- Email: [email protected]
Diabetic nephropathy
SYSTEMIC DISEASE AND THE KIDNEY
Diabetic nephropathy
20e200 mg/24 hours) and usually occurs after 6e15 years of diabetes. Although hypertension per se is not a manifestation at this stage, a loss of nocturnal ‘dipping’ of blood pressure has been noted in this patient group and is thought to precede and predict the development of microalbuminuria. Although microalbuminuria is a marker of incipient nephropathy, not all patients will progress to overt nephropathy. Roughly 25% of patients will revert to normal albumin excretion, and 40% will remain microalbuminuric (Figure 1). The development of proteinuria (UAER >200 mg/24 hours) with established hypertension defines the onset of overt nephropathy. Subsequently, the rate of decline in renal function correlates with blood pressure, with the development of endstage renal failure occurring within a median of 7 years from the onset of overt nephropathy. In non-Caucasian populations, however, rates of development of microalbuminuria and proteinuria are higher than in Caucasian individuals, and the rate of progression of nephropathy may be faster.
AO Phillips
Abstract Diabetic nephropathy (DN) is a common complication of diabetes mellitus. It has a major impact on patient morbidity and mortality, and therefore a profound impact on the delivery of healthcare in this country. It affects more than one-third of patients with type 1 diabetes and an ever-increasing proportion of patients with type 2 diabetes, and is now the single most common cause of end-stage renal failure in Western countries. This article sets out to define the natural history of the disease and its significance in terms of patient morbidity and mortality. Therapeutic strategies are discussed with particular emphasis on the relative importance of glycaemic control, blood pressure treatment and blockade of the renineangiotensin system. In addition, guidelines are presented on screening, diagnosis and referral to specialist services.
How should the diagnosis be made? Keywords diabetic nephropathy; diagnosis; hypertension; referral
Urinalysis Establishing the diagnosis of microalbuminuria requires the demonstration of a persistent elevation in albumin excretion. It should be emphasized that fever, exercise, heart failure and poor glycaemic control are common factors that can cause transient microalbuminuria. While it is accepted that timed urine collection provides the gold standard for the detection of microalbuminuria by albumin excretion rates (AER), in practice this can be difficult to coordinate. As an alternative, screening can more simply be achieved by analysis of albumin concentration in untimed urine specimens. The influence of urine volume on albumin concentration in an untimed collection can be avoided by calculation of the albumin-to-creatinine ratio (ACR; albumin
guidelines; renineangiotensin
Diabetic nephropathy (DN) is now the commonest cause of renal failure requiring renal replacement therapy worldwide. In the UK, diabetes accounts for roughly one in five patients on dialysis. In the past, it was assumed that nephropathy was an uncommon complication of type 2 diabetes. However, the majority of patients with diabetic nephropathy have type 2 diabetes. This reflects the increased incidence and earlier onset of type 2 diabetes and also increased life expectancy due to the improved management of cardiovascular disease in this patient group.
Definition DN is a clinical syndrome characterized by persistent albuminuria (>300 mg/24 hours) on at least two occasions separated by 3e6 months. Patients invariably develop associated hypertension, which may be considered part of the syndrome.
Natural history of diabetic nephropathy highlighting the percentage of patients who are likely to progress through each stage
Clinical course
Normal albumin excretion
Epidemiological studies suggest that the natural history of nephropathy in both type 1 and type 2 diabetes is identical, with roughly 30e50% of patients developing microalbuminuria within 20 years of the onset of diabetes. Population-based studies suggest a prevalence of nephropathy of 5e10% at the time of diagnosis of type 2 diabetes, which presumably reflects a prolonged period of undetected hyperglycaemia. Traditionally, nephropathy is divided into two types based on the urinary albumin excretion rate (UAER): incipient and overt. Incipient nephropathy is manifest as microalbuminuria (UAER
~50% (2–4% per annum)
Microalbuminuria 20–30%
30%
Rising blood pressure and cardiovascular disease risk
Persistant microalbuminuria
40% Proteinuria
Renal failure AO Phillips BSc FRCP is a Professor in Nephrology and Honorary Consultant at the University of Cardiff School of Medicine, where he is Director of the Institute of Nephrology, UK. Competing interests: none declared.
MEDICINE 39:8
It is of note that only when patients develop overt nephropathy and proteinuria is a progressive decline in renal function inevitable
Figure 1
470
Ó 2011 Elsevier Ltd. All rights reserved.
SYSTEMIC DISEASE AND THE KIDNEY
(mg):creatinine (mmol)). The increase in proteinuria that may be associated with upright posture can be avoided by determining ACR in an early morning sample. Generally, the threshold for microalbuminuria is taken as an ACR more than 3.5 for women and more than 2.5 for men. The lower value in men reflects their higher muscle bulk, and subsequent higher creatinine generation. Screening recommendations are that all patients with type 1 diabetes diagnosed more than 5 years ago and over 12 years of age, and all patients with type 2 diabetes from diagnosis, should have annual urinalysis. Although many guidelines suggest the use of ACR, timed urine albumin excretion rate (AER) is also used and quoted in the definitions of albumin excretion and classification of diabetic nephropathy. However, systematic differences exist between urine ACR and AER, which may lead to differences in the classification of prevalent albuminuria states and their changes over time, so it is important to be consistent in the method used to determine serial albumin excretion.
be responsible for increased susceptibility. Although some studies suggest that the double deletion (DD) angiotensin-converting enzyme (ACE) genotype may be linked with the development of DN, this is not supported by all published reports. It appears likely that this genotype may be associated with a faster rate of disease progression, but is not in itself associated with disease susceptibility.
Therapeutic options (Figure 2) There is consensus that patients with DN who have developed persistent proteinuria will progress to end-stage renal failure, provided they survive the added cardiovascular risk burden associated with nephropathy. However, numerous studies have demonstrated that it is possible to delay the rate of progression. Hypertension There is a strong correlation between the degree of hypertension and the rate of progression of overt DN in both type 1 and type 2 diabetes. Furthermore, there is compelling evidence that lowering blood pressure reduces albuminuria and attenuates the rate of loss of glomerular filtration rate (GFR) in both type 1 and type 2 diabetes. A major question relates to the desired target blood pressure (BP). Current evidence would support a treatment goal of BP less than 125/75 mmHg in proteinuric states such as diabetic nephropathy, but the relationship between blood pressure and progression of renal disease is linear, with no evidence of a ‘safe threshold’, and this has contributed to the drive towards ever lower treatment targets. However, it is important to recall that many of the patients enrolled in trials assessing the value of lower blood pressure targets continued to show benefit from blood pressure values considerably higher than the ‘mean’ values achieved in the study population as a whole. Furthermore, among patients with coronary artery disease, which is highly prevalent in patients with diabetes and renal disease, there is a consistent relationship between cardiac events and diastolic pressure: a diastolic pressure less than 60 mmHg significantly increases the risk of cardiac events. It is, therefore, important to individualize blood pressure control in our patients, balancing the population/epidemiological evidence with each patient’s co-morbidity and the potential harmful/ adverse effects of multiple pharmacological interventions.
Who needs a biopsy? Generally, the diagnosis of DN is by clinical evaluation, providing a presumptive diagnosis and avoiding renal biopsy. However, renal biopsy is indicated if the clinical presentation is atypical, such as in patients with a short duration of diabetes (type 1), absence of retinopathy, nephrotic range proteinuria or microscopic haematuria, or who develop significant renal dysfunction in the absence of proteinuria.
Significance of nephropathy Although the prognosis of patients with DN has improved, there remains a 70e100-fold excess mortality compared with an otherwise matched normal population. Once renal replacement therapy is required, the patient with diabetes has an even worse prognosis. Morbidity as assessed by hospitalization is two to three times greater for diabetic patients with end-stage renal disease than for non-diabetic patients. Up to one-third of diabetic patients die within a year of starting dialysis and diabetic patients who receive a renal transplant continue to have a higher mortality rate than their nondiabetic counterparts. Significantly, however, the survival advantage conferred by transplantation, compared to dialysis, is significantly greater in diabetics than non-diabetics. The increase in mortality of diabetic patients with renal disease is in large part secondary to cardiovascular disease, the risk of which is increased at all stages of nephropathy and rises as nephropathy progresses.
Blockade of the renineangiotensin system One of the most important developments in the management of DN in the last 10 years has been the demonstration of the benefit (beyond blood pressure reduction) of blockade of the renineangiotensin system (RAS).1,2 In type 1 diabetes, there have been numerous studies demonstrating the beneficial effects of angiotensin-converting enzyme (ACE) inhibition at both the incipient and overt stages of nephropathy, which are independent of its effects on blood pressure reduction. In type 2 diabetes, the largest trials have been performed using angiotensin II receptor antagonists (ARB) rather than ACE inhibitors (ACEI).2,3 As with ACEI, these studies show benefit at both incipient and overt stages of nephropathy. Several small short-term studies in both type 1 and type 2 diabetes have demonstrated similar reductions in blood pressure and albumin excretion using ACEI or ARB, and it seems likely that the two classes of drug are equally effective. However, pending longer-term studies with harder end-points, many have a preference for ACEI in type 1 diabetes and ARB in type 2, although the evidence is not strong
Susceptibility The pattern of risk indicates that accumulation of exposure to diabetes is not sufficient to explain the development of clinically manifest kidney disease, and suggests that only a subset of patients are susceptible to renal complications. Hyperglycaemia is certainly an important contributor to susceptibility. However, although necessary, the metabolic abnormalities of diabetes are not sufficient for the development of clinical nephropathy. Familial clustering (in both type 1 and 2 diabetes) and the increased incidence in several different populations, including African-Americans, Native Americans, Polynesians and Indo-Asian immigrants in the UK, suggests a genetic basis for the risk of nephropathy. To date, however, no gene has been clearly shown to
MEDICINE 39:8
471
Ó 2011 Elsevier Ltd. All rights reserved.
SYSTEMIC DISEASE AND THE KIDNEY
Simplified algorithm for management of diabetic nephropathy Annual urinalysis
Urinalysis Type I – post-pubertal Type II – at presentation
Microalbuminuria Negative
Pharmacological blockade of RAS (ACEI/ARB)
Monitor renal function and urinary PCR Optimize blood pressure control
Monitor renal function and urinary PCR Optimize blood pressure control
Positive Fall in eGFR >15% during first 2 months
Yes
Referral nephrology
No CKD stage 1/2 PCR >100 mg/mmol no retinopathy
Yes
Referral nephrology
No No Fall in PCR Increase (AEI/ARB) consider dual blockade
Yes Monitor renal function and urinary PCR Optimize blood pressure control
Yes CKD stage 3
Referral nephrology
No
ACEI, ACE inhibitor; ARB, angiotensin II receptor blocker; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; PCR, protein:creatinine ratio; RAS, renin-angiotensin system.
Figure 2
inhibition of the actions of aldosterone, another key component of this hormonal axis. Studies in animal models have demonstrated that aldosterone can cause renal injury independent of angiotensin II. In addition, clinical studies have demonstrated that mineralocorticoid receptor blockade may exert an antialbuminuric effect in patients with (and without) diabetes. Add-on aldosterone blockade to existing use of ACEI may also constitute an additional therapeutic strategy to retard progression. Furthermore, there is some evidence to suggest that this approach may be at least as effective as the combination of ACEI and ARB, and may offer greater renoprotection.5 There is understandable concern about the risk of hyperkalaemia with this approach but in practice this has not been found to limit therapeutic benefit, although frequent monitoring is important.
enough to warrant a switch in those who are already receiving and tolerating one of the two classes of drugs. Although there is a large body of evidence supporting the use of these drugs, it is essential to monitor renal function and be aware of their adverse effects in the context of reno-vascular disease, which may co-exist with DN, particularly in type 2 diabetes. There is emerging evidence of added benefit for the reduction of blood pressure and proteinuria from combination therapy with both classes of drug. More recent data suggest that dual blockade of the RAS with both ACEI and ARB provides superior short-term renoprotection, independent of systemic blood pressure changes, in comparison to the use of ACEI alone, even in patient groups in which monotherapy with ACEI has achieved target blood pressure. When using dual blockade, particular care must be paid to the serum potassium concentration. It has been previously suggested, on the basis of earlier, relatively small studies, that inhibition of the RAS may prevent the development of incipient nephropathy, representing primary prevention of renal disease. However, the most recent reports suggest that this therapeutic approach has no beneficial effect on the development of microalbuminuria4 and should not be considered ‘routine clinical practice’ at the present time.
Glycaemic control In the prevention of DN, tight control of blood glucose is essential.6e8 There is good evidence, in both type 1 and type 2 diabetes, demonstrating that the lower the HbA1c, the lower the risk of developing nephropathy (both the development of microalbuminuria and its progression to overt proteinuria). Significantly, there is no threshold value for HbA1c below which benefit does not occur; the current recommended target is less than 6.5% (<48 mmol/mol). Glycaemic control also correlates with the rate of progression following the appearance of microalbuminuria. There is less evidence from intervention trials that
Inhibition of aldosterone Whilst much of the focus of research on the RAS has focused on ACEI and ARB, much less attention has been given to the effect of
MEDICINE 39:8
472
Ó 2011 Elsevier Ltd. All rights reserved.
SYSTEMIC DISEASE AND THE KIDNEY
strict glycaemic control delays progression of overt nephropathy, and it is likely that this reflects the masking effect of poorly controlled blood pressure. This emphasizes the importance of aggressive blood pressure management, which represents the first priority in the management of DN.
function and higher-than-average muscle mass. These limitations have contributed to the under-recognition of chronic renal disease, late referral to nephrologists, and inadvertent discrimination against women and the elderly. Recognition of this has led to the adoption of a formula-derived estimate of glomerular filtration rate (eGFR), routine reporting of which is now used throughout the UK (cross reference). It is recommended that diabetic patients with nephropathy and chronic kidney disease stage 3 (CKD3), or CKD1/2 and proteinuria in the absence of retinopathy, should be assessed by nephrology services. Changes to the GP contract, introduced in 2006 (GMS contract), which required remuneration to be dependent upon the generation of patient registers, based on a classification of the stages of renal disease, has highlighted the extent of undiagnosed renal impairment. This classification derives from the Kidney Disease Outcomes Quality Initiative (K/DOQI), in which classification of chronic renal disease is based on the GFR and has been accepted internationally.14 In the UK, guidelines have been produced and published based on the K/DOQI classification, which are designed to facilitate earlier recognition and appropriate timely referral of patients to specialist services. Patients with diabetic nephropathy constitute the largest single group of patients with renal disease, with very high morbidity and mortality, and are likely to derive particular benefit from these initiatives. A
Other therapeutic considerations Beyond these specific strategies it is likely that a multifactorial approach, which includes intensive lifestyle modification coupled with aggressive management of blood pressure, blood glucose and blood lipids, is the key to significant reduction in the rate of progression of diabetic nephropathy and associated cardiovascular disease. The role of smoking in diabetic nephropathy deserves special consideration. Smoking accelerates progression at all stages of diabetic nephropathy and is associated with higher mortality on dialysis, and smoking cessation advice should be standard practice for doctors reviewing patients with DN.
Monitoring our treatment strategies A common question, especially in terms of the dose of ACEI/ ARB, is ‘what is “adequate” therapy?’ The correlation between the amount of albuminuria and poor renal outcome has led to adoption of albuminuria as a surrogate end-point for monitoring treatment efficacy. With the emerging body of evidence that the degree of renoprotection, and indeed cardioprotection, is directly correlated to the reduction in albumin excretion achieved by a therapeutic intervention, we are now moving towards using changes in albuminuria as a measure of therapeutic benefit against which the dosage of ACEI/ARB may be titrated.9e11 Moreover, residual proteinuria is a strong predictor of adverse renal outcome in long-term studies of patients treated with either ACEI or ARB. This would suggest that, while proteinuria persists, intensification of our anti-proteinuria strategy by an increase in the dose of ACEI or ARB, or addition of aldosterone antagonism, followed by combination therapy with these agents should be encouraged provided the treatment is tolerated.
REFERENCES 1 Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensinconverting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993; 329: 1456e62. 2 Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor anagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345: 851e60. €chner-Mortensen J, Gomis R, Andersen S, 3 Parving HH, Lehnert H, Bro Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345: 870e8. 4 Bilous R, Chaturvedi N, Sjølie AK, et al. Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes. Ann Intern Med 2009; 151: 11e20. 5 Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol 2009; 20: 2641e50. 6 The Diabetes Control and Complications Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int 1995; 47: 1703e20. 7 The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long term complications in insulin dependant diabetes mellitus. N Engl J Med 1993; 329: 977e86. 8 The diabetes control and complications trial/epidemiology of diabetes intervention and complications research group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med 2000; 342: 381e9.
Who should be referred to a nephrologist? Despite the available evidence for therapy, the incidence of diabetic nephropathy and its poor prognosis remains a major problem. One factor implicated in this is the late referral of diabetic patients to specialist renal clinics with resulting sub-optimal clinical management of renal disease, so that many patients are not referred until complications of renal failure are already present. Many studies have clearly demonstrated that late referral is an independent risk factor for poor outcome among patients requiring renal replacement therapy. The timely transfer of care to specialist renal clinics is known to delay the progression of diabetic nephropathy and reduce patient morbidity.12,13 Serum creatinine is widely used as an indirect measure of renal function. However, its concentration is determined not only by the rate of renal excretion of creatinine but also by the rate of production, which is dependent on muscle mass. Serum creatinine may remain within the reference range in patients with low muscle mass and abnormal renal function; conversely, it may be above the upper limit of normal in individuals with normal renal
MEDICINE 39:8
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Ó 2011 Elsevier Ltd. All rights reserved.
SYSTEMIC DISEASE AND THE KIDNEY
9 Atkins RC, Briganti EM, Lewis JB, et al. Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy. Am J Kidney Dis 2005; 45: 281e7. 10 de Zeeuw D, Remuzzi G, Parving H-H, et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 2004; 110: 921e7. 11 de Zeeuw D, Remuzzi G, Parving H-H, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 2004; 65: 2309e20.
MEDICINE 39:8
12 Joint Speciality Committee of the Royal College of Physicians and Renal Association. The U.K. CKD guidelines, www.renal.org/ CKDguide/ckd.html; 2007. 13 Welsh Assembly Government. Designed to tackle renal disease in wales: Renal National Service Framework, http://www.wales.nhs.uk/ nsf; 2007. 14 National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39: S1e266.
474
Ó 2011 Elsevier Ltd. All rights reserved.
Diabetic nephropathy
20e200 mg/24 hours) and usually occurs after 6e15 years of diabetes. Although hypertension per se is not a manifestation at this stage, a loss of nocturnal ‘dipping’ of blood pressure has been noted in this patient group and is thought to precede and predict the development of microalbuminuria. Although microalbuminuria is a marker of incipient nephropathy, not all patients will progress to overt nephropathy. Roughly 25% of patients will revert to normal albumin excretion, and 40% will remain microalbuminuric (Figure 1). The development of proteinuria (UAER >200 mg/24 hours) with established hypertension defines the onset of overt nephropathy. Subsequently, the rate of decline in renal function correlates with blood pressure, with the development of endstage renal failure occurring within a median of 7 years from the onset of overt nephropathy. In non-Caucasian populations, however, rates of development of microalbuminuria and proteinuria are higher than in Caucasian individuals, and the rate of progression of nephropathy may be faster.
AO Phillips
Abstract Diabetic nephropathy (DN) is a common complication of diabetes mellitus. It has a major impact on patient morbidity and mortality, and therefore a profound impact on the delivery of healthcare in this country. It affects more than one-third of patients with type 1 diabetes and an ever-increasing proportion of patients with type 2 diabetes, and is now the single most common cause of end-stage renal failure in Western countries. This article sets out to define the natural history of the disease and its significance in terms of patient morbidity and mortality. Therapeutic strategies are discussed with particular emphasis on the relative importance of glycaemic control, blood pressure treatment and blockade of the renineangiotensin system. In addition, guidelines are presented on screening, diagnosis and referral to specialist services.
How should the diagnosis be made? Keywords diabetic nephropathy; diagnosis; hypertension; referral
Urinalysis Establishing the diagnosis of microalbuminuria requires the demonstration of a persistent elevation in albumin excretion. It should be emphasized that fever, exercise, heart failure and poor glycaemic control are common factors that can cause transient microalbuminuria. While it is accepted that timed urine collection provides the gold standard for the detection of microalbuminuria by albumin excretion rates (AER), in practice this can be difficult to coordinate. As an alternative, screening can more simply be achieved by analysis of albumin concentration in untimed urine specimens. The influence of urine volume on albumin concentration in an untimed collection can be avoided by calculation of the albumin-to-creatinine ratio (ACR; albumin
guidelines; renineangiotensin
Diabetic nephropathy (DN) is now the commonest cause of renal failure requiring renal replacement therapy worldwide. In the UK, diabetes accounts for roughly one in five patients on dialysis. In the past, it was assumed that nephropathy was an uncommon complication of type 2 diabetes. However, the majority of patients with diabetic nephropathy have type 2 diabetes. This reflects the increased incidence and earlier onset of type 2 diabetes and also increased life expectancy due to the improved management of cardiovascular disease in this patient group.
Definition DN is a clinical syndrome characterized by persistent albuminuria (>300 mg/24 hours) on at least two occasions separated by 3e6 months. Patients invariably develop associated hypertension, which may be considered part of the syndrome.
Natural history of diabetic nephropathy highlighting the percentage of patients who are likely to progress through each stage
Clinical course
Normal albumin excretion
Epidemiological studies suggest that the natural history of nephropathy in both type 1 and type 2 diabetes is identical, with roughly 30e50% of patients developing microalbuminuria within 20 years of the onset of diabetes. Population-based studies suggest a prevalence of nephropathy of 5e10% at the time of diagnosis of type 2 diabetes, which presumably reflects a prolonged period of undetected hyperglycaemia. Traditionally, nephropathy is divided into two types based on the urinary albumin excretion rate (UAER): incipient and overt. Incipient nephropathy is manifest as microalbuminuria (UAER
~50% (2–4% per annum)
Microalbuminuria 20–30%
30%
Rising blood pressure and cardiovascular disease risk
Persistant microalbuminuria
40% Proteinuria
Renal failure AO Phillips BSc FRCP is a Professor in Nephrology and Honorary Consultant at the University of Cardiff School of Medicine, where he is Director of the Institute of Nephrology, UK. Competing interests: none declared.
MEDICINE 39:8
It is of note that only when patients develop overt nephropathy and proteinuria is a progressive decline in renal function inevitable
Figure 1
470
Ó 2011 Elsevier Ltd. All rights reserved.
SYSTEMIC DISEASE AND THE KIDNEY
(mg):creatinine (mmol)). The increase in proteinuria that may be associated with upright posture can be avoided by determining ACR in an early morning sample. Generally, the threshold for microalbuminuria is taken as an ACR more than 3.5 for women and more than 2.5 for men. The lower value in men reflects their higher muscle bulk, and subsequent higher creatinine generation. Screening recommendations are that all patients with type 1 diabetes diagnosed more than 5 years ago and over 12 years of age, and all patients with type 2 diabetes from diagnosis, should have annual urinalysis. Although many guidelines suggest the use of ACR, timed urine albumin excretion rate (AER) is also used and quoted in the definitions of albumin excretion and classification of diabetic nephropathy. However, systematic differences exist between urine ACR and AER, which may lead to differences in the classification of prevalent albuminuria states and their changes over time, so it is important to be consistent in the method used to determine serial albumin excretion.
be responsible for increased susceptibility. Although some studies suggest that the double deletion (DD) angiotensin-converting enzyme (ACE) genotype may be linked with the development of DN, this is not supported by all published reports. It appears likely that this genotype may be associated with a faster rate of disease progression, but is not in itself associated with disease susceptibility.
Therapeutic options (Figure 2) There is consensus that patients with DN who have developed persistent proteinuria will progress to end-stage renal failure, provided they survive the added cardiovascular risk burden associated with nephropathy. However, numerous studies have demonstrated that it is possible to delay the rate of progression. Hypertension There is a strong correlation between the degree of hypertension and the rate of progression of overt DN in both type 1 and type 2 diabetes. Furthermore, there is compelling evidence that lowering blood pressure reduces albuminuria and attenuates the rate of loss of glomerular filtration rate (GFR) in both type 1 and type 2 diabetes. A major question relates to the desired target blood pressure (BP). Current evidence would support a treatment goal of BP less than 125/75 mmHg in proteinuric states such as diabetic nephropathy, but the relationship between blood pressure and progression of renal disease is linear, with no evidence of a ‘safe threshold’, and this has contributed to the drive towards ever lower treatment targets. However, it is important to recall that many of the patients enrolled in trials assessing the value of lower blood pressure targets continued to show benefit from blood pressure values considerably higher than the ‘mean’ values achieved in the study population as a whole. Furthermore, among patients with coronary artery disease, which is highly prevalent in patients with diabetes and renal disease, there is a consistent relationship between cardiac events and diastolic pressure: a diastolic pressure less than 60 mmHg significantly increases the risk of cardiac events. It is, therefore, important to individualize blood pressure control in our patients, balancing the population/epidemiological evidence with each patient’s co-morbidity and the potential harmful/ adverse effects of multiple pharmacological interventions.
Who needs a biopsy? Generally, the diagnosis of DN is by clinical evaluation, providing a presumptive diagnosis and avoiding renal biopsy. However, renal biopsy is indicated if the clinical presentation is atypical, such as in patients with a short duration of diabetes (type 1), absence of retinopathy, nephrotic range proteinuria or microscopic haematuria, or who develop significant renal dysfunction in the absence of proteinuria.
Significance of nephropathy Although the prognosis of patients with DN has improved, there remains a 70e100-fold excess mortality compared with an otherwise matched normal population. Once renal replacement therapy is required, the patient with diabetes has an even worse prognosis. Morbidity as assessed by hospitalization is two to three times greater for diabetic patients with end-stage renal disease than for non-diabetic patients. Up to one-third of diabetic patients die within a year of starting dialysis and diabetic patients who receive a renal transplant continue to have a higher mortality rate than their nondiabetic counterparts. Significantly, however, the survival advantage conferred by transplantation, compared to dialysis, is significantly greater in diabetics than non-diabetics. The increase in mortality of diabetic patients with renal disease is in large part secondary to cardiovascular disease, the risk of which is increased at all stages of nephropathy and rises as nephropathy progresses.
Blockade of the renineangiotensin system One of the most important developments in the management of DN in the last 10 years has been the demonstration of the benefit (beyond blood pressure reduction) of blockade of the renineangiotensin system (RAS).1,2 In type 1 diabetes, there have been numerous studies demonstrating the beneficial effects of angiotensin-converting enzyme (ACE) inhibition at both the incipient and overt stages of nephropathy, which are independent of its effects on blood pressure reduction. In type 2 diabetes, the largest trials have been performed using angiotensin II receptor antagonists (ARB) rather than ACE inhibitors (ACEI).2,3 As with ACEI, these studies show benefit at both incipient and overt stages of nephropathy. Several small short-term studies in both type 1 and type 2 diabetes have demonstrated similar reductions in blood pressure and albumin excretion using ACEI or ARB, and it seems likely that the two classes of drug are equally effective. However, pending longer-term studies with harder end-points, many have a preference for ACEI in type 1 diabetes and ARB in type 2, although the evidence is not strong
Susceptibility The pattern of risk indicates that accumulation of exposure to diabetes is not sufficient to explain the development of clinically manifest kidney disease, and suggests that only a subset of patients are susceptible to renal complications. Hyperglycaemia is certainly an important contributor to susceptibility. However, although necessary, the metabolic abnormalities of diabetes are not sufficient for the development of clinical nephropathy. Familial clustering (in both type 1 and 2 diabetes) and the increased incidence in several different populations, including African-Americans, Native Americans, Polynesians and Indo-Asian immigrants in the UK, suggests a genetic basis for the risk of nephropathy. To date, however, no gene has been clearly shown to
MEDICINE 39:8
471
Ó 2011 Elsevier Ltd. All rights reserved.
SYSTEMIC DISEASE AND THE KIDNEY
Simplified algorithm for management of diabetic nephropathy Annual urinalysis
Urinalysis Type I – post-pubertal Type II – at presentation
Microalbuminuria Negative
Pharmacological blockade of RAS (ACEI/ARB)
Monitor renal function and urinary PCR Optimize blood pressure control
Monitor renal function and urinary PCR Optimize blood pressure control
Positive Fall in eGFR >15% during first 2 months
Yes
Referral nephrology
No CKD stage 1/2 PCR >100 mg/mmol no retinopathy
Yes
Referral nephrology
No No Fall in PCR Increase (AEI/ARB) consider dual blockade
Yes Monitor renal function and urinary PCR Optimize blood pressure control
Yes CKD stage 3
Referral nephrology
No
ACEI, ACE inhibitor; ARB, angiotensin II receptor blocker; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; PCR, protein:creatinine ratio; RAS, renin-angiotensin system.
Figure 2
inhibition of the actions of aldosterone, another key component of this hormonal axis. Studies in animal models have demonstrated that aldosterone can cause renal injury independent of angiotensin II. In addition, clinical studies have demonstrated that mineralocorticoid receptor blockade may exert an antialbuminuric effect in patients with (and without) diabetes. Add-on aldosterone blockade to existing use of ACEI may also constitute an additional therapeutic strategy to retard progression. Furthermore, there is some evidence to suggest that this approach may be at least as effective as the combination of ACEI and ARB, and may offer greater renoprotection.5 There is understandable concern about the risk of hyperkalaemia with this approach but in practice this has not been found to limit therapeutic benefit, although frequent monitoring is important.
enough to warrant a switch in those who are already receiving and tolerating one of the two classes of drugs. Although there is a large body of evidence supporting the use of these drugs, it is essential to monitor renal function and be aware of their adverse effects in the context of reno-vascular disease, which may co-exist with DN, particularly in type 2 diabetes. There is emerging evidence of added benefit for the reduction of blood pressure and proteinuria from combination therapy with both classes of drug. More recent data suggest that dual blockade of the RAS with both ACEI and ARB provides superior short-term renoprotection, independent of systemic blood pressure changes, in comparison to the use of ACEI alone, even in patient groups in which monotherapy with ACEI has achieved target blood pressure. When using dual blockade, particular care must be paid to the serum potassium concentration. It has been previously suggested, on the basis of earlier, relatively small studies, that inhibition of the RAS may prevent the development of incipient nephropathy, representing primary prevention of renal disease. However, the most recent reports suggest that this therapeutic approach has no beneficial effect on the development of microalbuminuria4 and should not be considered ‘routine clinical practice’ at the present time.
Glycaemic control In the prevention of DN, tight control of blood glucose is essential.6e8 There is good evidence, in both type 1 and type 2 diabetes, demonstrating that the lower the HbA1c, the lower the risk of developing nephropathy (both the development of microalbuminuria and its progression to overt proteinuria). Significantly, there is no threshold value for HbA1c below which benefit does not occur; the current recommended target is less than 6.5% (<48 mmol/mol). Glycaemic control also correlates with the rate of progression following the appearance of microalbuminuria. There is less evidence from intervention trials that
Inhibition of aldosterone Whilst much of the focus of research on the RAS has focused on ACEI and ARB, much less attention has been given to the effect of
MEDICINE 39:8
472
Ó 2011 Elsevier Ltd. All rights reserved.
SYSTEMIC DISEASE AND THE KIDNEY
strict glycaemic control delays progression of overt nephropathy, and it is likely that this reflects the masking effect of poorly controlled blood pressure. This emphasizes the importance of aggressive blood pressure management, which represents the first priority in the management of DN.
function and higher-than-average muscle mass. These limitations have contributed to the under-recognition of chronic renal disease, late referral to nephrologists, and inadvertent discrimination against women and the elderly. Recognition of this has led to the adoption of a formula-derived estimate of glomerular filtration rate (eGFR), routine reporting of which is now used throughout the UK (cross reference). It is recommended that diabetic patients with nephropathy and chronic kidney disease stage 3 (CKD3), or CKD1/2 and proteinuria in the absence of retinopathy, should be assessed by nephrology services. Changes to the GP contract, introduced in 2006 (GMS contract), which required remuneration to be dependent upon the generation of patient registers, based on a classification of the stages of renal disease, has highlighted the extent of undiagnosed renal impairment. This classification derives from the Kidney Disease Outcomes Quality Initiative (K/DOQI), in which classification of chronic renal disease is based on the GFR and has been accepted internationally.14 In the UK, guidelines have been produced and published based on the K/DOQI classification, which are designed to facilitate earlier recognition and appropriate timely referral of patients to specialist services. Patients with diabetic nephropathy constitute the largest single group of patients with renal disease, with very high morbidity and mortality, and are likely to derive particular benefit from these initiatives. A
Other therapeutic considerations Beyond these specific strategies it is likely that a multifactorial approach, which includes intensive lifestyle modification coupled with aggressive management of blood pressure, blood glucose and blood lipids, is the key to significant reduction in the rate of progression of diabetic nephropathy and associated cardiovascular disease. The role of smoking in diabetic nephropathy deserves special consideration. Smoking accelerates progression at all stages of diabetic nephropathy and is associated with higher mortality on dialysis, and smoking cessation advice should be standard practice for doctors reviewing patients with DN.
Monitoring our treatment strategies A common question, especially in terms of the dose of ACEI/ ARB, is ‘what is “adequate” therapy?’ The correlation between the amount of albuminuria and poor renal outcome has led to adoption of albuminuria as a surrogate end-point for monitoring treatment efficacy. With the emerging body of evidence that the degree of renoprotection, and indeed cardioprotection, is directly correlated to the reduction in albumin excretion achieved by a therapeutic intervention, we are now moving towards using changes in albuminuria as a measure of therapeutic benefit against which the dosage of ACEI/ARB may be titrated.9e11 Moreover, residual proteinuria is a strong predictor of adverse renal outcome in long-term studies of patients treated with either ACEI or ARB. This would suggest that, while proteinuria persists, intensification of our anti-proteinuria strategy by an increase in the dose of ACEI or ARB, or addition of aldosterone antagonism, followed by combination therapy with these agents should be encouraged provided the treatment is tolerated.
REFERENCES 1 Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensinconverting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993; 329: 1456e62. 2 Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor anagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345: 851e60. €chner-Mortensen J, Gomis R, Andersen S, 3 Parving HH, Lehnert H, Bro Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345: 870e8. 4 Bilous R, Chaturvedi N, Sjølie AK, et al. Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes. Ann Intern Med 2009; 151: 11e20. 5 Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol 2009; 20: 2641e50. 6 The Diabetes Control and Complications Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int 1995; 47: 1703e20. 7 The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long term complications in insulin dependant diabetes mellitus. N Engl J Med 1993; 329: 977e86. 8 The diabetes control and complications trial/epidemiology of diabetes intervention and complications research group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med 2000; 342: 381e9.
Who should be referred to a nephrologist? Despite the available evidence for therapy, the incidence of diabetic nephropathy and its poor prognosis remains a major problem. One factor implicated in this is the late referral of diabetic patients to specialist renal clinics with resulting sub-optimal clinical management of renal disease, so that many patients are not referred until complications of renal failure are already present. Many studies have clearly demonstrated that late referral is an independent risk factor for poor outcome among patients requiring renal replacement therapy. The timely transfer of care to specialist renal clinics is known to delay the progression of diabetic nephropathy and reduce patient morbidity.12,13 Serum creatinine is widely used as an indirect measure of renal function. However, its concentration is determined not only by the rate of renal excretion of creatinine but also by the rate of production, which is dependent on muscle mass. Serum creatinine may remain within the reference range in patients with low muscle mass and abnormal renal function; conversely, it may be above the upper limit of normal in individuals with normal renal
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9 Atkins RC, Briganti EM, Lewis JB, et al. Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy. Am J Kidney Dis 2005; 45: 281e7. 10 de Zeeuw D, Remuzzi G, Parving H-H, et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 2004; 110: 921e7. 11 de Zeeuw D, Remuzzi G, Parving H-H, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 2004; 65: 2309e20.
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12 Joint Speciality Committee of the Royal College of Physicians and Renal Association. The U.K. CKD guidelines, www.renal.org/ CKDguide/ckd.html; 2007. 13 Welsh Assembly Government. Designed to tackle renal disease in wales: Renal National Service Framework, http://www.wales.nhs.uk/ nsf; 2007. 14 National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39: S1e266.
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