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Diabetes mellitus and the kidney 

Diabetes mellitus and the kidney
Chapter:
Diabetes mellitus and the kidney
Author(s):

Rudolf Bilous

DOI:
10.1093/med/9780199204854.003.211001_update_004

Update:

Chapter updated throughout

Further reading updated to reflect recent research

Updated on 27 April 2017. The previous version of this content can be found here.
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Essentials

Diabetic nephropathy is the commonest cause of endstage renal disease in the developed world, causing 44% of prevalent cases requiring renal replacement therapy in the United States of America in 2012 and 25% in the United Kingdom in 2013. Incident rates have increased slightly in the UK at 25% of all new patients accepted onto RRT in 2013. Most patients have type 2 diabetes, and in most countries the proportion 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, inflammation, genetic factors, and dietary and other environmental factors. Pathological hallmarks in the glomerulus are thickening of the glomerular basement membrane and mesangial expansion, with or without nodule formation, secondary to an accumulation of extracellular matrix. Many patients have a varying severity of tubulo-interstitial inflammation and fibrosis.

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, but now termed moderately increased albuminuria)—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, but now termed severely increased albuminuria)—UAER greater than 200 µg/min, ACR greater than 30 mg/mmol. This staging maps better to the latest classification of 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 moderately increased albuminuria each year. Once UAER exceeds 200 µg/min, there tends to be a relentless increase in proteinuria and GFR declines progressively at a rate that largely depends upon blood pressure control.

Prevention—in both type 1 and type 2 diabetes, tight glycaemic control can prevent moderately increased albuminuria. Whether intensive blood pressure control using angiotensin converting enzyme (ACE) inhibitors can also prevent this remains 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 moderately to severely increased albuminuria and also slows the rate of decline in GFR in those with severely increased albuminuria.

Management—aims for: (1) control of glycaemia (typical recommendations are for HbA1c level <48 mmol/mol (<6.5%) (NICE) and <53 mmol/mol (<7.0%) (National Kidney Foundation and American Diabetes Association); (2) control of hypertension (<130/80 mmHg) using an ACE inhibitor or an ARB as first line; and (3) other interventions, including some or all of serum lipid lowering, 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 severely increased albuminuria, and 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, although overall rates are improving. Cardiovascular disease is the commonest cause of death, and multifactorial cardiovascular risk-factor intervention has been shown to reduce mortality and morbidity in people with type 2 diabetes and moderately increased albuminuria, and is now recommended for all patients with diabetic nephropathy.

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. Historically, up to 40% of patients with type 1 and 20% of those with type 2 diabetes developed nephropathy (although these rates are time and duration of diabetes dependent and are declining, particularly in type 1), and consequently are at high risk of developing endstage renal disease. The numbers of people with diabetes worldwide is increasing, with a current estimated prevalence of 387 million rising to nearly 600 million by 2035, 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 Box 21.10.1.1 (see also ‘Glycaemic control’).

CTGF, connective tissue growth factor; FGF, fibroblast 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 moderately increased albuminuria. There is also 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 moderately increased albuminuria 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 (Fig. 21.10.1.1) and thereby glomerulosclerosis. Hyperfiltration and raised intraglomerular capillary pressure are thought to be caused in part 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.

Fig. 21.10.1.1 Schematic of a glomerulus. In diabetes there is relative afferent arteriolar dilatation and angiotensin II induced efferent arteriolar constriction. This leads to increased glomerular capillary flow and pressure resulting in elevated GFR (hyperfiltration) and increased albumin filtration. Blockade of the renin-angiotensin system dilates the efferent arteriole and reduces GFR and capillary pressure.

Fig. 21.10.1.1
Schematic of a glomerulus. In diabetes there is relative afferent arteriolar dilatation and angiotensin II induced efferent arteriolar constriction. This leads to increased glomerular capillary flow and pressure resulting in elevated GFR (hyperfiltration) and increased albumin filtration. Blockade of the renin-angiotensin system dilates the efferent arteriole and reduces GFR and capillary pressure.

The evidence for a causative role of hyperfiltration for nephropathy 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 moderately increased albuminuria 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 moderately increased albuminuria 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 Box 21.10.1.1 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 Box 21.10.1.1 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. There are recent data linking the serum concentration of circulating TNF receptors 1 and 2 and FGF to subsequent development of nephropathy, but these results require confirmation and there are problems with standardising the assays.

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. These changes may be secondary to haemodynamic alterations in early nephropathy or represent an adaptive response to loss of filtration surface in established glomerulopathy. 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.

Diabetes mellitus and the kidneyReductions of heparan sulfate proteoglycan in the extracellular matrix of diabetic patients and the glomerular basement membrane of those with moderately and severely increased albuminuria 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. More recently there has been a focus on changes in the composition of the endothelial glycocalyx as an explanation of increasing albuminuria in diabetes, and it may be that changes in heparan sulphate proteoglycan in this structure, rather than the GBM, are more important in terms of protein permselectivity.

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 albuminuria 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 lipid lowering therapy on nephropathy progression 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 moderately increased albuminuria.

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 moderately increased albuminuria, and also in those with a persistently increased UAER at baseline. The EURODIAB investigators have suggested that endothelial dysfunction provides a unifying hypothesis for the causation of microvascular and macrovascular disease in diabetes.

Genetics

A greater than 80% concordance for nephropathy and a more than 73% concordance for normoalbuminuria in diabetic siblings of probands with type 1 diabetes has been reported, and 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, and meta-analysis confirms an association between the deletion polymorphism and ESRD in some populations. 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 with a major epigenetic influence.

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) (Fig. 21.10.1.2). 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 severely increased albuminuria 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 causing glomerular ischaemia, leads to eventual total glomerulosclerosis and permanent loss of filtration capacity, ultimately resulting in endstage renal disease.

Fig. 21.10.1.2 Glomerulus from patient with type 1 diabetes and severely increased albuminuria (haematoxylin and eosin stain). Note afferent (A) and efferent (E) arteriolar hyalinosis, thickened and split Bowman’s capsule (B), and mesangial expansion (M) (b) Glomerulus from patient with type 1 diabetes and severely increased albuminuria (toluidine blue stain) showing typical nodule (N). Note central accumulation of matrix material with surrounding nuclei.

Fig. 21.10.1.2
Glomerulus from patient with type 1 diabetes and severely increased albuminuria (haematoxylin and eosin stain). Note afferent (A) and efferent (E) arteriolar hyalinosis, thickened and split Bowman’s capsule (B), and mesangial expansion (M) (b) Glomerulus from patient with type 1 diabetes and severely increased albuminuria (toluidine blue stain) showing typical nodule (N). Note central accumulation of matrix material with surrounding nuclei.

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, although glomeruli tend to be much larger in type 2 patients with severely increased albuminuria for reasons that are unclear. Pathological changes in type 2 patients with moderately increased albuminuria are more heterogeneous than type 1, 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 type 1 and type 2 patients with severely increased albuminuria.

Epidemiology

Reported incidence and prevalence rates of nephropathy are heavily dependent on the diagnostic criteria (see below) and the population under study. Historically, nephropathy has been classified based on UAER into normoalbuminuria, moderately increased albuminuria (microalbuminuria), and severely increased albuminuria (clinical proteinuria)(Table 21.10.1.1). Selecting only population-based cohorts with good patient ascertainment gives prevalence rates for moderately increasedalbuminuria 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 21.10.1.2). For severely increased albuminuria, 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, moderately increased (microalbuminuria), and severely increased albuminuria (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

Moderately increased albuminuria (Microalbuminuria)

30–300

20–200

50–300

  • 2.5–30 male

  • 3.5–30 female

  • 20–300 male

  • 40–300 femalec

Severely increased albuminuria (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

Moderately increased albuminuria

everely increased albuminuria

UAER

<20 µg/min

1–2% p.a progress to moderately increased albuminuria

20–200 µg/min (increasing by 20% p.a) (up to 25% type 1 revert to normal)

1–4% p.a progress to Severely increased albuminuria

>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) although this reduction is not seen in African Americans who continue to show a year on year increase. 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 moderately and severely increased albuminuria 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. Analysis of the UKPDS cohort has suggested a cumulative incidence of a urinary albumin concentration between 50 and 299 mg/litre (moderately increased albuminuria) of 42% at 20 years and severely increased albuminuria of 20% after 20 years. Almost 20% of adults with diabetes in the 2007–2012 NHANES cohort in the USA had a diagnosis of CKD, and 30% had moderately increased albuminuria. 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 44% incidence and prevalence. Incidence rates are now declining in the Pima Indians and Hispanics but continuing to rise for African Americans. Rates are still rising in the United Kingdom (25.4% prevalence and 26% incidence in 2013) and Europe, but more slowly than previously.

There is dramatic variation in the risk of moderately and severely elevated albuminuria, and of endstage renal disease, in different ethnic subgroups. In the USA 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 disease registers of patients entering renal replacement therapy and in 2009/10 prevalent rates of 51–63% for diabetes were reported for Mexico, Singapore, Malaysia and New Zealand, with incident rates of 49–66%. Pacific Islanders and Maori people in New Zealand 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 landmark studies were the Diabetes Control and Complications Trial (DCCT) in type 1 and the UKPDS in type 2 (Table 21.10.1.3). 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 moderately increased albuminuria in type 1 (DCCT + EDIC) and newly diagnosed type 2 (UKPDS) patients

Study

Number

Ethnicity

Duration of study (years)

Achieved HbA1c

Moderately severe albuminuria

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.

Diabetes mellitus and the kidneyBoth DCCT and UKPDS demonstrated a significant reduction in numbers developing moderately increased albuminuria, although there was still a substantial incidence of 15 and 19.2%, respectively, in the intensively treated cohorts (Table 21.10.1.3). 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 66 mmol/mol (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 moderately increased albuminuria or progression of retinopathy. However, the study was closed early because of excess cardiac deaths and it was not powered for microvascular end points. Nonetheless, there is now debate as to the role of intensive glucose control in people with type 2 diabetes and a recognition that targets will need to be adjusted for the individual taking into account co-morbidities and age.

There is continuing controversy as to whether intensive glycaemic control alone can prevent the progression of moderately increased albuminuria to severely increased albuminuria. Careful analysis of the DCCT cohort failed to show an impact, but a post hoc analysis of the Joslin clinic nephropathy cohort demonstrated a slower progression in terms of rate of loss of GFR in those with better glycaemic control. 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. The DCCT/EDIC cohort have shown a reduction in the number of patients in the intensively treated versus conventional arm who went on to develop an eGFR < 60 ml/min/1.73m2 (incident rates of 1.6 vs 3.0 / 1000 person years; p = 0.006), but no effect on rates of ESRD, partly because of the remarkably few individuals who reached this end point ( 8 vs 16 respectively; p = 0.10). 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 also very small. A meta analysis has shown no effect of intensive glycaemic control on hard nephropathy end points in type 2 diabetes. 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 many studies of intensive control 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 moderately increased albuminuria), secondary prevention (of severely increased albuminuria), 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 impact on the numbers developing moderately increased albuminuria. 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 moderately increased albuminuria after 3 years on trandolapril (6%), compared to verapamil (11.9%), or placebo (10%). The HOPE and ADVANCE studies also showed a significant benefit in patients at high cardiovascular risk. 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 moderately increased albuminuric range, with drugs blocking the renin–angiotensin system seeming to be more effective.

Diabetes mellitus and the kidneyIn mainly European patients with type 1 diabetes, a meta-analysis has shown an adjusted risk reduction of more than 60% for the development of severely increased albuminuria comparing ACE inhibitors with placebo. The angiotensin-II receptor blocker (ARB) irbesartan has demonstrated a similar magnitude of effect in moderately increased albuminuric 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 severely increased albuminuria. 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. In addition, there are some data showing a return of albuminuria to pre-treatment levels following withdrawal of therapy, calling into question the durability of effect. There are no conclusive long-term data showing a positive benefit on hard end points such as mortality or ESRD.

Tertiary prevention

Studies in the early 1980s established that lowering blood pressure in hypertensive type 1 patients with severely elevated albuminuria 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 who had a blood pressure below 140/90 mmHg and severely elevated albuminuria 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. The ACCORD blood pressure trial investigated whether a systolic blood pressure of <120 mmHg vs <140 mmHg would be more reno-protective, but while there were fewer cases of severely elevated albuminuria there was no benefit in terms of GFR.

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 moderately and severely elevated albuminuric 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, GFR, 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 moderately and severely elevated albuminuria has proved to be clinically useful and has been incorporated into the latest classification of CKD. There is an increasing realisation that an elevated UAER is not an invariable finding in patients with diabetes and CKD. This is a particular feature of older people with type 2 diabetes, but has also been described in type 1. Because of this there has been a huge interest in exploring other biomarkers for diabetic kidney disease and there are promising data using proteomics and metabolomics suggesting improved predictive performance when combined with albuminuria. These methods are not yet available for routine clinical use.

UAER

UAER may be raised 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 moderately increased albuminuria 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 moderately increased albuminuria 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 moderately increased albuminuria is historically around 20% per annum, but this is lower in those commencing antihypertensive therapy or intensified insulin regimens (Table 21.10.1.2).

It is unusual to develop moderately increased albuminuria within the first 5 years of diabetes onset, but it can develop at any time thereafter, even after 40 years. Many patients with type 1 diabetes and moderately increased albuminuria will progress to severely elevated albuminuria unless treated; those with longer durations of diabetes before moderately increased albuminuria tend to progress more slowly. More recent prospective studies have shown that as many as 25% of type 1 moderately increased albuminuric patients may spontaneously regress to normoalbuminuria. Around 12.5% may oscillate between normoalbuminuria and moderately increased albuminuria 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. What seems clear, however, is that these patients are at lower risk of progressing to ESRD.

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 severely elevated albuminuria 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 moderately increased albuminuria is harder to estimate, although the UKPDS suggests that rates are similar to type 1 (Table 21.10.1.2). Up to 7% of newly diagnosed type 2 patients in the United Kingdom will have a urinary albumin concentration above 50 mg/litre, and 1% will be above 300 mg/litre. 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

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 severely elevated albuminuria 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 in 7 to 10 years. More recently, the rate of decline is 2–4 ml/min per year in patients with well-controlled systemic blood pressure, effectively delaying endstage renal disease by 15–20 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) or CKD-Epi 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 moderately elevated albuminuria 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 moderately elevated albuminuria 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 severely elevated albuminuria 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 precise prevalence of functionally significant renal artery stenosis is uncertain.

Whereas the vast majority of type 1 patients with moderately increased albuminuria 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 helpful as those with it are almost certain to have diabetic glomerulopathy and those without it much less so. Even so, there are few cases of specifically treatable glomerular disease in those with nondiabetic lesions, hence management is unlikely to be significantly different; although those with nonclassic lesions tend to have slower rates of decline of GFR and may be at lower risk of ESRD.

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 unusual clinical course such as rapidly deteriorating GFR, or the presence of features of other systemic diseases should prompt referral and investigation (Box 21.10.1.2). Current United Kingdom guidelines suggest expert review of all with an eGFR of less than 30 ml/min per 1.73m2.

Criteria for diagnosis

Diabetic nephropathy is a clinical diagnosis based upon the finding of albuminuria in a patient with diabetes and in whom there is no evidence of urinary infection. The definitions of moderate and severe elevations are shown in the table (Table 21.10.1.1). Current United Kingdom guidelines suggest confirming the diagnosis with one or two repeat tests over the subsequent 1 to 6 months (Fig. 21.10.1.3).

Fig. 21.10.1.3 Flowchart for diagnosis of moderately and severely elevated albuminuria.
NB: Assumes sterile urine throughout. Exclude infection when proteinuria first detected and at any time thereafter if a history of UTI.

Fig. 21.10.1.3
Flowchart for diagnosis of moderately and severely elevated albuminuria.

NB: Assumes sterile urine throughout. Exclude infection when proteinuria first detected and at any time thereafter if a history of UTI.

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 moderately and severely elevated albuminuria, 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 21.10.1.1.

The latest modification of the classification of chronic kidney disease has divided Stage 3 into 3a and 3b (eGFR 45–60 and 30–45 ml/min/1.73 m2 respectively). It also incorporates an assessment of albuminuria as it is now acknowledged that increased urine excretion of albumin represents an independent risk factor for cardiovascular disease. This goes some way to aligning the historical classification of diabetic and chronic kidney disease (Table 21.10.1.4). eGFR estimated from the MDRD equation consistently underestimates measured GFR in large diabetic cohorts, and it is not very accurate at values above 90 ml/min. The newer CKD-Epi equation has improved accuracy at higher values. However, as many newly diagnosed type 1 and type 2 patients have an elevated GFR, significant reductions over time may pass undetected.

Table 21.10.1.4 Cross-tabulation of latest classification of chronic kidney disease (CKD) and historical definition of diabetic kidney disease (DKD).

GFR stage, description and definition

Albuminuria stage, description and definition

A1 (Normal) <3.0 mg/mmol < 30 mg/g

A2 Moderate increase (microalbuminuria) <3.0–30 mg/mmol; < 30–299 mg/g

A3 Severe increase (macroalbuminuria) >30 mg/mmol; > 300 mg/g

G1 (Normal) >90 ml/min/1.73m2

At risk of DKD

Possible DKD (probable if DR)

Probable DKD (consider other causes albuminuria in type 2)

G2 (mild reduction) 60–89 ml/min/1.73m2

At risk of DKD

Possible DKD (probable if DR)

Probable DKD (consider other causes albuminuria in type 2)

G3a (mild-moderate reduction) 45–59 ml/min/1.73m2

Possible DKD (probable if DR)

Probable DKD (definite if DR)

DKD

G3b (moderate-severe reduction) 30–44 ml/min/1.73m2

Possible DKD (probable if DR)

Probable DKD (definite if DR)

DKD

G4 (severe reduction) 15–29 ml/min/1.73m2

Possible DKD (probable if DR)

Probable DKD (definite if DR)

DKD

G5 (kidney failure) <15–29 ml/min/1.73m2

Possible DKD (probable if DR)

Probable DKD (definite if DR)

DKD

DR, diabetic retinopathy.

Treatment

Glycaemic control and blood pressure

Diabetes mellitus and the kidneyThe 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 48 mmol/mol (6.5%) for type 1 and type 2 patients. The American Diabetes Association target is 53 mmol/mol (<7.0%) for both. Blood pressure targets are below 130/80 mmHg for patients with elevated albuminuria. Recent analyses suggest that values lower than this are of no benefit and may cause harm. 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 post myocardial infarction. Following publication of the OnTARGET and ALTITUDE trials, multiple blockade of the renin-angiotensin system is no longer recommended. Meta analysis has shown that although dual blockade appears to be more effective at reducing albuminuria, it is also associated with more adverse events, notably hyperkalaemia and acute kidney injury.

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 ≤ 48mmol/mol (≤ 6.5%) and <120/80 mmHg, respectively, suggesting that there may be little benefit for patients by 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 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 should be considered for all patients with an increased UAER (unless contraindicated) because of their high risk for cardiovascular disease. Lipid-lowering therapy should also be commenced for all diabetic patients with CKD.

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 160 moderately albuminuric 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 severely elevated albuminuria 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 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

Moderately albuminuric 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 severely elevated albuminuric patients with type 2 diabetes. Data from the FinnDiane and Pittsburgh Epidemiology Studies and Joslin Clinic cohorts also showed that the excess cardiovascular mortality associated with type 1 diabetes is confined to those patients who develop elevated albuminuria; normoalbuminuric individuals have a mortality risk indistinguishable from the background population.

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 severely increased albuminuria, and almost 20% for those with a serum creatinine above 175 µmol/litre or in endstage renal disease (Fig. 21.10.1.4), cardiovascular disease being the main cause of death. Pima Indians also show an increase in mortality with increasing ACR but 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. In a largely white Europid population in the UK, a reduced eGFR of <60 ml/min per 1.73m2 conferred a more than 3 -fold increased hazard ratio for cardiovascular mortality irrespective of albuminuria status.

Fig. 21.10.1.4 Annual transition rates and 95% CI through stages of nephropathy in 5097 newly diagnosed type 2 diabetic patients in the UKPDS. (Reproduced with permission).

Fig. 21.10.1.4
Annual transition rates and 95% CI through stages of nephropathy in 5097 newly diagnosed type 2 diabetic patients in the UKPDS. (Reproduced with permission).

Survival on dialysis remains worse for patients with diabetes compared to those without but they are improving; around 37% are alive after 5 years in American registries compared to 44% for hypertensive renal disease and 54% for glomerulonephritis. Overall survival for diabetic patients is best in those who have an early successful kidney transplant.

Diabetes mellitus and the kidneyAreas 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, based on the diagnostic flowchart shown in Fig. 21.10.1.3. Extrapolating the known effects of ACE inhibitors on a reduction of UAER to a possible prevention of severe albuminuria and thus endstage renal disease has led several authors to propose a potential cost benefit from the early use of these agents. However, there are no consistent data showing a benefit of these drugs in terms of prevention of moderately increased albuminuria in normoalbuminuric patients with normal or well controlled blood pressures.

Can glycaemic control reverse established nephropathy?

The DCCT was inconclusive, but data from clinic populations and following pancreas transplantation suggest benefit, at least in type 1 diabetes. The situation in type 2 is much less certain.

Why does intensive glycaemic control fail to completely prevent development of moderately increased albuminuria?

Glycaemia is one of many factors leading to nephropathy, so correction of this alone may not be enough. 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 and enable us to test its effectiveness.

Do drugs that block the renin–angiotensin system (RAAS) 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.

For those with severely elevated albuminuria and chronic kidney disease stages 3 and beyond, there is no doubt that renin–angiotensin system blocking drugs delay endstage renal disease. For moderately increased albuminuria there are no studies of sufficient power to confirm benefit on hard clinical endpoints such as mortality or endstage renal disease. Primary prevention of moderately increased albuminuria using RAAS blockade has only been shown in hypertensive type 2 patients or those at high cardiovascular risk.

Likely developments in the near future

Hyperglycaemia is thought to lead to nephropathy through several pathways, as outlined in Box 21.10.1.1. There are developments in most of these fields, with the following being studied in trials: pyridoxamine and other inhibitors of glycation; atrasentan and other endothelin inhibitors; allopurinol; antifibrotic agents; aldosterone antagonists; and inhibitors of inflammatory pathways.

Further reading

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American Diabetes Association. (2015). Executive summary: standards of medical care in diabetes – 2015. Diabetes Care, 38 suppl 1.Find this resource:

    Bilous R. (2008). Microvascular disease: what does the UKPDS tell us about diabetic nephropathy? Diabetic Med, 25 suppl 2, 25–29.Find this resource:

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    DCCT/EDIC Research Group. (2003). Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy. JAMA, 290, 2159–2167.Find this resource:

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