Module 205.3 en

Editor's Notes

1. 30% of people with type 2 diabetes may have kidney disease that is unrelated to diabetes, that is their eGFR is declining but they do not have significant microalbuminuria or proteinuria. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. (2008). Canadian Diabetes Association 2008 Clinical Practice Guidelines for the prevention and management of diabetes in Canada. Can J Diabetes,32 (Suppl 1): S126-33.
2. The glomerular function is affected by changes such as mesangial expansion, basement membrane thickening and extensive scarring. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. (2008). Canadian Diabetes Association 2008 Clinical Practice Guidelines for the prevention and management of diabetes in Canada. Can J Diabetes, 32 (Suppl 1): S126-33.
3. There are a number of risk factors that make people with diabetes more prone to renal disease, including those listed in the slide. Poor glycaemic control – there is evidence for this from the DCCT and UKPDS and their respective follow-up studies. People with hypertension or a family history of hypertension are more likely to develop renal disease than people without a family history of hypertension or renal disease. People of certain ethnicities are more likely to develop the disease, such as Afro-Caribbean people, Pacific Islanders and Pima Indians. Not surprisingly, the longer you have diabetes, the higher the risk of renal disease. Tobacco smoking damages the blood vessels and endothelial cells and induces hyperglycaemia, increasing the risk of renal disease.
4. Due to improvements in blood glucose control and blood pressure control, the incidence of renal disease in people with type 1 diabetes has been steadily decreasing over the last 35 years. One study reported an overall incidence of 2.2% after 20 years of diabetes and 7.8% after 30 years. Finne P., Reunanen A., Stenman S., Groop P.H., Gronhagen-Riska C. (2005). Incidence of end-stage renal disease in patients with type 1 diabetes. JAMA. 294(14): 1782-7. However most do not report incidence as low as this. DCCT/EDIC report a cumulative incidence of 9% after 30 years in the DCCT intensive therapy group. DCCT/EDIC Research group. (2009). Modern day clinical course of type 1 diabetes mellitus after 30 years’ duration. Arch Intern Med., 169(14), 1307-16.
5. Microalbuminuria usually develops towards the end of the first decade (in type 1 diabetes). And if this is left untreated, overt diabetic nephropathy and subsequent renal failure will ensue. Management of blood glucose levels and blood pressure will slow not prevent progression of the disease at this stage.
6. The glomerular capillary wall normally limits the filtration of macromolecules by size selective properties. However, when the kidney is damaged, one of the warning signs is that its filtering system is affected and molecules like protein are leaked into the urine. One of these proteins is called albumin. If small amounts of albumin are leaked this is called microalbuminuria. Levels for microalbuminuria are 30-300 mg per day. And the albumin creatinine ratio (ACR) is 2.5-25 mg/mmol (men) and 3.5-35 mg/mmol (women). Once more than 300 mg per day of albumin is leaked and the ACR is more than 25 mg/mmol in men and 35 mg/mmol in women in ACR, this is called macroalbuminuria. Macroalbuminuria just means that more protein is leaked by the kidney than in microalbuminuria. Some countries have slightly different levels for microalbuminuria. IDF Clinical Guidelines Task Force. (2005). Global Guideline for Type 2 Diabetes. Brussels: International Diabetes Federation.
7. Particularly at levels less than 70 mg/day, microalbuminuria can be transient. If a person has low levels of microalbuminuria, it is important to take into consideration some factors that may affect albumin levels – such as those listed on the slide. If any of these are present, another test will have to be carried out at another time.
8. Urinalysis: Results of 2+ using dipstick testing confirms that the person has dipstick positive proteinuria or macroalbuminuria. It does NOT confirm diabetic nephropathy. There are many causes of proteinuria. 24 Hour Urine Collection: The 24-hour urine collection is the gold standard; however, it has several disadvantages such as the risk that a urine specimen may be discarded making the test inaccurate. Other forms of assessment of kidney function are generally used unless you are trying to quantify grams of protein in someone with established disease. Morning Spot Urine or Albumin to Creatinine Ratio: The most common tests ordered are either the morning spot urine or an albumin to creatinine (ACR) ratio. The ACR ratio is generally preferred because the effect of volume can be avoided entirely by calculation of the ACR in an untimed urine specimen. ADA and others recommend normal values be <2.5mM for men and <2.8mM for women, IDF states <2.5mM for men and <3.5mM for women. (ADA 2010, IDF 2005) Estimated Glomerular Filtration Rate (eGFR): eGFR indicates how well the kidneys are functioning. To calculate the eGFR the serum creatinine must be measured first and this measurement used to estimate the eGFR. If eGFR falls below 30 ml/min, refer to a nephrologist for a thorough assessment. Renal function should be assessed annually. (CDA 2008)
9. Studies have documented that the early detection of microalbuminuria is currently the best way to slow the progression of diabetic nephropathy. In type 1 diabetes, microalbuminuria is a sign of increased risk for End Stage Renal Disease (ESRD). In type 2 diabetes, it may even be present at diagnosis and indicates increased risk for a vascular event. People with type 2 diabetes and microalbuminuria have a 3-4-fold increased risk of a macrovascular event. Dinneen, S.F., Gerstein, H.C. (1997). The association of microalbuminuria and mortality in non-insulin-dependent diabetes mellitus. A systematic overview of the literature. Arch Intern Med., 157, 1413–1418. Once patients have microalbuminuria, intensive interventions targeting all cardiovascular risk factors such as improving control and treatment with an anti-hypertensive medication should be undertaken. Gaede, P., Lund-Andersen, H., Parving, H., Pedersen, O. (2008). Effect of a multifactorial intervention on mortailty in type 2 diabetes. NEJM, 358(6),580-591.
10. Most people in the DCCT had normal albumin excretion at baseline. In the ~76 with microalbuminuria at entry, there was NO benefit of intensive control on progression.So there is no evidence in type 1 diabetes that tight glucose control slows progression of microalbuminuria.DCCT Research Group. (1995). Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int., 47, 1703–1720.
11. In type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS) did not report on progression of microalbuminuria. It did provide good evidence that tight glucose control delays the onset of microvascular complications. However, there is some weak evidence from the ADVANCE study and a very small Japanese study that intensive glucose control may delay progression of microalbuminuria. The ADVANCE Collaborative Group. (2008). Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med., 358, 2560-2572. Ohkubo, Y.. Kishikawa, H., Araki, E., Myata, Isami, Motoyoshi, et al. (1996). Intensive insulin therapy prevents the progression of diabetes microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract., 28, 103–117 .
12. Adults with persistent albuminuria (>2.0mg/mmol in men, 2.8mg/mmol in women) should be started on an ACE or ARB regardless of blood pressure. These medications have some additional renal protective properties. What is far more important is intensive blood pressure (BP) treatment. Guidelines suggest a target BP <130/80 mmHg. It is also important to reduce salty foods in the diet. There is evidence that the antihypertensive drugs are more effective when salt intake is reduced. DASH stands for Dietary Approaches to Stop Hypertension. The study showed how important it is to reduce sodium in the diet. The findings suggest that the current recommendation for how much dietary sodium we consume may need to be lowered. By reducing their dietary sodium to 1,500 milligrams a day, all of us and especially those at high risk for hypertension, can decrease their chance of developing high blood pressure as they age. Sacks F.M., Svetkey L.P., Vollmer W.M., Appel, L.J., Bray, G.A., Harsha, D., et al. (2001). DASH-Sodium Collaborative Research Group. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med, 344(1): 3-10. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2008 Clinical Practice Guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2008; 32 (Suppl 1): S126-133.
13. The Lewis Study, a landmark investigation, examined the role of anti-hypertensive therapy in the management of diabetic nephropathy in people with type 1 diabetes. In this study, people with type 1 diabetes were randomly given either an ACE inhibitor or placebo. Those taking the ACE inhibitor (captopril) had better results than those on placebo. It was also found that ACE inhibitors had a protective effect on the kidneys, above and beyond their effect on blood pressure. Lewis E.J., Hunsicker L.G., Bain R.P., Rohde, R.D. (1993). The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. The Collaborative Study Group (published erratum appears in N Eng J Med 1993; 330: 152). N Eng J Med, 329, 1456-62.
14. Two studies provide the evidence for the management of chronic kidney disease in type 2 diabetes: IRMA and IDNT. Together, these two studies are commonly known as the PRIME study. The IRMA study, tested the ARB antagonist, irbesartan, and was undertaken in people with type 2 diabetes and microalbuminuria. one group received conventional anti-hypertensive therapy, while the other group received irbesartan. Primary outcome was time to onset of diabetic nephropathy. Over two years onset of diabetic nephropathy occurred 30% less frequently in the group that was treated with irbesartan, compared with conventional treatment. Angiotensin receptor blockers (ARB) and angiotensin converting enzyme (ACE) inhibitors are known to reduce proteinuria. The Ontarget study investigated the renal effects of ramipril (an ACE inhibitor), telmisartan (an ARB), and their combination in patients aged 55 years or older with established atherosclerotic vascular disease or with diabetes with end-organ damage. The endpoint was defined as the doubling of baseline serum creatinine, the onset of end stage renal disease (ESRD) or death. The study found that in this population the ACE and the ARB performed similarly in reducing the incidence of the endpoint. In addition the researcher’s found that although combination therapy reduces proteinuria more than monotherapy, overall it worsens major renal outcomes. Combination of ACE plus ARB - all the trials on combination therapy in diabetes have been small and short (max 1 year). All show added reduction in blood pressure and urine albumin excretion. However, none have been long enough to show any benefit on eGFR or progression to ESRD. The one study which is big enough and long enough, actually showed an INCREASED risk of acute renal failure on ACE plus ARB . Thus we should NOT be recommending ACEI and A2RB together - if it is prescribed, then patients should be counselled to stop ACE and ARB when they are unwell and likely to become dehydrated. When ACE or ARB are started it is important to remind people to titrate the dose to maximum recommended / maximum tolerated, and that renal function should be checked 1-2 weeks after each dose adjustment. Parving, H.H., Lehnert, H., Brochner-Mortensen, J. et al. (2001). The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med., 345, 12, 870-8. Mann, J.F., Schmieder, R.E., McQueen, M. et al (2008). Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet, 372(9638), 547-53.
15. If ACE inhibitor or ARB are not available, or are too expensive, any type of anti-hypertensive medication can be used. Most guidelines recommend either calcium channel blockers or diuretics as the next choice if ACE inhibitor or ARB are not suitable. Alpha blockers, centrally acting agents and b-blockers are recommended as third choice in whatever order seems best for the individual patient. Common practice of healthcare professionals is often to try one agent and, if the person does not reach target blood pressure, change medication. This is not recommended. Healthcare professionals should use combination therapy; in many cases, three or more different blood pressure agents are required to achieve the target blood pressure. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. (2008). Canadian Diabetes Association 2008 Clinical Practice Guidelines for the prevention and management of diabetes in Canada. Can J Diabetes, 32 (Suppl 1): S126-133.
16. Some precautions should be taken when a person has an elevated creatinine: Metformin dosage should be used with caution when eGFR <60mL/min and stopped when eGFR < 30 mL/min. (Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. (2008). Canadian Diabetes Association 2008 Clinical Practice Guidelines for the prevention and management of diabetes in Canada. Can J Diabetes, 32 (Suppl 1): S126-133.) 2.Use of nephrotoxic medication, such as non-steroidal anti-inflammatory drugs, should be avoided; these may worsen renal failure and exacerbate hypertension due to fluid-retention effect. 3. Caution when using sulphonylureas in persons with ESRD as there is a significant risk of profound hypoglycaemia, which is difficult to treat. 4. As eGFR declines, insulin dose may need to be reduced. In addition, initiation of dialysis will require further dose adjustment. 5. Contrast-induced nephropathy – beware of transient deterioration in glomerular filtration rate (GFR) after contrast-related studies. If a person has to have a test that requires contrast dye – such as IVP – the person performing the test should be informed that the patient has raised serum creatinine so that he/she can be well hydrated during and after the test. Cavanaugh, K.L. (2007). Diabetes management issues for patients with chronic kidney disease. Clinical Diabetes, 25(3), 90-97 Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2008 Clinical Practice Guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2008; 32 (Suppl 1): S126-133.
17. The kidney is an endocrine organ producing the hormone erythropoetin, which regulates the production of red blood cells. With the onset of renal failure, erythropoetin production drops and results in progressive anaemia. This anaemia occurs at an earlier stage in people with diabetes than in those without the condition. People with diabetes should have their haemoglobin checked regularly; if anaemic they may need iron (oral or parental) before starting erythropoietin as epo will not work if they are iron deficient. A1C may not be accurate in people who have anaemia from chronic kidney disease. Fructosamine may be used instead of A1C. Self monitoring is the most important.
18. CKD usually has no symptoms until very late in the disease (eGFR < 15 mL/min). This is why it is so important that people are screened on a regular basis. The clinical features that appear late in the disease are listed on this slide. These are a result of the retention of fluids, uremic toxins (waste products) and decreased levels of erythropotein.
19. The principle is to improve overall health and well-being of people with renal failure. Adequate intake of calories is important; these give the body energy and maintain a healthy weight. A balanced diet with carbohydrates, protein, fat, fibre, vitamins and minerals, and calcium is recommended. Fluid may be limited in CKD but not at the earlier stage. Cochrane review - recommended 6 month trial of low protein diet to ~0.9 g/kg body weight/day, with those showing benefit to continue. Robertson, L., Waugh, N., Robertson, A. (2007). Protein Restriction for diabetic renal disease. Cochrane Database Syst Rev, 17: CD002181
20. May underestimate actual renal function especially in women, the young and the obese. As eGFR falls, CVD risk increases. This is independent of increasing risk with increasing albuminuria ie albuminuria and eGFR independently alter CVD risk. McCullough P.A., Jurkovitz, C.T., Pergola, P.E., McGill, J.B., Brown, W.W., Collins, A.J., et al. (2007). Independent Components of Chronic Kidney Disease as a Cardiovascular Risk Stage. Arch Intern Med, 167, 1122-1129.
21. If the eGFR is : <60 ml/min - osteodystrophy - anaemia <30 ml/min - pre-dialysis <15 ml/min - dialysis and transplant
22. The treatment options for ESRD are peritoneal dialysis, haemodialysis or renal transplantation. It is important to prepare people psychologically for the need for dialysis before the expected date of dialysis. This will help the person to cope – including counselling sessions from a renal nurse specialists. In many cases, renal dialysis is not available to the person unless he/she moves to a nearby city. Issues such as cost, travel or a lack of nearby family support should be considered and discussed. Many people may decide to forgo dialysis. It is very important to ensure adequate communication between the diabetes and renal teams. In many places in the world people having a kidney transplant may be offered a pancreas transplant at the same time.
23. Some of the problems encountered in peritoneal dialysis are: A high risk of catheter-related infection Peritonitis Glucose absorption from peritoneal dialysis fluid affect glycaemic control. A special warning: the peritoneal dialysis solution, icodextrin 7.5%, and human immune globulin are metabolized to maltose. If blood glucose test strips use the glucose dehydrogenase method of testing, people may exhibit falsely high glucose readings. There are several reports describing profound hypoglycaemia and even death in this situation. Therefore, if these products have to be used, blood glucose strip that do not use the glucose dehydrogenase method should be used. Remember in any situation to treat the patient, not the result of their glucose meter.
24. There are also problems associated with haemodialysis. These include: Increased risk of vascular access problem Increased incidence of hypotension during hemodialysis Pre-dialysis hyperkalaemia Susceptibility to hypoglycaemia.
25. In summary, diabetes is a common cause of CKD. It is important to remember that there are grades of diabetic nephropathy. We should try to find changes early; interventions are most effective early in the course of the disease. There is no doubt that blood glucose control matters and this is why we try and help people with diabetes to reach HbA1c targets. But blood pressure is the central factor and should be our major concern.