Diabetic Kidney Disease in the Elderly: Diagnosis, Treatment Goals, and Management
ABSTRACT: Current guidelines recommend screening patients with diabetes for diabetic kidney disease (DKD) using measurements of kidney damage (albuminuria) and function (estimated glomerular filtration rate [eGFR]) beginning 5 years after the diagnosis of type 1 diabetes mellitus (DM) or at the time of diagnosis of type 2 DM, and then annually there after. Early intervention in patients with chronic kidney disease (CKD)—especially those with DKD—is important, not only to delay the development of endstage renal disease (ESRD) and the need for renal replacement therapy, but also to decrease mortality. One of the main treatment strategies for DKD is to decrease albuminuria through inhibition of the reninangiotensinaldosterone system. The use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has become the standard of care for the treatment of DKD; however, although these drugs slow progression to ESRD, they are not curative, nor are they necessarily preventative once estab lished diabetic nephropathy is present. Control of other confounding conditions, including blood pressure, lipids, and hyperglycemia, is also important in optimizing patient care.
Chronic kidney disease (CKD) affects an estimated 13% of the population, and its prevalence is increasing, largely because of the increased prevalence of several known CKD risk factors, including diabetes mellitus (DM), hypertension, and obesity.1 The leading cause of CKD is diabetic kidney disease (DKD), a clinical diagnosis generally defined as an elevated urinary albumin excretion rate in a person with DM in the absence of other causes of CKD. It is estimated that 20% to 40% of patients with DM will develop DKD.2,3
Like all forms of CKD, DKD not only puts patients at risk for developing end-stage renal disease (ESRD), but it is also an independent risk factor for cardiovascular events and death.4 Furthermore, in elderly patients with CKD and DM, the risk of death far exceeds the risk of progression to ESRD.5-7 Therefore, it is essential that clinicians treating the older patient understand how to appropriately screen patients for DKD so that they may implement an appropriate treatment strategy that is focused not only on slowing the progression of renal disease, but also on reducing cardiovascular risk.
The diagnosis and staging of CKD is based upon estimated glomerular filtration rate (eGFR) measurements (the main determinant of overall kidney function) and the presence of kidney damage, most often defined as an increased rate of urinary albumin excretion. According to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI), stage 1 CKD is defined as persistent albuminuria with a normal GFR (≥90 mL/min/1.73 m2); stage 2 CKD as persistent albuminuria with a GFR of 60 to 89 mL/min/1.73 m2; stage 3 CKD as a GFR of 30 to 59 mL/min/1.73 m2; stage 4 CKD as a GFR of 15 to 29 mL/min/1.73 m2; and stage 5 CKD (kidney failure) as a GFR of less than 15 mL/min/1.73 m2 (Table 1; electronic permission not given by rightsholder; see original article in Clinical Geriatrics).8
It is important to note that the presence of albuminuria, even at a normal eGFR level, classifies one as having CKD. In fact, most patients with early DKD have an elevated eGFR secondary to hyperfiltration.9-12 Conversely, CKD is often diagnosed without evidence of kidney damage based solely on a reduced eGFR.
It is for this reason that the current CKD classification system has been criticized by experts who have argued that diagnosing CKD without evidence of kidney damage overestimates CKD prevalence.13 This is particularly true in the elderly population, in whom a decline in eGFR is an expected physiologic component of aging, starting in the third or fourth decades of life, due to an increase in glomerulosclerosis and a decrease in the number of functioning nephrons.14 It is estimated that while 80% of patients with stage 3 CKD are over 60 years of age, only one-third have albuminuria.14 However, because the diagnosis of DKD requires the presence of either microalbuminuria (30-300 mg/g) or macroalbuminuria (>300 mg/g) on a spot urinary albumin-creatinine ratio (UACR; Table 2),2 this controversial bias in the current CKD classification system does not apply to elderly patients with CKD secondary to DKD.
Current guidelines recommend screening patients with diabetes for DKD using measurements of kidney damage (albuminuria) and function (eGFR) beginning 5 years after the diagnosis of type 1 DM or at the time of diagnosis of type 2 DM, and then annually thereafter (Table 3).2,8,15
Microalbuminuria, a marker of early diabetic nephropathy, will not be detected through routine urine dipstick measurements and therefore should be evaluated using a spot UACR. Twenty-four hour urine collections for proteinuria, which are cumbersome and prone to collection errors, are not recommended for routine DKD screening. A positive spot UACR should be confirmed within 3 to 6 months in the absence of factors that may contribute to false-positive results, including exercise within 24 hours of the test, concurrent urinary tract infection, fever, heart failure, hyperglycemia, hypertension, and high protein dietary intake over the several days prior to testing.2,3,16 Albuminuria will usually be present for several years prior to a decline in eGFR; therefore, attempts to slow DKD progression should be initiated once microalbuminuria is confirmed. Although measures of kidney function are often less useful than measures of kidney damage in screening for early DKD, it is still recommended in order to stage DKD and possibly detect atypical DKD or other causes of CKD that may present without albuminuria and develop in patients with DM (eg, hypertensive nephropathy). An eGFR of less than 60 mL/min/1.73 m2 for greater than 3 months in the absence of any evidence of kidney damage is sufficient to diagnose a patient with a minimum of stage 3 CKD.8
In patients with DKD, progression to ESRD closely correlates with the degree of proteinuria, affecting less than 10% of patients with less than 1 gram of proteinuria per day as compared with nearly 3 times that in patients with 2 to 4 grams of proteinuria per day.17 Thus, one of the main treatment strategies for DKD is to decrease albuminuria through inhibition of the renin-angiotensin-aldosterone system (RAAS).
The RAAS is an integral part of DKD progression, secondary to DKD’s effect on the development of systemic and glomerular hypertension, increased glomerular capillary permeability, and local inflammation within the kidneys.16,18 Three large studies have demonstrated the renoprotective effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in patients with type 1 and type 2 DM with macroalbuminuria, using measures of both kidney damage (proteinuria) and kidney function (eGFR), including doubling of serum creatinine and progression to ESRD.19-21 The use of ACEIs and ARBs has become the standard of care for the treatment of DKD; however, although these drugs slow progression to ESRD, they are not curative, nor are they necessarily preventative once established diabetic nephropathy is present. Unfortunately, initiating RAAS blockade early, prior to the development of DKD, is likely to be of little use. This is suggested by a recent study of normotensive, normoalbuminuric patients with type 1 DM treated with either an ACEI (enalapril) or an ARB (losartan), which found no benefit in preserving renal function or preventing proteinuria over a 5-year period.22
It is unclear whether combination therapy with both an ACEI and an ARB provides added benefit in patients with established DKD or simply increases the risk of an adverse event. The Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ON-TARGET) examined the utility of dual blockade of RAAS in patients with vascular disease or high-risk diabetes (diabetes with end-organ damage).23 Combination therapy with an ACEI (ramipril) and an ARB (telmisar tan) resulted in significantly higher rates of renal dysfunction as compared with treatment with either agent alone. These results may not apply to patients with DKD, however, as less than 40% of the participants had diabetes, the average baseline serum creatinine in the study was 1.1 mg/dL, and less than 15% of the par ticipants had microalbuminuria.23 Therefore, it is still not known whether dual RAAS blockade with an ACEI and an ARB may be of benefit in patients with DKD. The ongoing Combination Angiotensin Receptor Blocker and Angiotensin-Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy (VA NEPHRON-D) study, which is comparing the use of an ACEI and an ARB versus an ARB alone in patients with diabetes with 300 mg/g of albuminuria and a decreased eGFR, may provide more information regarding this as yet unanswered question.24
Additional alternative or adjunctive RAAS-inhibiting agents, including aldosterone receptor antagonists and direct renin inhibitors (DRIs), may also play a role in the treatment of DKD. Because an “aldosterone escape” may exist in patients treated with ACEI or ARB therapy, aldosterone receptor antagonists, such as spironolactone, have been studied for use in conjunction with an ACEI or ARB and have significantly reduced 24-hour urinary protein excre tion.25 Studies with DRIs have yielded similar results.
A study published in 2008 comparing the addition of aliskiren versus placebo in patients with type 2 DM with DKD already receiving an ARB demonstrated a 20% reduction in mean spot UACR in the group receiving the DRI plus an ARB as compared with the group receiving an ARB alone.26 The Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE), an ongoing, long-term study, will further determine how DRIs may be utilized in the management of DKD and will also examine the renal and cardiovascular effects of the addition of a DRI to ACEI or ARB therapy in patients with type 2 DM with varying stages of DKD.27
Early intervention in patients with CKD—especially those with DKD—is important, not only to delay the development of ESRD and the need for renal replacement therapy (RRT), but also to decrease mortality. Multiple studies have shown that the risk of mortality is higher than the risk of progression to ESRD in patients with CKD.5-7 Increased risk of death appears to be more pronounced in the earlier stages of CKD. One study demonstrated a 3-year mortality risk that was over 20-fold the risk of initiating RRT in patients with stage 2 to 3 CKD, compared with a 2-fold increased risk in patients with stage 4 CKD.6 Another study involving approximately 5000 patients with diabetes from the United Kingdom Prospective Diabetes Study (UKPDS) reported a higher risk of death than of the risk of DKD progression at every stage of diabetic nephropathy, beginning with the onset of microalbuminuria.7 This same observation has been reported in a large study of elderly Medicare patients, in which persons with DM and CKD were 5 times more likely to die than to progress to ESRD.5
The increased mor tality risk associated with CKD is likely the result of a significantly increased risk of cardiovascular events in patients with CKD. In patients with DM and CKD, both independent risk factors for cardiovascular disease (CVD), the mortality risk appears to be additive and is likely even higher in older patients.28 In the Medicare population, CVD is twice as common in individuals with CKD as compared with those without CKD.5 In a study of over 1 million adult ambulatory patients, the risk of a cardiovascular event progressively increased once the eGFR fell below 60 mL/min/1.73 m2, with a nearly 3.5-fold increased risk for patients with stage 5 CKD as compared with the general population.29 However, reduced renal function alone may not be the only marker of increased cardiovascular risk. Kidney damage, as evidenced by the development of microalbuminuria, may even better correlate with cardiovascular events, especially in patients with stages 1 and 2 CKD.30-34 For this reason, it is imperative that primary care providers and geriatricians recognize the importance of screening for DKD using spot UACRs and not simply rely on eGFRs, which are now routinely reported by most laboratories with every serum creatinine level.
Control of other confounding conditions, including blood pressure (BP), lipids, and hyperglycemia, is also important in optimizing patient care (Table 4).2,17,28,35-45
Most evidence regarding the benefits of tight glycemic control is based on studies of persons with type 1 DM; however, benefits have also been shown in persons with type 2 DM,2,35,46-50 although these data are inconclusive. Tight glycemic control is a cornerstone in DKD prevention, as a graded association exists (ie, for every 1% increase in hemoglobin A1c [HbA1c] levels, there is a 31% increased risk of developing CKD).35 Patients with an HbA1c level of higher than 8% were more than 3.5 times more likely to develop CKD as compared with those with an HbA1c level of less than 6%35; however, implementing intensive blood glucose control beyond current guidelines increases the risk of hy- poglycemia and possibly mor tality. This is par ticularly important in older patients, as the evidence of tight glucose control in this population is less clear. It is imperative to make decisions regarding glucose control in older patients on an individual basis. In frail patients who are over age 65 years with a life expectancy of fewer than 5 years or who are at high risk of adverse events from hypoglycemia, the HbA1c goal should be 8%.36
KDOQI BP recommendations are consistent with those of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), mandating a systolic BP goal of less than 130 mm Hg2,42; studies have shown increased progression to ESRD in persons with type 2 DM with a BP of greater than 130/80 mm Hg.37Based on the results of the Reduction of Endpoints in NIDDM [noninsulin- dependent diabetes mellitus] With the Angiotensin II Antagonist Losartan (RENAAL) study, it is estimated that the risk of progressing to ESRD increases by 37% for patients with a systolic BP of 140 to 159 mm Hg compared with patients with a systolic BP of less than 130 mm Hg, and the risk more than doubles in patients with a systolic BP of greater than 160 mm Hg.37 When adjusted for covariables, it was shown that for every 10-mm Hg increase in systolic BP, risk of ESRD or death increased by 6.7%.37 A lower BP goal of less than 125/75 mm Hg is recommended for all patients with proteinuria greater than 1 gram/day, regardless of the etiology of their renal disease.38-40
These goals, however, are inconsistent with data in older adults that show an increased rate of adverse events in patients with a BP of less than 140/90 mm Hg and recommendations to avoid a diastolic BP of less than 55 to 60 mm Hg in this population.41 More data are clearly needed on BP control in older patients with renal disease; therefore, management decisions should be made on an individual basis.
Smoking is associated with the development of microalbuminuria in persons with diabetes, and cessation has been shown to be beneficial in slowing the progression of DKD. In addition, smoking is a risk factor for CVD, and therefore should be discouraged.43,44
KDOQI dyslipidemia guidelines for patients with DM and CKD stages 1 to 4 recommend low-density lipoprotein cholesterol levels of less than 100 mg/dL or less than 70 mg/dL, if possible.2 A large meta-analysis of the use of statins in patients with CKD who were not on RRT revealed a decrease in all-cause mortality and cardiovascular deaths as compared with placebo.45 However, this benefit was not demonstrated in another meta-analysis of patients with diabetes already on dialysis,51 which suggests that screening and treatment of other nontraditional risk factors, including CKD-mineral bone disorder, may be of greater benefit in patients with more advanced DKD.
As important as identifying who to screen for DKD and understanding how to initiate appropriate treatment, clinicians should also be able to recognize when to refer a patient with DKD to a nephrologist. According to KDOQI guidelines, referral is typically warranted in patients with stage 4 CKD, but it should be considered in patients with DM with an eGFR of greater than 30 mL/ min/1.73 m2 and any one of the following comorbid conditions: microalbuminuria; hyperkalemia; or resistant hyper tension.42 Approximately 30% to 40% of patients with CKD are referred late to a nephrologist.52 Late referrals, defined as less than 120 days before the onset of ESRD, have been associated with a 2-fold increase in mortality 1 year after starting RRT.53 Patients with early referrals benefit from reduced rates of eGFR decline, higher albumin and hematocrit levels, shorter hospitalizations at the initiation of RRT, and better BP control and higher arteriovenous fistula rates.53,54 In addition, timely referral to a nephrologist may help establish goals of care and aid in the decision-making process regarding whether or not a patient—particularly an elderly patient with several comorbid conditions—is an appropriate candidate for RRT.
Early identification of DKD by clinicians with subsequent RAAS blockade and optimization of associated comorbid conditions, including nontraditional risk factors, will not only retard CKD progression, but may also reduce cardiovascular risk and improve overall survival. Although there is clearly a need for further research and newer therapeutic strategies, properly implementing current guidelines may greatly improve survival in this increasingly prevalent disease.
Editor's note: This article originally appeared in Clinical Geriatrics, April 2011, volume 19, pages 34 to 39. It is also available on the Clinical Geriatrics website.
1. Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United States. JAMA. 2007;298(17):2038-2047.
2. National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommen- dations for diabetes and chronic kidney disease. Am J Kidney Dis. 2007;49(2 suppl 2):S12-S154.
3. American Diabetes Association. Standards of medical care in diabetes–2007. Diabetes Care. 2007;30(suppl 1):S4-S41.
4. Weiner DE, Tighiouart H, Amin MG, et al. Chronic kidney disease as a risk factor for cardio- vascular disease and all cause mortality: a pooled analysis of community-based studies. J Am Soc Nephrol. 2004;15(5):1307-1315.
5. Collins AJ, Li S, Gilbertson DT, Liu J, Chen SC, Herzog CA. Chronic kidney disease and cardiovas- cular disease in the Medicare population. Kidney
Int Suppl. 2003;(87):S24-S31.
6. Keith DS, Nichols GA, Gullion CM, Brown JB, Smith DH. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med. 2004;164(6):659-663.
7. Adler AI, Stevens RJ, Manley SE, et al; UKPDS Group. Development and progression of nephropa- thy in type 2 diabetes: the United Kingdom Pro- spective Diabetes Study (UKPDS 64). Kidney Int. 2003;63(1):225-232.
8. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis. 2002;39(suppl 1):S1-S266.
9. Christiansen JS, Frandsen M, Parving HH. Effect of intravenous glucose infusion on renal func- tion in normal man and in insulin-dependent diabet- ics. Diabetologia. 1981;21(4):368-373. 10.RemuzziA,VibertiG,RuggenentiP,etal. Glomerular response to hyperglycemia in human
diabetic nephropathy. Am J Physiol. 1990;259(4 pt 2): F545-F552.
11. Skøtt P, Vaag A, Hother-Nielsen O, et al. Effects of hyperglycaemia on kidney function, atrial natri- uretic factor and plasma renin in patients with insu- lin-dependent diabetes mellitus. Scand J Clin Lab I nvest. 1991;51(8):715-727.
12. Christensen PK, Lund S, Parving HH. The impact of glycaemic control on autoregulation of glomerular filtration rate in patients with non-insu- lin dependent diabetes. Scand J Clin Lab Invest. 2001;61(1):43-50.
13. Winearls CG, Glassock RJ. Dissecting and re- fining the staging of chronic kidney disease. Kidney Int. 2009;75(10):1009-1014.
14. Glassock RJ, Winearls C. Ageing and the glomer ular filtration rate: tr uths and consequences. Trans Am Clin Climatol Assoc. 2009;120:419-428. 15. American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care. 2011;34(suppl 1):S11-S61.
16. Radbill B, Murphy B, LeRoith D. Rationale
and strategies for early detection and management of diabetic kidney disease. Mayo Clinic Proc. 2008;83(12):1373-1381.
17. Atkins RC, Briganti EM, Lewis JB, et al. Pro- teinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy. Am J Kidney Dis. 2005;45(2):281-287. 18. Ruilope LM. Angiotensin receptor blockers: RAAS blockade and renoprotection. Curr Med Res Opin. 2008;24(5):1285-1293.
19. Brenner BM, Cooper ME, de Zeeuw D, et al; RENAAL Study Investigators. Ef fects of losar tan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861-869.
20. Lewis EJ, Hunsicker LG, Clarke WR, et al; Collaborative Study Group. Renoprotective ef fect of the angiotensin-receptor antagonist irbesar tan in patients with nephropathy due to type 2 diabetes.
N Engl J Med. 2001;345(12):851-860.
21. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibi- tion on diabetic nephropathy. The Collaborative Study Group [published correction appears in
N Engl J Med. 1993;330(2):152]. N Engl J Med. 1993;329(20):1456-1462.
22. Mauer M, Zinman B, Gardiner R, et al. Renal and retinal effects of enalapril and losartan in type I diabetes. N Engl J Med. 2009;361(1):40-51.
23. Mann JF, Schmieder RE, McQueen M, et al; ONTARGET investigators. Renal outcomes with telmisartan, ramipril or both in people with high vas- cular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled study. Lancet. 2008;372(9638):547-553.
24. Fried LF, Duckworth W, Zhang JH, et al; VA NEPHRON-D Investigators. Design of combination angiotensin receptor blocker and angiotensin-con- verting enzyme inhibitor for treatment of diabetic nephropathy (VA NEPHRON-D). Clin J Am Soc Nephrol. 2009;4(2):361-368.
25. Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF. Aldosterone antagonists for preventing the progression of chronic kidney disease: a system- ic review and meta-analysis. Clin J Am Soc Nephrol. 2009;4(3):542-551.
26. Parving HH, Persson F, Lewis JB, et al; AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358(23):2433-2446.
27. Parving HH, Brenner BM, McMurray JJ, et al. Aliskiren Trial in Type 2 Diabetes Using Cardio- Renal Endpoints (ALTITUDE): rationale and
study design. Nephrol Dial Transplant. 2009;24(5): 1663-1671.
28. Foley RN, Murray AM, Li S, et al. Chronic kidney disease and the risk for cardiovascular dis- ease, renal replacement, and death in the United States Medicare population, 1998 to 1999. J Am Soc Nephrol. 2005;16(2):489-495.
29. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks
of death, cardiovascular events, and hospitalizations [published correction appears in N Engl J Med. 2008;18(4):4]. N Engl J Med. 2004;351(13): 1296-1305.
30. Gerstein HC, Mann JF, Yi Q, et al; HOPE
Study Investigators. Albuminuria and risk of cardio- vascular events, death and heart failure in diabetic and nondiabetic individuals. JAMA. 2001;286(4): 421-426.
31. Rifkin DE, Katz R, Chonchol M, et al. Albumin- uria, impaired kidney function and cardiovascular outcomes or mortality in the elderly. Nephrol Dial Transplant. 2010;25(5):1560-1567.
32. Klausen K, Borch-Johnsen K, Feldt-Rasmussen B, et al. Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension and diabetes. Circulation. 2004; 110(1):32-35.
33. Dinneen SF, Gerstein HC. The association of microalbuminuria and mortality in non-insulin- dependent diabetes mellitus. A systemic overview of the literature. Arch Intern Med. 1997;157(13): 1413-1418.
34. Brantsma AH, Bakker SJ, Hillege HL, et al; PREVEND Study Group. Cardiovascular and renal outcome in subjects with K/DOQI stage I-3 chronic kidney disease: the importance of urinary albumin excretion. Nephrol Dial Transplant. 2008;23(12):3851-3858.
35. Bash LD, Selvin E, Steffes M, Coresh J, Astor BC. Poor glycemic control in diabetes and the risk of incident chronic kidney disease even in the ab- sence of albuminuria and retinopathy: Atherosclero- sis Risk Communities (ARIC) Study. Arch Intern Med. 2008;168(22):2440-2447.
36. Brown AF, Mangione CM, Saliba D, et al; California Healthcare Foundation/American Geriat- rics Society Panel on Improving Care for Elders with Diabetes. Guidelines for improving the care of the older person with diabetes mellitus. J Am Geriatr Soc. 2003;51(5 suppl):S265-S280.
37. Bakris GL, Weir MR, Shanifar S, et al; RENAAL Study Group. Effects of blood pressure level on progression of diabetic nephropathy: results from the RENAAL study. Arch Intern Med. 2003;163(13): 1555-1565.
38. Bakris GL, Williams M, Dworkin L, Elliott WJ, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36(3):646-661.
39. Lazarus JM, Bourgoignie JJ, Buckalew VM,
et al. Achievement and safety of a low blood pres- sure goal in chronic renal disease. The Modification of Diet in Renal Disease Study Group. Hypertension. 1997;29(2):641-650.
40. Peterson JC, Adler S, Burkart JM, et al. Blood pressure control, proteinuria, and the progression
of renal disease. The Modification of Diet in
Renal Disease Study. Ann Intern Med. 1995;123(10): 754-762.
41. Weiss JW, Petrik AF, Thorp ML. Identification and management of chronic kidney disease in older adults. Clinical Geriatrics. 2011;19(2):33-37.
42. K/DOQI clinical practice guidelines on hyper- tension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004;43(5 suppl 1): S1-S290.
43. Thomas SM, Viberti GC. Cardiovascular risk in diabetic kidney disease: a model of chronic renal disease. Kidney Int. 2005;68(S98):S18-S20.
44. Phisitkul K, Hegazy K, Chuahirun T, et al. Con- tinued smoking exacerbates but cessation amelio- rates progression of early type 2 diabetic nephropa- thy. Am J Med Sci. 2008;335(4):284-291.
45. Navaneethan SD, Pansini F, Perkovic V, et al. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev. 2009;(2):CD00784.
46. Gaster B, Hirsch IB. The effects of improved glycemic control on complications in type 2 diabetes. Arch Intern Med. 1998;158(2):134-140.
47. Stratton IM, Adler AI, Neil AW, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): a pro- spective obser vational study. BMJ. 2000;321(7258): 404-412.
48. Intensive blood glucose control with sulphonyl- ureas or insulin compared with conventional treat- ment and risk of complications in patients with
type 2 diabetes (UKPDS 33). UK Prospective Dia- betes Study (UKPDS) Group [published correction appears in Lancet. 1999;354(9178):602]. Lancet. 1998;352(9131):837-853.
49. Levin SR, Coburn JW, Abraira C, et al. Effect of intensive glycemic control on microalbuminuria in type 2 diabetes. Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes Feasibility Trial Investigators. Diabetes Care. 2000;23(10):1478-1485.
50. Ohkubo Y, Kishikawa H, Araki E, et al. Inten- sive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin dependent diabetes melli- tus: a randomized prospective 6 year study. Diabetes Res Clin Pract. 1995;28(2):103-117.
51. Navaneethan SD, Nigwekar SU, Perkovic V,
et al. HMG CoA reductase inhibitors (statins) for dialysis patients. Cochrane Database Syst Rev. 2009;(3):CD004289.
52. Lee BJ, Forbes K. The role of specialists in managing the health of populations with chronic illness: the example of chronic kidney disease. BMJ. 2009;339:b2395. doi:10.1136/bmj.2395.
53. Chan MR, Dall AT, Fletcher KE, Lu N, Trivedi H. Outcomes in patients with chronic kidney dis- ease referred late to nephrologists: a meta-analysis. Am J Med. 2007;120(12):1063-1070.
54. Jones C, Roderick P, Harris S, Rogerson M. Decline in kidney function before and after nephrol- ogy referral and the effect on survival in moderate to advanced chronic kidney disease. Nephrol Dial Transplant. 2006;21(8):2133-2143.