Prevention and management of Nephropathy
Diabetic nephropathy is one of the most common diabetes complications, and is the leading cause of renal replacement therapy in the Western world. Diabetic nephropathy is also associated with a markedly increased risk of cardiovascular morbidity and mortality. To decrease these risks, prevention and adequate management of diabetic nephropathy is of utmost importance. In order to detect the presence and progression of diabetic nephropathy, screening for albuminuria and glomerular filtration rate should be performed on a regular basis. Good glycaemic control and normotension are the corner- stones of both prevention and management of diabetic nephropathy. As the cause of diabetic nephropathy is multifactorial, treatment should also be multifactorial, including cardiorenal protection with a healthy lifestyle, avoidance of smoking, and, in addition, statin therapy and aspirin in high risk subjects.
Prevention of Nephropathy
The key in prevention of diabetic nephropathy is optimized glucose control and blood pressure treatment, in order to reduce the risk of development and to slow progression of nephropathy. It is also of importance to screen for albuminuria and impaired renal function in people with diabetes to identify individuals at risk.
Screening for Chronic Kidney Disease
Screening for albuminuria is recommended yearly, e.g. with the albumin-to-creatinine ratio from spot urine. In type 2 diabetes the screening should be initiated at the time of diagnosis, and in type 1 diabetes five years after diagnosis. Positive test results should be confirmed before classifying the person. In addition, screening for creatinine, and based on this, calculation of the estimated glomerular filtration rate (eGFR) should be performed yearly in all subjects with diabetes. Non-albuminuric renal impairment is common, especially in type 2 diabetes, and is also associated with increased cardiovascular morbidity and mortality . Reduction in eGFR identifies subjects at a later stage of kidney disease, so although not perfect, albuminuria remains the best marker to detect subjects at an early stage of the disease process.
There is clear evidence that improved glycaemic control lowers the risk of developing microvascular diabetes complications, including diabetic nephropathy. In type 1 diabetes, the DCCT Study showed that intensive compared with conventional insulin therapy resulted in a 39% reduction in the incidence of microalbuminuria and a 54% reduction in the incidence of overt nephropathy. The effect has persisted after the study closeout . Similar findings were reported from the UKPDS Study of newly diagnosed people with type 2 diabetes . More recently, concerns have been raised towards the increased risk of hypoglycaemia and excess mortality when targeting near normal HbA1c. Thus, the current guidelines suggest targeting an HbA1c of around 52 mmol/mol (7.0%) in individuals with diabetes. Less stringent goals can be adapted if the subject has a history of severe hypoglycaemia, cardiovascular disease, other co-morbidities, or short life expectancy .
There is a strong relationship between higher blood pressure levels and decreased kidney function in diabetes. If blood pressure exceeds 140/80-85 mmHg in people with diabetes, antihypertensive medication should be initiated. The agent of choice is an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin receptor blocker (ARB) as first-line treatment, titrated to the maximum tolerated dose . These agents not only lower blood pressure, but also have renoprotective as well as cardioprotective effects. Usually more than one antihypertensive agent is needed to meet the target blood pressure of <140/80-85 mmHg . Dual therapy of ACE-I and ARB is not recommended due to increased adverse effects, and the combination does not provide additional cardiovascular benefit. Diuretics, calcium channel blockers, or β-blockers are the preferred agents to be used in combination with renin-angiotensin blockade.
Studies on normotensive subjects (blood pressure <130-135/80-85 mmHg) without microalbuminuria have shown no benefit of ACE-I or ARBs in prevention of microalbuminuria, and thus are not recommended for normotensive subjects without albuminuria .
Management of Nephropathy
The management of nephropathy in diabetes should be multifaceted, advocating a healthy lifestyle and targeting all the individual renal and cardiovascular risk factors. The goal of the management is to reduce the risk of renal disease progression, as well as the risk of cardiovascular morbidities.
Regarding glycaemic control, the evidence for renoprotection of good glycaemic control is far stronger in the early stages of nephropathy, especially in the prevention of microalbuminuria. There is, however, supporting evidence to reach recommended HbA1c targets also in subjects with chronic kidney disease .
In individuals with albuminuria, usage of an ACE-I or ARB is recommended even though the person is normotensive ,, thereby slowing the progression of renal disease and reducing the risk of end-stage renal disease. The benefits of ACE-I and ARBs increase as the levels of albuminuria rise.
As in the prevention of nephropathy, blood pressure treatment is essential also in the later stages of nephropathy to reduce the risk of progression. The target blood pressure in subjects with diabetes and chronic kidney disease is <130/80 mmHg . Lowering of the systolic blood pressure even further might be of benefit, especially for subjects with high levels of albuminuria, but levels below 110 mmHg should, however, be avoided . The agents at firsthand are ACE-I or ARBs, and these can be used at all stages of CKD with appropriate monitoring of renal function . In order to reach target blood pressure levels, combination therapy is usually needed, preferably with a diuretic .
Dietary Protein Intake
Protein intake might have an effect on progression of nephropathy and high-protein diets should be avoided. The optimal amount of protein intake is, however, debated. The American Diabetes Association does not recommend restricting protein intake below usual intake, but recognizes that some subjects with advancing kidney disease might benefit from protein restriction . The guidelines of the National Kidney Foundation, on the other hand, recommend protein restriction to less than 0.8 g/kg bodyweight daily .
Cardiovascular Risk Management
Diabetic nephropathy is associated with an increased risk of cardiovascular morbidity as well as with an early mortality, mainly from cardiovascular causes. This highlights the importance of cardiovascular risk management in subjects with diabetic nephropathy, to improve overall survival of these subjects. Chronic kidney disease and cardiovascular disease share some of the same risk factors, and intensified multifactorial intervention reduces both micro- and macrovascular complications in people with type 2 diabetes . In cardiovascular risk management it is, therefore, important in addition to optimizing glycaemic control and blood pressure, to adapt a multifaceted approach, targeting all the individual risk factors.
Lifestyle. Smoking cessation should be advised in all subjects with diabetic nephropathy. This might have an effect on reduction of albuminuria, in addition to the well-known reduction in cardiovascular risk . In addition, exercise, weight control, and a healthy diet, as recommended for the general population, are also beneficial for subjects with diabetes . A recent study showed that a healthier diet rich in fruits and vegetables, with moderate alcohol consumption, has renoprotective effects in people with type 2 diabetes .
Antiplatelet therapy. Low-dose aspirin therapy (75-162 mg daily) should be initiated as primary prevention in all individuals with diabetic nephropathy, since they are at a markedly increased cardiovascular risk (10-year risk >10%) . Statins. Statin therapy is recommended in all subjects aged >40 years with diabetic nephropathy in order to prevent cardiovascular events . In subjects <40 years, statin therapy should be considered on an individual basis taking into account the cardiovascular risk, adverse effects of the drug and patient preference . The initiation of statins should be avoided in subjects on haemodialysis due to lack of evidence of a favourable effect of statins in this group of subjects . In subjects with nephropathy, the treatment goal with statins is LDL <2.6 mmol/l. Lowering LDL to <1.8 mmol/l might have added benefit and can be considered in high-risk subjects ,. In case of difficulties in reaching targets, an LDL reduction of 30% can be considered a sufficient goal ,.
Changes to Therapy as Renal Function Declines
When renal function starts to decline (eGFR<60 ml/min), potential complications of chronic kidney disease should be recognized. This includes consideration of dose adjustment of medications that are excreted by the kidneys. It is also important to take into account that with declining renal function, the risk of hypoglycaemia increases. Metformin therapy is also associated with an increased risk of lactic acidosis and caution is, thus, recommended in persons with chronic kidney disease. There are, however, no uniform criteria at what eGFR level to withdraw or reduce metformin.The American Diabetes Association recommend to withdraw metformin when creatinine is >135 μmol/l in men and >110 μmol/l in women .
Insulin can be used at all stages of CKD, but dose adjustments are often needed due to increased risk of hypoglycaemia. Dose adjustments and/or withdrawal are needed also for most other glucose lowering medications, and also for other medication frequently used in diabetes (e.g. ACE-I/ARB, diuretics).
Monitoring in CKD
When eGFR declines to <60 ml/min, monitoring of eGFR every 6 months is advised. In addition haemoglobin, electrolytes, calcium, phosphate, parathyroid hormone, and bicarbonate should be measured at least yearly. With further decline in renal function (eGFR <45 ml/min), eGFR should be monitored every 3 months and the other parameters every 3 to 6 months. In addition, sufficient vitamin D intake should be assured and bone density testing considered.
Referral to Nephrology
Since diabetes is a common condition, non-diabetic kidney diseases may coexist. Referral to a nephrologist should be considered if there is uncertainty of the kidney disease aetiology (i.e. short duration of diabetes, absence of retinopathy, heavy proteinuria, or rapid disease progression). Referral to a nephrologist is appropriate at the latest when advanced kidney disease is present (eGFR <30 ml/min).
Table 1 : Prevention and Management of Nephropathy
|Glucose control||HbA1c target ≤ 52 mmol/mol (7.0%). Less stringent goals if severe hypoglycaemia, cardiovascular disease or other co-morbidities, or short life expectancy.||HbA1c target ≤ 52 mmol/mol (7.0%). Consider dose adjustments of glucose medication when eGFR declines.|
|Blood pressure||Anti-hypertensive treatment in all subjects if blood pressure >140/80-85 mmHg, or if albuminuria present. Target <140/80-85 mmHg.||Anti-hypertensive treatment in all subjects. Target <130/80 mmHg. Consider dose adjustments of medication when eGFR declines.|
|ACE-I/ARBs||In all subjects with blood pressure >140/80-85 mmHg and/or albuminuria.||In all subjects, even if normotensive.|
|Protein intake||-||Avoid high-protein intake.|
Table 2 : Cardiovascular risk management
|Lifestyle||-||Smoking cessation. Exercise, weight control, healthy diet, as for the general population. Avoid excess alcohol consumption.|
|Antiplatelet therapy||-||Low-dose aspirin therapy (75-162 mg) daily in all subjects.|
|Statins||-||Statin therapy in all persons >40 years. In persons <40 years, statins on individual basis. Avoid initiation in people on haemodialysis. Treatment goal LDL <2.6 mmol/l (<1.8 mmol/l is an option in high-risk subjects).|
^ Foster, M.C., et al., Cross-classification of microalbuminuria and reduced glomerular filtration rate: associations between cardiovascular disease risk factors and clinical outcomes. Arch Intern Med, 2007. 167(13): p. 1386-92.
^ de Boer, I.H., Kidney disease and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care, 2014. 37(1): p. 24-30.
^ Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet, 1998. 352(9131): p. 837-53.
^ American Diabetes Association, Standards of medical care in diabetes--2014. Diabetes Care, 2014. 37 Suppl 1: p. S14-80.
^ National Kidney Foundation, KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis, 2007. 49(2 Suppl 2): p. S12-154.
^ Mancia, G., et al., 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens, 2013. 31(7): p. 1281-357.
^ National Kidney Foundation, KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 Update. Am J Kidney Dis, 2012. 60(5): p. 850-86.
^ Gaede, P., et al., Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med, 2003. 348(5): p. 383-93.
^ Voulgari, C., N. Katsilambros, and N. Tentolouris, Smoking cessation predicts amelioration of microalbuminuria in newly diagnosed type 2 diabetes mellitus: a 1-year prospective study. Metabolism, 2011. 60(10): p. 1456-64.
^ Dunkler, D., et al., Diet and kidney disease in high-risk individuals with type 2 diabetes mellitus. JAMA Intern Med, 2013. 173(18): p. 1682-92.
^ Stone, N.J., et al., 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation, 2014. 129(25 Suppl 2): p. S1-45.
^ Catapano, A.L., et al., ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis, 2011. 217 Suppl 1: p. S1-44.
^ Lalau, J.D., et al., Metformin and other antidiabetic agents in renal failure patients. Kidney Int, 2014.