. The Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) studied 1204 hypertensive type 2 patients with normoalbuminuria and demonstrated a significant reduction in the numbers developing microalbuminuria after 3 years on trandolapril (6%), compared to verapamil (11.9%), or placebo (10%). However, these findings were not confirmed in normotensive or well controlled hypertensive patients in DIRECT. In the UKPDS, the number of hypertensive patients developing a urinary albumin concentration of more than 50 mg/litre at 6 years was 2.3% in the tight (blood pressure 144/82 mmHg) and 12.5% in the less tight (blood pressure 154/87 mmHg) groups (P <0.009).

Secondary prevention

Most studies have shown a short- to medium-term benefit of antihypertensive therapy on UAER in the microalbuminuric range, with drugs blocking the renin–angiotensin system seeming to be more effective.

In mainly European patients with type 1 diabetes, a meta-analysis has shown an adjusted risk reduction of more than 60% for the development of clinical proteinuria comparing ACE inhibitors with placebo. More recently the angiotensin-II receptor blocker (ARB) irbesartan has demonstrated a similar magnitude of effect in microalbuminuric type 2 diabetic patients. Thus, blockade of the renin–angiotensin system by any means appears to confer benefit in terms of a reduction in the numbers of patients developing clinical proteinuria. Accurate data on GFR are not given in many of these studies, but in type 1 patients long-term ACE inhibitor therapy appears to stabilize renal function after an initial reduction. Interpretation of all these studies is complicated by the fact that the actively treated patients have nearly always had significantly lower blood pressures than the placebo groups. While statistical correction for these differences has been applied, it is uncertain whether mathematical correction can completely allow for the biological consequences of blood pressure reduction.

Tertiary prevention

Studies in the early 1980s established that lowering blood pressure in hypertensive type 1 patients with clinical proteinuria resulted in a more than 50% reduction in UAER and a significant slowing of the rate of decline of GFR from 10 to 3 ml/min per year. The Collaborative Study Group Trial in type 1 diabetic patients with a blood pressure below 140/90 mmHg and clinical proteinuria showed that the addition of captopril 100 mg a day resulted in a significant reduction in the numbers of patients doubling baseline serum creatinine compared to placebo (35% vs 78%; P <0.001). This significance was confined to those with an entry serum creatinine concentration of more than 133 µmol/litre (1.5 mg/dl). There was a similar reduction in the numbers reaching a combined endpoint of death or the need for renal replacement therapy in the captopril-treated patients.

In patients with type 2 diabetes the results are complicated due to an increased cardiovascular comorbidity. Two large studies using ARBs in patients with clinical proteinuria have shown a reduction of 25 to 33% in the rate of doubling of serum creatinine after 2 to 3 years treatment. This is considerably less than that seen in the captopril trial in type 1 patients, possibly because the type 2 patients had more advanced diabetic nephropathy at entry.

Taken together, the studies in type 1 and 2 patients support the use of drugs which block the renin–angiotensin system as first-line therapy in both microalbuminuric and clinically proteinuric patients and are recommended in all national and international guidelines.

Nonrenal outcomes

Although there are many large studies of the effects of antihypertensive therapy on cardiovascular mortality and morbidity in patient groups that have included sizeable cohorts of diabetic patients, their nephropathic status has rarely been specified. Most have shown that low blood pressure is associated with the reduction in overall mortality and stroke incidence, although the effect on myocardial infarction is inconsistent. Diabetic patients on the whole showed a greater benefit from active treatment.

Clinical features

Clinical progression is usually defined in terms of changes in UAER (urinary albumin excretion rate), GFR (glomerular filtration rate), and blood pressure. Much of our current understanding is based on cross-sectional data, although more long-term prospective studies of individual patients are being reported. Albuminuria is clearly a continuous variable and its separation into stages is artificial, but the distinction between microalbuminuria and clinical proteinuria has proved to be useful.

UAER (urinary albumin excretion rate)

UAER may increase at diagnosis of type 1 diabetes and during acute hyperglycaemia, but usually returns to normal with glycaemic correction. Thereafter most patients (>60%) will have a normal UAER throughout their diabetic life, but the remainder develop persistent microalbuminuria at incident rates of between 1 and 2% per annum, usually preceded by intermittently positive tests. Interestingly, an inception cohort of Danish type 1 patients followed from diagnosis showed that UAER was significantly higher (but well within the normal range) in those subsequently going on to develop microalbuminuria after 15 to 20 years, compared to those who did not (11 vs 8 µg/min; P = 0.002). The rate of increase of UAER in patients with microalbuminuria is historically around 20% per annum, but this is lower in those commencing antihypertensive therapy or intensified insulin regimens (Table 2 above).

It is unusual to develop microalbuminuria within the first 5 years of diabetes onset, but it can develop at any time thereafter, even after 40 years. Most patients with type 1 diabetes and microalbuminuria will progress to clinical proteinuria unless treated; those with longer durations of diabetes before microalbuminuria tend to progress more slowly. More recent prospective studies have shown that up to 25% of type 1 microalbuminuric patients may spontaneously regress to normoalbuminuria. Around 12.5% may oscillate between normoalbuminuria and microalbuminuria for many years. The significance of these movements is unclear and is possibly the result of blood pressure-lowering therapies and short-term changes in glycaemic control.

Once UAER exceeds 300 mg/day there tends to be a relentless increase, occasionally into the nephrotic range. The rate of change varies between patients and is very dependent on systemic blood pressure. Historically the incidence of clinical proteinuria peaked after 15 to 17 years duration of diabetes, but more recent studies are showing a delay to 25 years or more.

Because the onset of type 2 diabetes is more difficult to define, the precise incidence of microalbuminuria is harder to estimate, although the UKPDS suggests that rates are similar to type 1 (Table 2 above). Up to 7% of newly diagnosed type 2 patients in the United Kingdom will have a urinary albumin concentration above 50 mg/litre (microalbuminuria), and 1% will be above 300 mg/litre (clinical proteinuria). Some studies have reported a reduction in UAER with initial glycaemic correction, but many patients have a sustained increase suggesting established nephropathology at diagnosis.

GFR (glomerular filtration rate)

As previously mentioned, GFR at diagnosis of type 1 and type 2 diabetes is increased in 40 to 45% of patients. It returns to normal in most following glycaemic correction, although a significant minority maintain persistently high values (hyperfiltration). In non-diabetic humans the GFR declines by 1 ml/min per year after the age of 40, and it does so also in normotensive diabetic patients who have normal UAER. As the UAER approaches and exceeds the clinical proteinuria threshold, there tends to be a steady decline. This is particularly so in hypertensive patients, in whom the rate of loss of GFR varies considerably. In historical series in those with poorly controlled hypertension the average decline was 10 ml/min per year, leading to endstage renal disease 7 to 10 years after the onset of clinical proteinuria. More recently, the rate of decline is <4 ml/min per year in patients with well-controlled systemic blood pressure, effectively delaying endstage renal disease by more than 10 years. Patients with type 2 diabetes and a normal UAER tend to have a much slower rate of loss of GFR. It is now recommended that all people with diabetes have an estimate of GFR (eGFR) performed annually using the Modification of Diet in Renal Disease (MDRD) equation.

Blood pressure

In patients with type 1 diabetes, blood pressure is virtually always normal at diagnosis. This is not the case in type 2 diabetes, where over one-third will have blood pressure higher than 160/95 mmHg and many more are hypertensive by recent criteria. Type 1 patients who go on to develop microalbuminuria have significantly higher blood pressures than those who remain with a normal UAER, although the averages remain below 140/90 mm Hg in both groups. Patients with newly developed microalbuminuria show a steady increase in blood pressure such that over 45% exceed 140/90 mmHg within 4 years. Most type 1 and type 2 patients with clinical proteinuria are hypertensive and on therapy.

Clinical concomitants of nephropathy

Many patients with diabetic nephropathy will also have retinopathy and neuropathy, which will tend to progress. Both of these complications can be reversed or at least ameliorated by improved glycaemic control. There is an increased incidence of cardiovascular, cerebrovascular, and peripheral vascular disease; intensive management of modifiable cardiovascular risk factors is essential (see below). Amputation rates in patients with diabetic nephropathy are high; careful foot surveillance and preventative podiatry are essential.

Differential diagnosis

It is important to remember that not all renal or urinary tract disease in diabetic patients is due to diabetic nephropathy. Urinary tract infection is more common in diabetic women compared to age-matched nondiabetic controls. Infection is often asymptomatic and culture should always be performed in any patient with an isolated positive urinalysis for protein, blood, leucocytes, or nitrite. A positive result is much more likely if two or more of these tests are positive.

Papillary necrosis has been described in women with long-standing type 1 diabetes and is a recognized complication of hyperosmolar coma in patients with both types of diabetes. Atheromatous renovascular disease is also common in diabetes, but the prevalence of functionally significant renal artery stenosis is uncertain.

Whereas the vast majority of type 1 patients with microalbuminuria have histologically proven diabetic glomerulopathy, the situation is less certain in type 2 diabetes. Up to 10% of such patients have evidence of nondiabetic pathologies, many have nonspecific ischaemic changes, and only a minority have classic diabetic lesions. The presence of diabetic retinopathy is partly helpful as those with it are almost certain to have diabetic lesions and those without it much less so. Even so, there are few cases of specifically treatable glomerulopathy in those with nondiabetic disease, hence management is unlikely to be significantly different, although those with nonclassic lesions tend to have slower rates of decline of GFR.

Clinical investigation

Type 2 diabetes is becoming more common and as a result the chance of concomitant nondiabetic renal or urological disease is increased. The need to exclude urinary tract infection has already been mentioned. Current United Kingdom guidelines suggest investigation and possible referral of all diabetic patients with persistent microscopic or macroscopic haematuria. An atypical presentation of proteinuria, or an unusually rapid clinical course such as rapidly deteriorating GFR, or the presence of features of other systemic diseases should prompt referral and investigation (Bullet list 2). Current United Kingdom guidelines suggest expert review of all with an eGFR of loss than 60 ml/min per 1.73m2.

Bullet list 2 Clinical features suggestive of nondiabetic renal disease

  • Increased UAER/clinical proteinuria/nephrotic syndrome in absence of retinopathy
  • Low GFR with normal UAER
  • Rapidly declining GFR
  • Rapidly increasing proteinuria
  • Refractory hypertension—consider renal artery stenosis
  • Presence of active urinary sediment (red cells, cellular casts)
  • Signs or symptoms of other systemic disease
  • A greater than 30% reduction in GFR within 2–3 months of initiation of renin–angiotensin system blocking agents—consider renal artery stenosis

Criteria for diagnosis

Diabetic nephropathy is a clinical diagnosis based on the finding of proteinuria in a patient with diabetes and in whom there is no evidence of urinary infection. Conventionally, the level of proteinuria for a diagnosis of clinical proteinuria is 0.5 g/day, which is roughly equivalent to a UAER of 300 mg/day (Table 1 above). Patients with a UAER between 30 and 300 mg/day are defined as having microalbuminuria. Current United Kingdom guidelines suggest confirming the diagnosis with one or two repeat tests over the subsequent 1 to 6 months. 


Although timed urine collections remain the gold standard for diagnosis, they are cumbersome to use in routine clinical practice and most definitions depend on a spot urine sample and thus a test of albumin concentration. Levels above 50 mg/litre or above 300 mg/litre define microalbuminuria and clinical proteinuria, respectively. Sensitivity and specificity can be improved by using an early morning, first-voided specimen and correcting the urinary albumin level for creatinine concentration (an albumin/creatinine ratio, ACR). Defining levels are shown in Table 1.

It is unfortunate that the recent diagnostic and classification system for chronic kidney disease based on eGFR and now widely adopted does not map neatly to the more classic staging of diabetic nephropathy based on UAER (Table 4 below). eGFR estimated from the MDRD equation has not been validated in large diabetic cohorts, nor is it very accurate at values above 90 ml/min. As many newly diagnosed type 1 and type 2 patients have an elevated GFR, significant reductions may therefore pass undetected. Small retrospective cohorts using the MDRD equation have reported an underestimate of true GFR in diabetes and large prospective studies are urgently required.

Table 4 Cross-tabulation of different classification of diabetic kidney disease using classical staging by UAER and the CKD staging system

 

  eGFR ml/min/1.73m2
>60 (stage 1 and 2) 30–60 (stage 3) <30 (stages 4 and 5)
Normoalbuminuria (<30 mg/day) Possible DKD (at risk) Possible DKD (could be DM + CKD) Possible DKD (could be DM + CKD)
Microalbuminuria (30–299 mg/day) Possible DKD (probable if DR) Probable DKD (definite if DR) Probable DKD (definite if DR)
Clinical proteinuria (>300 mg/day) DKD DKD DKD

CKD, chronic kidney disease; DKD, diabetic kidney disease; DM, diabetes mellitus; DR, diabetic retinopathy, eGFR, estimated glomerular filtration rate; UAER, urinary albumin excretion rate.

NB: Staging by UAER may be confounded by proteinuria-lowering therapies such as renin–angiotensin system blockers. Wherever possible, classification by UAER should be based on pretreatment levels. A reduced GFR in the presence of normoalbuminuria is well described in both type 1 and type 2 diabetes; renal biopsy often shows DKD in such patients.

Treatment

Glycaemic control and blood pressure

The roles of glycaemic control and blood pressure management have been discussed earlier in this chapter. Current target HbA1c levels from the National Institute of Health and Clinical Excellence (NICE) guidelines in the United Kingdom are less than 7.5% (58 mmol/mol) for type 1 and 6.5 to 7.5% (48 – 58 mmol/mol) for type 2 patients. The American Diabetes Association target is <7.0% (53 mmol/mol) for both. Blood pressure targets are below 130/80 mmHg for type 1 and below 135/75 mmHg for type 2 patients with microalbuminuria. Because of the pivotal role that angiotensin II is thought to play in diabetic nephropathy development, all guidelines suggest using renin–angiotensin system blocking agents as first-line treatment. However, the UKPDS has shown that most type 2 patients will require two or more agents in order to achieve target. The British Hypertension Society guidelines suggest the addition of a diuretic as the next step, followed by a choice of calcium channel blocker, α-blocker, and then other agents. β-blockers are no longer recommended in diabetic patients, except for postmyocardial infarction. The blood pressure target for patients with heavy proteinuria (>1 g/day) is 125/75 mmHg.

There has been increasing interest in using combined ACE inhibitor/ARB combinations, together with aldosterone antagonists such as spironolactone or eplerenone. The rationale is that each of these agents alone is not enough to completely block angiotensin II production. Studies to date have demonstrated a modest benefit on blood pressure and UAER, but have been too short to address endstage renal disease or rate of decline of GFR. It is also important to recognize that there is a real risk of significant hyperkalaemia on these regimens, and patients need to be monitored carefully and told to stop therapy during illnesses that may lead to dehydration such as diarrhoea and vomiting. The ONTARGET (Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) study which included a large number of diabetic subjects reported worsening GFR and high rates of hyperkalaemia in those on dual (telmisartan and ramipril) versus single blockade.

Achieving blood pressure targets is difficult, particularly in patients with type 2 diabetes and systolic hypertension. Although the UKPDS showed a linear relationship between glycaemia and blood pressure and microvascular risk implying that that the lower the better, the ACCORD glycaemia and blood pressure studies failed to show benefit of HbA1c of 6.5% (48mmol/mol) and <120/80 mmHg, respectively, suggesting that there may be little benefit for patients of reducing current targets.

Other aspects

Low protein diets have been shown by meta-analysis to slow the rate of decline of GFR in diabetic patients, and a more recent study from Denmark has also shown benefit on mortality. Current dietary recommendations are for an intake of between 0.7 and 0.9 g protein/kg body weight per day.

Aspirin in a dose of 325 mg/day reduced myocardial infarction (RR 0.72; 99% CI 0.55–0.95) in 3711 type 1 and 2 patients with retinopathy. Although nephropathy status was not determined in this study, the use of low-dose aspirin is advised for all patients with an increased UAER (unless contraindicated) because of their high risk for cardiovascular disease. Lipid-lowering therapy should also be commenced.

Observational studies suggest that patients with better glycaemic control have a better overall survival on haemodialysis. Active foot surveillance and eye screening for these patients also confers benefit in terms of limb and sight preservation.

A multiple risk factor approach

Because the outlook for patients with diabetic nephropathy is poor, many national guidelines now suggest a multiple risk factor approach to management. However, many patients with advanced diabetic nephropathy referred to renal units in Europe and the United States of America have inadequate blood pressure control, low use of therapies of proven benefit, e.g. β-blockers, ACE inhibitors, lipid-lowering therapy, and low-dose aspirin, and poor assessment of comorbidities such as retinopathy and foot care.

The Steno 2 study in microalbuminuric type 2 diabetic patients involved a multifactorial intervention for 7 to 8 years that addressed glycaemia, blood pressure (using renin–angiotensin system blocking agents in all), serum lipid lowering, low-dose aspirin, smoking cessation, reduction of dietary fat and salt, exercise, and antioxidant vitamins. Compared to routine care this significantly reduced the development of clinical proteinuria and the composite cardiovascular outcome of fatal and nonfatal myocardial infarction and stroke, myocardial revascularization (surgical or percutaneous), and peripheral vascular surgery or amputation. The recently reported SHARP (Study of Heart And Renal Protection) Trial demonstrated a 2% absolute risk reduction in cardiovascular end points in patients with CKD (many of whom had diabetes) treated with a combination of simvastatin and ezetimibe. There is, therefore, a real challenge for our patients as well as their carers to implement multiple therapies in a way that will facilitate compliance and deliver long-term benefit.

Prognosis

Microalbuminuric type 1 and type 2 patients have a two- to fourfold increased mortality, mainly from cardiovascular disease. The reported relative mortality for European 40-year-old type 1 patients with clinical proteinuria in Denmark was between 80 and 100 times that of the nondiabetic population, while the World Health Organization study revealed a three- to fourfold excess for clinically proteinuric patients with type 2 diabetes. Most of these deaths are due to stroke or myocardial infarction. In Finland, type 1 patients with nephropathy have a 10-fold relative risk for both stroke and myocardial infraction compared to nondiabetic controls. The UKPDS cohort demonstrated an annual mortality of 4.6% for those with clinical proteinuria, and almost 20% for those with a serum creatinine above 175 µmol/litre or in endstage renal disease, cardiovascular disease being the main cause of death. Pima Indians also show an increase in mortality with increasing ACR. The causes of death are somewhat different to white Europid patients; vascular disease is much less prevalent in native Americans, although more frequent in those with diabetic nephropathy. A reduced eGFR of less than 60 ml/min per 1.73m2 confers a more than 3.3-fold increased hazard ratio for cardiovascular mortality irrespective of albuminuria status.

Survival on dialysis remains much worse for patients with diabetes compared to those without; around 25% are alive after 5 years in both European and American registries. While 5-year survival has improved in recent years for those with nondiabetic renal disease, diabetic patients have shown only a modest improvement from 25 to 27%, and in the United States of America the death rate for never transplanted 20- to 44-year-old diabetic patients with endstage renal disease is nearly twice as great as that for nondiabetic controls. Overall survival for diabetic patients is best in those who have an early successful kidney transplant.

Areas of uncertainty or controversy

Should we screen for diabetic nephropathy?

Because of the strong associations between an increase in UAER and cardiovascular disease, a case for screening for diabetic nephropathy can be made with some confidence, although the evidence base for beneficial intervention at lower levels of albuminuria is not secure. Current recommendations from national diabetes associations advise at least annual screening. Extrapolating the known effects of ACE inhibitors on a reduction of UAER to a possible prevention of clinical proteinuria and thus endstage renal disease has led several authors to propose a potential cost benefit from the early use of these agents. However, only long-term prospective studies of primary prevention can conclusively answer this question, and no such trials are currently being undertaken.

Can glycaemic control reverse established nephropathy?

The DCCT was inconclusive, but data from pancreas transplant series suggest that glomerulopathology can be reversed in native kidneys after 10 years of normoglycaemia.

Why does intensive glycaemic control fail to completely prevent development of microalbuminuria?

Glycaemia is one of many factors leading to nephropathy. Moreover, even in the DCCT complete glycaemic normalization was not achieved. It is possible that newer insulins and delivery systems with continuous glucose monitoring may make sustained normoglycaemia more easily achievable.

Do drugs that block the renin–angiotensin system prevent or only delay the development of nephropathy? Can they reverse established nephropathy?

The data are not conclusive, partly because of the relatively short duration of many trials, but most studies show a benefit in terms of reduction of UAER. A meta-analysis published in 2005 raised concerns about the effectiveness of these drugs, but was itself flawed by the overwhelming influence of the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which was not designed to study renal outcomes as a primary endpoint.

For those with established clinical proteinuria and chronic kidney disease stages 3 and beyond there is no doubt that renin–angiotensin system blocking drugs delay endstage renal disease. For microalbuminuria there are no studies of sufficient power to confirm benefit on hard clinical endpoints such as mortality or endstage renal disease. Primary prevention of microalbuminuria itself has only been shown in hypertensive type 2 patients.

Likely developments in the near future

Hyperglycaemia is thought to lead to nephropathy through several pathways, as outlined in Bullet list 1 above. There are developments in most of these fields, with the following being studied in trials: pyridoxamine and other inhibitors of glycation; ruboxistaurin, a protein kinase Cβ inhibitor; atrasentan and other endothelin inhibitors; and aliskirena direct renin inhibitor.