Chronic kidney disease in diabetes

Contents lists available at Canadian Journal of Diabetes Clinical Practice Guidelines Chronic Kidney Disease in Diabetes Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Philip McFarlane MD, FRCPC,Richard E. Gilbert MBBS, PhD, FACP, FRACP, FRCPC, Lori MacCallum BScPhm, PharmD,Peter Senior MBBS, PhD, MRCP length and quality of life A variety of forms of kidney disease can be seen in people with diabetes, including diabetic nephrop-athy, ischemic damage related to vascular disease and hyperten-  Identification of chronic kidney disease (CKD) in diabetes requires screening for proteinuria, as well as an assessment of renal function.
sion, as well as other renal diseases that are unrelated to diabetes  All individuals with CKD should be considered at high risk for cardiovas- (In this chapter, we will discuss how to screen for cular events and should be treated to reduce these risks.
and diagnose chronic kidney disease (CKD) in people with diabetes,  The progression of renal damage in diabetes can be slowed through how to treat them with an aim to slow progression of CKD and intensive glycemic control and optimization of blood pressure. Progression discuss the impact of CKD on other aspects of diabetes of diabetic nephropathy can be slowed through the use of medications thatdisrupt the renin-angiotensin-aldosterone system.
Diabetic Nephropathy The classic description of diabetic nephropathy is of a progres- Management of Potassium and Creatinine During the Use sive increase in proteinuria in people with longstanding diabetes of Angiotensin-Converting Enzyme (ACE) Inhibitor or followed by declining function that eventually can lead to end stage Angiotensin II Receptor Blocker (ARB) or Direct Renin renal disease (ESRD) ) . Key risk factors for diabetic nephropathy include long duration of diabetes, poor glycemiccontrol, hypertension, male gender, obesity and cigarette smoking.
 Check serum potassium and creatinine at baseline and within 1 to 2 Many of these factors are modifiable.
weeks of initiation or titration of therapy AND during times of acute illness.
The earliest stage of diabetic nephropathy is hyperfiltration,  If potassium becomes elevated or creatinine increases by more than 30% where the glomerular filtration rate (GFR) is significantly higher from baseline, therapy should be reviewed and serum creatinine andpotassium levels should be rechecked.
than normal. Identification of hyperfiltration is not clinically useful,  Mild-to-moderate stable hyperkalemia: as it is difficult to determine from routine testing. Persistent Counsel on a low-potassium diet.
albuminuria is considered the earliest clinical sign of diabetic If persistent, nonepotassium-sparing diuretics and/or oral sodium nephropathy Initially, small amounts of albumin are bicarbonate (in those with a metabolic acidosis) should beconsidered.
leaked, below the detection threshold of a urine dipstick. This stage Consider temporarily holding renin-angiotensin-aldosterone system is referred to as "microalbuminuria." This can worsen so that the (RAAS) blockade (i.e. ACE inhibitor, ARB or DRI).
urinary albumin excretion is sufficiently high to be detectable by  Severe hyperkalemia: a urine dipstick, a stage known as "overt nephropathy." The rate of In addition to emergency management strategies, RAAS blockade progression from normoalbuminuria to microalbuminuria then to should be held or discontinued.
overt nephropathy usually is slow, typically taking 5 years or longerto progress through each stage . During the early stages ofdiabetic nephropathy, the rate of loss of renal function is relativelyslow (1 to 2 mL/min/1.73 m2 per year) and not impressively higherthan what is seen in the general population (0.5 to 1 mL/min/ 1.73 m2 per year). However, late in the overt nephropathy phase,the rate of decline of renal function can accelerate (5 to 10 mL/min/ Diseases of the kidney are a common finding in people with 1.73 m2 per year). Thus, significant renal dysfunction is not usually diabetes, with up to half demonstrating signs of kidney damage in seen until late in the course of diabetic nephropathy .
their lifetime eDiabetes is the leading cause of kidney disease It is important to note that the rate of progression can vary in Canada . Kidney disease can be a particularly devastating between individuals, and that the clinical markers of the disease complication, as it is associated with significant reductions in both (i.e. estimated glomerular filtration rate [eGFR], urinary albumin 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association

P. McFarlane et al. / Can J Diabetes 37 (2013) S129eS136 Screening for Kidney Disease in People with Diabetes Screening for kidney disease in people with diabetes involves an assessment of urinary albumin excretion and a measurement ofthe overall level of kidney function through an estimation of theGFR. Persistent abnormalities of either urinary albumin excretionor GFR, or significant urinalysis abnormalities, lead to the diag-nosis of kidney disease in people with diabetes. People with type 1diabetes are not expected to have kidney disease at the time ofonset of diabetes, so screening can be delayed until the duration ofdiabetes exceeds 5 years. As the delay between onset and diag-nosis of type 2 diabetes can be many years and as nondiabetickidney disease is common, significant renal disease can be presentat the time of diagnosis of type 2 diabetes , so screeningshould be initiated immediately at the time of diagnosis in thisgroup.
Screening for Albuminuria When screening for albuminuria, the test of choice is the random urine albumin-to-creatinine ratio (urinary ACR). The24-hour urine collection for protein/albumin remains the goldstandard; however, it is cumbersome to implement on a large scale Figure 1. Causes of chronic kidney disease (CKD) in people with and without diabetes.
and is often performed incorrectly The random urine foralbumin is insufficient, as the urinary albumin concentration can levels) do not always correlate well with the severity of renal vary due to urine concentration A random urine ACR predicts disease seen on biopsy . Additionally, aggressive control of 24-hour urinary albumin excretion sufficiently well and is the test blood pressure (BP) and glycemia, and the use of renal protective of choice for screening for albuminuria drugs can slow or stop progression of diabetic nephropathy.
There is substantial day-to-day variability in albuminuria. In addition, transient increases in albuminuria can be provoked bya number of factors () When such conditions arepresent, screening for kidney disease should be delayed to avoid Other Kidney Diseases in People with Diabetes false positives. Furthermore, diagnosing a person as havingalbuminuria requires the elevated urinary albumin level to be People with diabetes (particularly type 2 diabetes) often persistent. At least 2 of 3 urine samples over time exhibiting develop kidney diseases other than diabetic nephropathy. Kidney elevations in urinary albumin levels are required before it is biopsy series in type 2 diabetes have found that nondiabetic considered to be abnormal.
nephropathy, is as common as diabetic nephropathy in people with Estimation of GFR diabetes In addition, there can be significant overlap While these biopsy series are biased (biopsies are usually done in The serum creatinine is the most common measurement of people with diabetes when nondiabetic renal disease is suspected), kidney function; however, it can inaccurately reflect renal function other studies have suggested that half of everyone with diabetes in many scenarios, particularly in extremes of patient age or size and significant kidney function impairment do not have albumin- . Indeed, in people with diabetes, the GFR usually will be less uria . These studies suggest that testing for albuminuria may be than half of normal before the serum creatinine exceeds the lab insufficient in identifying all patients with diabetes who have renal normal range .
disease. In addition to measurements of urinary albumin excretion, As mentioned, the 24-hour urine collection can be difficult to estimations of the level of kidney function and urinalyses are perform accurately. For this reason, a variety of methods have been required to identify patients with kidney disease other than dia- developed to better estimate the level of glomerular filtration by betic nephropathy. In most cases, the risk of ESRD in diabetes does combining the patient's serum creatinine with factors such as age, not appear to matter whether the renal diagnosis is one of diabetic weight, and gender. The most common method of estimating renal nephropathy or an alternative diagnosis as management is the function in Canada currently is the eGFR, using the 4-variable same . However, lists some concerning clinical and MDRD ("Modification of Diet in Renal Disease") equation laboratory features that would lead to suspicion of a kidney disease This equation requires knowledge of the patient's age, sex, serum unrelated to diabetes, requiring such a person to undergo addi- creatinine and race and is automatically computed and reported by tional testing or referral many labs whenever a serum creatinine is ordered. The MDRDeGFR performs well when the GFR is <60 mL/min and despiteits flaws is generally a better estimate of glomerular filtration thanthe serum creatinine value. Kidney diseases of all forms can bestaged based on the degree of impairment of eGFR ().
The eGFR is useful for assessing chronic changes in renal func- tion but should not be used in situations where kidney function ischanging rapidly. Dehydration and other conditions that lead tointravascular volume contraction can lead to a transient decline inrenal function. When such conditions are present, assessment of Figure 2. Level of urinary albumin by various test methods and stage of diabeticnephropathy. ACR, albumin-to-creatinine ratio.
the level of kidney function may be clinically necessary but should

P. McFarlane et al. / Can J Diabetes 37 (2013) S129eS136 Table 1Stages of diabetic nephropathy by level of urinary albumin level not be used to assess the stage of CKD. Because renal function can suspected of having acute kidney injury or nondiabetic renal be transiently depressed, a persistent reduction in eGFR is required disease. Screening should be delayed in the presence of conditions before it is considered to be abnormal.
that can cause transient albuminuria or a transient fall ineGFR.
Other Clinical Features and Urinary Abnormalities: When to Screening for CKD in people with diabetes should be performed Consider Additional Testing or Referral with a random urine ACR and a serum creatinine that is thenconverted into an eGFR (This can be delayed 5 years from Urinalysis findings of red blood cell casts are not a common the onset of type 1 diabetes but should begin immediately at the finding in renal disease due to diabetes, and white blood cell casts time of diagnosis of type 2 diabetes. An abnormal screening test or heme-granular casts are not compatible with a diagnosis of should be confirmed by repeat testing of the eGFR within 3 months, kidney disease due to diabetes. Although persistent microscopic and 2 more random urine ACRs ordered during that interval. If hematuria can occur in about 20% of people with diabetic either the eGFR remains low or at least 2 of the 3 random urine nephropathy, its presence should lead to the consideration of other ACRs are abnormal, then a diagnosis of CKD is confirmed. The urological or nephrological conditions. lists other clinical exception to this approach is when the random urine ACR indicates clues that may point to a renal diagnosis other than kidney disease albuminuria in the overt nephropathy range, as this level of due to diabetes. Such patients should undergo an appropriate proteinuria rarely resolves spontaneously, so confirmatory testing assessment for the cause of their disease. A rapid decline in eGFR or is usually unnecessary.
development of severe hypertension would suggest prompt referral Once a diagnosis of CKD has been made, a urine sample for to a specialist.
dipstick and microscopy should be ordered. In the absence of any Although 24-hour collections are not needed for routine significant abnormalities other than proteinuria, then a presump- screening in diabetes, they can be useful when there is doubt about tive diagnosis of kidney disease due to diabetes is made. The the accuracy of an eGFR, when screening for nonalbumin urinary presence of clinical or laboratory abnormalities suggesting nondi- proteins (e.g. multiple myeloma) or when estimating daily sodium abetic kidney disease indicates the need for appropriate workup or intake in an individual with refractory edema or hypertension.
Individuals should be counseled to discard the first morning urineon the day of collection and then collect all subsequent urine Prevention, Treatment and Follow Up for a 24-hour period, including the first morning urine of the nextday.
Optimal glycemic control established as soon as possible after diagnosis will reduce the risk of development of diabetic nephropathy Optimal BP control also appears to beimportant in the prevention of diabetic nephropathy, although People with diabetes should undergo annual screening for the the results have been less consistent Blockade of the presence of kidney disease when they are clinically stable and not renin-angiotensin-aldosterone system (RAAS) with either an Table 2Factors favouring the diagnosis of classical diabetic nephropathy or alternative renal diagnoses

P. McFarlane et al. / Can J Diabetes 37 (2013) S129eS136 In CKD from causes other than diabetic nephropathy, ACE inhi- Conditions that can cause transient albuminuria bition has been shown to reduce proteinuria, slow progressive lossof glomerular filtration rate and delay the need for dialysis The issue of whether ARBs and ACE inhibitors are similarly effectivein CKD that is not caused by diabetic nephropathy remains contro-versial A variety of strategies to more aggressively block the RAAS have been studied in kidney disease, including combining RAASblockers or using very high doses of a single RAAS blocker. Thesestrategies reduce proteinuria but have not been proven toimprove patient outcomes in diabetic nephropathy eandcome at a risk of increased acute renal failure, typically whena Aggressive RAAS blockade strategies should be restricted tospecialized clinics.
Treating Kidney Disease Safely angiotensin-converting enzyme (ACE) inhibitor or an angiotensinII receptor blocker (ARB) can reduce the risk of diabetic The "sick day" medication list (see Appendix 7) nephropathy independent of their effect on BP. This protectiveeffect has been demonstrated in people with diabetes and Several classes of medications used commonly in people with hypertension but not in normotensive people with diabetes diabetes can reduce kidney function during periods of intercurrent illness and should be discontinued when patients are unwell, in All people with CKD are at risk for cardiovascular (CV) events particular when they develop significant intravascular volume and should be treated to reduce these risks (see Vascular Protection contraction due to reduced oral intake or excessive losses due to chapter, p. S100) e. The degree of risk of CV events or vomiting or diarrhea. Diuretics can exacerbate intravascular progression to ESRD increases as albuminuria levels rise, and as volume contraction during periods of intercurrent illness. Blockers eGFR falls, with the combination of albuminuria and low eGFR of the RAAS interfere with the kidney's response to intravascular predicting a very high level of risk () volume contraction, namely, the ability of angiotensin II to contract The progression of renal damage in diabetes can be slowed the efferent arteriole to support glomerular filtration during these through intensive glycemic control and optimization of BP periods. Nonsteroidal anti-inflammatory drugs cause constriction Progression of diabetic nephropathy can be slowed through of the afferent arterioles, which can further reduce blood flow into the use of an ACE inhibitor or ARB , independent of their effect the glomerulus in patients who are volume contracted. For these on BP, and these 2 medication classes appear to be equally effective reasons, all of these drugs can reduce kidney function during times for cardiorenal protection . In type 1 diabetes, ACE inhibitors of intercurrent illness. Consideration should be given to providing have been shown to decrease albuminuria and prevent worsening patients with a "sick day" medication list, instructing the patient to of nephropathy , and ARBs have been shown to reduce hold these medications if they feel that they are becoming dehy- proteinuria . In type 2 diabetes, ACE inhibitors and ARBs have drated for any reason. A number of additional medications need to been shown to decrease albuminuria and prevent worsening of be dose adjusted in patients with renal dysfunction, so their usage nephropathy, and ARBs have been shown to delay the time to and dosage should be reevaluated during periods where kidney dialysis in those with renal dysfunction at baseline . In type function changes.
2 diabetes, ACE inhibitors have also been shown to reduce thechance of developing new nephropathy . These renal-protective effects also appear to be present in proteinuric indivi- The safe use of RAAS blockers (ACE inhibitors, ARBs, and direct renin duals with diabetes and normal or near-normal BP. ACE inhibitors inhibitors [DRIs]) have been shown to reduce progression of diabetic nephropathy inalbuminuric normotensive individuals with both type 1 Drugs that block the RAAS reduce intraglomerular pressure, and type 2 diabetes .
which, in turn, leads to a rise in serum creatinine of up to 30%, whichthen stabilizes Although these drugs can be used safely inpatients with renovascular disease, these patients may have an even larger rise in serum creatinine when these drugs are used e. In Stages of chronic kidney disease the case of severe renovascular disease that is bilateral (or unilateralin a person with a single functioning kidney), RAAS blockade canprecipitate renal failure. In addition, RAAS blockade can lead tohyperkalemia. For these reasons, the serum creatinine and potas-sium should be checked between 1 and 2 weeks after initiation ortitration of a RAAS blocker In patients in whom a significantchange in creatinine or potassium is seen, further testing should beperformed to ensure that these results have stabilized.
Mild-to-moderate hyperkalemia can be managed through die- tary counselling, Diuretics, in particular furosemide, can increaseurinary potassium excretion. Sodium bicarbonate (500 to 1300 mgorally twice a day) can also increase urinary potassium excretion,especially amongst individuals with a metabolic acidosis asdemonstrated by a low serum bicarbonate level. If hyperkalemia issevere, RAAS blockade would need to be held or discontinued P. McFarlane et al. / Can J Diabetes 37 (2013) S129eS136 Figure 3. Screening for chronic kidney disease (CKD) in people with diabetes. ACR, albumin-to-creatinine ratio; eGFR, estimated glomerular filtration rate.
P. McFarlane et al. / Can J Diabetes 37 (2013) S129eS136 medications wishes to become pregnant, consideration should begiven to their discontinuation prior to conception.
Medication selection and dosing in CKD Many medications need to have their dose adjusted in the presence of low kidney function, and some are contraindicated inpeople with significant disease. Appendix 6 lists some medicationscommonly used in people with diabetes and how they should beused if kidney dysfunction is present.
Referral to a specialized renal clinic Figure 4. Relative risk of chronic kidney disease (CKD). Shading shows how adjusted Most people with CKD and diabetes will not require referral to relative risk is ranked for 5 outcomes from a meta-analysis of general population a specialist in renal disease. However, specialist care may be cohorts: all-cause mortality, cardiovascular mortality, kidney failure treated by dialysis necessary when renal dysfunction is severe, when there are dif and transplantation, acute kidney injury, and progression of kidney disease. GFR, glomerular filtration rate.
culties implementing renal-protective strategies or when there areproblems managing the sequelae of renal disease .
As the use of RAAS blockers during pregnancy has been asso- ciated with congenital malformations, women with diabetes of Other Relevant Guidelines childbearing age should avoid pregnancy if drugs from theseclasses are required If a woman with diabetes receiving such Targets for Glycemic Control, p. S31Monitoring Glycemic Control, p. S35Pharmacotherapy in Type 1 Diabetes, p. S56 Pharmacologic Management of Type 2 Diabetes, p. S61Type 1 Diabetes in Children and Adolescents, p. S153 1. In adults, screening for CKD in diabetes should be conducted using a random urine ACR and a serum creatinine converted into an eGFR [Grade Type 2 Diabetes in Children and Adolescents, p. S163 D, Consensus]. Screening should commence at diagnosis of diabetes in Diabetes and Pregnancy, p. S168 individuals with type 2 diabetes and 5 years after diagnosis in adults with Diabetes in the Elderly, p. S184 type 1 diabetes and repeated yearly thereafter. A diagnosis of CKD shouldbe made in patients with a random urine ACR 2.0 mg/mmol and/or aneGFR<60 mL/min on at least 2 of 3 samples over a 3-month period [Grade Relevant Appendices D, Consensus].
Appendix 6: Therapeutic Considerations for Renal Impairment 2. All patients with diabetes and CKD should receive a comprehensive, Appendix 7: Sick Day Medication List multifaceted approach to reduce cardiovascular risk (see VascularProtection, p. S100) [Grade A, Level 1A ].
3. Adults with diabetes and CKD with either hypertension or albuminuria should receive an ACE inhibitor or an ARB to delay progression of CKD 1. Warram JH, Gearin G, Laffel L, et al. Effect of duration of type I diabetes on the [Grade A, Level 1A for ACE inhibitor use in type 1 and type 2 diabetes, and prevalence of stages of diabetic nephropathy defined by urinary albumin/ for ARB use in type 2 diabetes; Grade D, Consensus, for ARB use in type 1 creatinine ratio. J Am Soc Nephrol 1996;7:930e7.
2. Reenders K, de Nobel E, van den Hoogen HJ, et al. Diabetes and its long-term complications in general practice: a survey in a well-defined population. Fam 4. People with diabetes on an ACE inhibitor or an ARB should have their serum creatinine and potassium levels checked at baseline and within 1 to 3. Weir MR. Albuminuria predicting outcome in diabetes: incidence of micro- 2 weeks of initiation or titration of therapy and during times of acute albuminuria in Asia-Pacific Rim. Kidney Int 2004;66:S38e9.
illness [Grade D, Consensus].
4. Canadian Institute for Health Information. Canadian Organ Replacement Register Annual Report: Treatment of End-Stage Organ Failure in Canada, 2000to 2009. Ottawa, ON: Canada; 2011.
5. Adults with diabetes and CKD should be given a "sick day" medication list 5. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease that outlines which medications should be held during times of acute in chronic renal disease. Am J Kidney Dis 1998;32:S112e9.
illness (see Appendix, 7) [Grade D, Consensus].
6. Bell CM, Chapman RH, Stone PW, et al. An off-the-shelf help list: a compre- hensive catalog of preference scores from published cost-utility analyses. Med 6. Combination of agents that block the renin-angiotensin-aldosterone Decision Making 2001;21:288e94.
system (ACE inhibitor, ARB, DRI) should not be routinely used in the 7. Mazzucco G, Bertani T, Fortunato M, et al. Different patterns of renal damage in management of diabetes and CKD [Grade A, Level 1].
type 2 diabetes mellitus: a multicentric study on 393 biopsies. Am J Kidney Dis2002;39:713e20.
7. People with diabetes should be referred to a nephrologist or internist with 8. Gambara V, Mecca G, Remuzzi G, et al. Heterogeneous nature of renal lesions in an expertise in CKD in the following situations: type II diabetes. J Am Soc Nephrol 1993;3:1458e66.
a. Chronic, progressive loss of kidney function 9. Mathiesen ER, Ronn B, Storm B, et al. The natural course of microalbuminuria in b. ACR persistently >60 mg/mmol insulin-dependent diabetes: a 10-year prospective study. Diabet Med 1995;12: 10. Lemley KV, Abdullah I, Myers BD, et al. Evolution of incipient nephropathy in d. Unable to remain on renal-protective therapies due to adverse effects type 2 diabetes mellitus. Kidney Int 2000;58:1228 such as hyperkalemia or e37. Published erratum >30% increase in serum creatinine within 3 appears in Kidney Int. 2000;58:2257.
months of starting an ACE inhibitor or ARB 11. Gall MA, Nielsen FS, Smidt UM, et al. The course of kidney function in type 2 e. Unable to achieve target BP (could be referred to any specialist in (non-insulin-dependent) diabetic patients with diabetic nephropathy. Dia- hypertension) [Grade D, Consensus] 12. Jacobsen P, Rossing K, Tarnow L, et al. Progression of diabetic nephropathy in normotensive type 1 diabetic patients. Kidney Int Suppl 1999;71:S101e5.
13. Hasslacher C, Ritz E, Wahl P, et al. Similar risks of nephropathy in patients with ACE, angiotensin-converting enzyme; ACR, albumin-to-creatinine ratio; type I or type II diabetes mellitus. Nephrol Dial Transplant 1989;4:859e63.
ARB, angiotensin II receptor block; CKD, chronic kidney disease; DRI, 14. Biesenbach G, Bodlaj G, Pieringer H, et al. Clinical versus histological diagnosis direct renin inhibitor.
of diabetic nephropathy: is renal biopsy required in type 2 diabetic patientswith renal disease? QJM 2011;104:771e4.
P. McFarlane et al. / Can J Diabetes 37 (2013) S129eS136 15. Middleton RJ, Foley RN, Hegarty J, et al. The unrecognized prevalence of chronic 46. Ruggenenti P, Fassi A, Ilieva AP, et al. Preventing microalbuminuria in type 2 kidney disease in diabetes. Nephrol Dial Transplant 2006;21:88e92.
diabetes. N Engl J Med 2004;351:1941e51.
16. Ruggenenti P, Gambara V, Perna A, et al. The nephropathy of non-insulin- 47. Chaturvedi N. Randomised placebo-controlled trial of lisinopril in normoten- dependent diabetes: predictors of outcome relative to diverse patterns of sive patients with insulin-dependent diabetes and normoalbuminuria or renal injury. J Am Soc Nephrol 1998;9:2336e43.
microalbuminuria. Lancet 1997;349:1787e92.
17. VenkataRaman TV, Knickerbocker F, Sheldon CV. Unusual causes of renal 48. Bilous R, Chaturvedi N, Sjolie AK, et al. Effect of candesartan on micro- failure in diabetics: two case studies. J Okla State Med Assoc 1990;83:164e8.
albuminuria and albumin excretion rate in diabetes: three randomized trials.
18. Anonymous. Clinical path conference. Unusual renal complications in diabetes Ann Intern Med 2009;151:11e20. W13-W14.
mellitus. Minn Med 1967;50:387e93.
49. Mauer M, Zinman B, Gardiner R, et al. Renal and retinal effects of enalapril and 19. Amoah E, Glickman JL, Malchoff CD, et al. Clinical identification of nondiabetic losartan in type 1 diabetes. N Engl J Med 2009;361:40e51.
renal disease in diabetic patients with type I and type II disease presenting 50. Gerstein HC, Mann JF, Yi Q, et al. Albuminuria and risk of cardiovascular events, with renal dysfunction. Am J Nephrol 1988;8:204e11.
death, and heart failure in diabetic and nondiabetic individuals. JAMA 2001; 20. El-Asrar AM, Al-Rubeaan KA, Al-Amro SA, et al. Retinopathy as a predictor of other diabetic complications. Int Ophthalmol 2001;24:1e11.
51. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular 21. Ballard DJ, Humphrey LL, Melton LJ, et al. Epidemiology of persistent protein- disease in patients with type 2 diabetes. N Engl J Med 2003;348:383e93.
uria in type II diabetes mellitus. Population-based study in Rochester, Minne- 52. Gaede P, Vedel P, Parving HH, et al. Intensified multifactorial intervention in sota. Diabetes 1988;37:405e12.
patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 22. Winaver J, Teredesai P, Feldman HA, et al. Diabetic nephropathy as the mode of randomised study. Lancet 1999;353:617e22.
presentation of diabetes mellitus. Metab Clin Exp 1979;28:1023e30.
53. Levey AS, Coresh J. Chronic kidney disease. Lancet 2012;379:165e80.
23. Ahn CW, Song YD, Kim JH, et al. The validity of random urine specimen 54. Levey AS, Eckardt KU, Tsukamoto Y, et al. Definition and classification of albumin measurement as a screening test for diabetic nephropathy. Yonsei chronic kidney disease: a position statement from Kidney Disease: Improving Med J 1999;40:40e5.
Global Outcomes (KDIGO). Kidney Int 2005;67:2089e100.
24. Kouri TT, Viikari JS, Mattila KS, et al. Microalbuminuria. Invalidity of simple 55. Maki DD, Ma JZ, Louis TA, et al. Long-term effects of antihypertensive agents on concentration-based screening tests for early nephropathy due to urinary proteinuria and renal function. Arch Intern Med 1995;155:1073e80.
volumes of diabetic patients. Diabetes Care 1991;14:591e3.
56. Kasiske BL, Kalil RS, Ma JZ, et al. Effect of antihypertensive therapy on the 25. Rodby RA, Rohde RD, Sharon Z, et al. The urine protein to creatinine ratio as kidney in patients with diabetes: a meta-regression analysis. Ann Intern Med a predictor of 24-hour urine protein excretion in type 1 diabetic patients with nephropathy. The Collaborative Study Group. Am J Kidney Dis 1995;26: 57. Barnett AH, Bain SC, Bouter P, et al. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J 26. Chaiken RL, Khawaja R, Bard M, et al. Utility of untimed urinary albumin measurements in assessing albuminuria in black NIDDM subjects. Diabetes 58. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart 27. Bakker AJ. Detection of microalbuminuria. Receiver operating characteristic Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342: curve analysis favors albumin-to-creatinine ratio over albumin concentration.
Diabetes Care 1999;22:307e13.
59. Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting- 28. Huttunen NP, Kaar M, Puukka R, et al. Exercise-induced proteinuria in children enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.
and adolescents with type 1 (insulin dependent) diabetes. Diabetologia 1981; N Engl J Med 1993;329:1456e62.
60. Andersen S, Tarnow L, Rossing P, et al. Renoprotective effects of angiotensin II 29. Solling J, Solling K, Mogensen CE. Patterns of proteinuria and circulating receptor blockade in type 1 diabetic patients with diabetic nephropathy.
immune complexes in febrile patients. Acta Med Scand 1982;212:167e9.
Kidney Int 2000;57:601e6.
30. Ritz E. Nephropathy in type 2 diabetes. J Intern Med 1999;245:111e26.
61. Strippoli GF, Craig MC, Schena FP, et al. Role of blood pressure targets and 31. Wiseman M, Viberti G, Mackintosh D, et al. Glycaemia, arterial pressure and specific antihypertensive agents used to prevent diabetic nephropathy and micro-albuminuria in type 1 (insulin-dependent) diabetes mellitus. Dia- delay its progression. J Am Soc Nephrol 2006;17:S153e5.
62. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the 32. Ravid M, Savin H, Lang R, et al. Proteinuria, renal impairment, metabolic angiotensin-receptor antagonist irbesartan in patients with nephropathy due control, and blood pressure in type 2 diabetes mellitus. A 14-year follow-up to type 2 diabetes. N Eng J Med 2001;345:851e60.
report on 195 patients. Arch Intern Med 1992;152:1225e9.
63. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and 33. Gault MH, Longerich LL, Harnett JD, et al. Predicting glomerular function from cardiovascular outcomes in patients with type 2 diabetes and nephropathy.
adjusted serum creatinine. Nephron 1992;62:249e56.
N Engl J Med 2001;345:861e9.
34. Bending JJ, Keen H, Viberti GC. Creatinine is a poor marker of renal failure.
64. Parving HH, Lehnert H, Brochner-Mortensen J, et al. The effect of irbesartan on Diabet Med 1985;2:65e6.
the development of diabetic nephropathy in patients with type 2 diabetes.
35. Shemesh O, Golbetz H, Kriss JP, et al. Limitations of creatinine as a filtration N Engl J Med 2001;345:870e8.
marker in glomerulopathic patients. Kidney Int 1985;28:830e8.
65. Laffel LM, McGill JB, Gans DJ. The beneficial effect of angiotensin-converting 36. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate enzyme inhibition with captopril on diabetic nephropathy in normotensive glomerular filtration rate from serum creatinine: a new prediction equation.
IDDM patients with microalbuminuria. North American Microalbuminuria Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130: Study Group. Am J Med 1995;99:497e504.
66. Mathiesen ER, Hommel E, Giese J, et al. Efficacy of captopril in postponing 37. Poggio ED, Wang X, Greene T, et al. Performance of the modification of diet in nephropathy in normotensive insulin dependent diabetic patients with renal disease and Cockcroft-Gault equations in the estimation of GFR in health microalbuminuria. BMJ 1991;303:81e7.
and in chronic kidney disease. J Am Soc Nephrol 2005;16:459e66.
67. Jerums G, Allen TJ, Campbell DJ, et al. Long-term comparison between peri- 38. Wang PH, Lau J, Chalmers TC. Meta-analysis of effects of intensive blood- ndopril and nifedipine in normotensive patients with type 1 diabetes and glucose control on late complications of type I diabetes. Lancet 1993;341: microalbuminuria. Am J Kidney Dis 2001;37:890e9.
68. ACE Inhibitors in Diabetic Nephropathy Trialist Group. Should all patients with 39. Anonymous. Effect of intensive therapy on the development and progression of type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting diabetic nephropathy in the Diabetes Control and Complications Trial. The enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med Diabetes Control and Complications (DCCT) Research Group. Kidney Int 1995; 69. Ravid M, Savin H, Jutrin I, et al. Long-term stabilizing effect of angiotensin- 40. Anonymous. Intensive blood-glucose control with sulphonylureas or insulin converting enzyme inhibition on plasma creatinine and on proteinuria in compared with conventional treatment and risk of complications in patients normotensive type II diabetic patients. Ann Intern Med 1993;118:577e81.
with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) 70. Ruggenenti P, Perna A, Gherardi G, et al. Renal function and requirement for Group. Lancet 1998;352:837e53.
dialysis in chronic nephropathy patients on long-term ramipril: REIN follow- 41. Retinopathy and nephropathy in patients with type 1 diabetes four years after up trial. Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN). Ram- a trial of intensive therapy. The Diabetes Control and Complications Trial/ ipril Efficacy in Nephropathy. Lancet 1998;352:1252e6.
Epidemiology of Diabetes Interventions and Complications Research Group.
71. Maschio G, Alberti D, Locatelli F, et al. Angiotensin-converting enzyme inhib- N Eng J Med 2000;342:381e9.
itors and kidney protection: the AIPRI trial. The ACE Inhibition in Progressive 42. Shichiri M, Kishikawa H, Ohkubo Y, et al. Long-term results of the Kumamoto Renal Insufficiency (AIPRI) Study Group. J Cardiovasc Pharmacol 1999;33(suppl Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care 1):S16e20. discussion S41eS43.
72. Shoda J, Kanno Y, Suzuki H. A five-year comparison of the renal protective effects 43. Tight blood pressure control and risk of macrovascular and microvascular of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study in patients with non-diabetic nephropathy. Intern Med 2006;45:193e8.
Group. BMJ 1998;317:703e13.
73. Igarashi M, Hirata A, Kadomoto Y, et al. Dual blockade of angiotensin II with 44. Schrier RW, Estacio RO, Mehler PS, et al. Appropriate blood pressure control in enalapril and losartan reduces proteinuria in hypertensive patients with type 2 hypertensive and normotensive type 2 diabetes mellitus: a summary of the diabetes. Endocr J 2006;53:493e501.
ABCD trial. Nat Clin Pract Nephrol 2007;3:428e38.
74. Jacobsen P, Parving HH. Beneficial impact on cardiovascular risk factors by dual 45. de Galan BE, Perkovic V, Ninomiya T, et al. Lowering blood pressure reduces blockade of the renin-angiotensin system in diabetic nephropathy. Kidney Int renal events in type 2 diabetes. J Am Soc Nephrol 2009;20:883e92.
P. McFarlane et al. / Can J Diabetes 37 (2013) S129eS136 75. Burgess E, Muirhead N, Rene de Cotret P, et al. Supramaximal dose of cande- 83. Palmer BF. Managing hyperkalemia caused by inhibitors of the renin- sartan in proteinuric renal disease. J Am Soc Nephrol 2009;20:893e900.
angiotensin-aldosterone system. N Engl J Med 2004;351:585e92.
76. Epstein M, Williams GH, Weinberger M, et al. Selective aldosterone blockade 84. Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital malfor- with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin J mations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006; Am Soc Nephrol 2006;1:940e51.
77. Parving HH, Persson F, Lewis JB, et al. Aliskiren combined with losartan in type 85. Levin A, Mendelssohn D. Care and referral of adult patients with reduced 2 diabetes and nephropathy. N Engl J Med 2008;358:2433e46.
kidney function: position paper from the Canadian Society of Nephrology.
78. Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a mul- 86. Gaede P, Lund-Andersen H, Parving HH, et al. Effect of a multifactorial inter- ticentre, randomised, double-blind, controlled trial. Lancet 2008;372:547e53.
vention on mortality in type 2 diabetes. N Engl J Med 2008;358:580e91.
79. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated 87. Mathiesen ER, Hommel E, Hansen HP, et al. Randomised controlled trial of long elevations in serum creatinine: is this a cause for concern? Arch Intern Med term efficacy of captopril on preservation of kidney function in normotensive patients with insulin dependent diabetes and microalbuminuria. BMJ 1999; 80. Reams GP, Bauer JH, Gaddy P. Use of the converting enzyme inhibitor enalapril in renovascular hypertension. Effect on blood pressure, renal 88. Viberti G, Wheeldon NM. Microalbuminuria reduction with valsartan in function, and the renin-angiotensin-aldosterone system. Hypertension 1986; patients with type 2 diabetes mellitus: a blood pressure-independent effect.
MicroAlbuminuria Reduction With VALsartan Study Investigators. Circulation 81. Franklin SS, Smith RD. Comparison of effects of enalapril plus hydrochloro- thiazide versus standard triple therapy on renal function in renovascular 89. Tobe SW, Clase CM, Gao P, et al. Cardiovascular and renal outcomes with tel- hypertension. Am J Med 1985;79:14e23.
misartan, ramipril, or both in people at high renal risk: results from the 82. Miyamori I, Yasuhara S, Takeda Y, et al. Effects of converting enzyme inhibition ONTARGET and TRANSCEND studies. Circulation 2011;123:1098e107.
on split renal function in renovascular hypertension. Hypertension 1986;8: 90. Parving H, Brenner BM, McMurray JJV, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012;367:2204e13.

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