Rationale and Strategies for Early Detection and Management of Diabetic Kidney Disease

Abstract

Diabetic kidney disease (DKD) occurs in 20% to 40% of patients with diabetes mellitus and is the leading cause of chronic kidney disease and end-stage renal disease in the United States. Despite the American Diabetes Association and the National Kidney Foundation advocating annual screening of diabetic patients, DKD remains underdiagnosed in the diabetic population. Early recognition of diabetic nephropathy by health care professionals is vital for proper management. The presence of microalbuminuria is particularly important as even low levels of dipstick-negative albuminuria indicate early disease long before a diminished glomerular filtration rate and are associated with an elevated cardiovascular disease risk. Like all forms of chronic kidney disease, DKD causes a progressive decline in renal function that, despite current treatment strategies, is largely irreversible. Many patients with DKD might be expected to develop end-stage renal disease, but many more patients will likely die of a cardiovascular event before renal replacement therapy is needed. Therefore, a renewed focus on cardiovascular risk factor reduction and a timely nephrology consultation with an emphasis on patient education is essential to proper DKD management. Diabetic kidney disease (DKD) occurs in 20% to 40% of patients with diabetes mellitus and is the leading cause of chronic kidney disease and end-stage renal disease in the United States. Despite the American Diabetes Association and the National Kidney Foundation advocating annual screening of diabetic patients, DKD remains underdiagnosed in the diabetic population. Early recognition of diabetic nephropathy by health care professionals is vital for proper management. The presence of microalbuminuria is particularly important as even low levels of dipstick-negative albuminuria indicate early disease long before a diminished glomerular filtration rate and are associated with an elevated cardiovascular disease risk. Like all forms of chronic kidney disease, DKD causes a progressive decline in renal function that, despite current treatment strategies, is largely irreversible. Many patients with DKD might be expected to develop end-stage renal disease, but many more patients will likely die of a cardiovascular event before renal replacement therapy is needed. Therefore, a renewed focus on cardiovascular risk factor reduction and a timely nephrology consultation with an emphasis on patient education is essential to proper DKD management. The prevalence of both diabetes mellitus (DM) and chronic kidney disease (CKD) is steadily increasing in the United States. Current estimates suggest that 7% of the population (approximately 21 million people) have DM and that 13% of the population (approximately 26 million people) have CKD.1KDOQI KDOQI Clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease.Am J Kidney Dis. 2007; 49: S12-S154PubMed Google Scholar, 2Coresh J Selvin E Stevens LA et al.Prevalence of chronic kidney disease in the United States.JAMA. 2007; 298: 2038-2047Crossref PubMed Scopus (3881) Google Scholar It may be argued that histologic findings of diabetic nephropathy, including glomerular basement membrane thickening and mesangial matrix expansion, are present in all patients with DM. However, diabetic kidney disease (DKD), defined as an elevated albumin excretion rate in a person with DM, occurs in 20% to 40% of patients with DM and is the leading cause of CKD and end-stage renal disease (ESRD) in the United States.1KDOQI KDOQI Clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease.Am J Kidney Dis. 2007; 49: S12-S154PubMed Google Scholar, 3American Diabetes Association Standards of medical care in diabetes—2007.Diabetes Care. 2007; 30: S4-S41Crossref PubMed Scopus (1524) Google Scholar The increased prevalence of CKD is no doubt linked to the increased prevalence of DKD and DM, which is attributed largely to a dramatic increase in the obesity rate.4Engelgau MM Geiss LS Saaddine JB et al.The evolving diabetes burden in the United States.Ann Intern Med. 2004; 140: 945-950Crossref PubMed Scopus (545) Google Scholar In response to the growing prevalence of DKD and DM, which is increasingly recognized as an epidemic, the American Diabetes Association (ADA) and the National Kidney Foundation (NKF) have advocated annual screening for DKD in patients with DM by measuring their serum creatinine and albuminuria levels.1KDOQI KDOQI Clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease.Am J Kidney Dis. 2007; 49: S12-S154PubMed Google Scholar, 3American Diabetes Association Standards of medical care in diabetes—2007.Diabetes Care. 2007; 30: S4-S41Crossref PubMed Scopus (1524) Google Scholar Despite these recommendations, DKD remains underdiagnosed in the DM population.5Middleton RJ Foley RN Hegarty J et al.The unrecognized prevalence of chronic kidney disease in diabetes.Nephrol Dial Transplant. 2006 Jan; 21 (Epub 2005 Oct 12.): 88-92Crossref PubMed Scopus (135) Google Scholar, 6McClellan WM Knight DF Karp H Brown WW Early detection and treatment of renal disease in hospitalized diabetic and hypertensive patients: important differences between practice and published guidelines.Am J Kidney Dis. 1997; 29: 368-375Abstract Full Text PDF PubMed Scopus (148) Google Scholar, 7Kraft SK Lazaridis EN Qiu C Clark Jr, CM Marrero DG Screening and treatment of diabetic nephropathy by primary care physicians.J Gen Intern Med. 1999; 14: 88-97Crossref PubMed Scopus (29) Google Scholar In a review of Medicare beneficiaries' records, proteinuria was measured in only 63% of patients with DM.6McClellan WM Knight DF Karp H Brown WW Early detection and treatment of renal disease in hospitalized diabetic and hypertensive patients: important differences between practice and published guidelines.Am J Kidney Dis. 1997; 29: 368-375Abstract Full Text PDF PubMed Scopus (148) Google Scholar Furthermore, in a survey of more than 1000 primary care physicians, only 12% detected microalbuminuria in more than half of their patients with type 2 DM.7Kraft SK Lazaridis EN Qiu C Clark Jr, CM Marrero DG Screening and treatment of diabetic nephropathy by primary care physicians.J Gen Intern Med. 1999; 14: 88-97Crossref PubMed Scopus (29) Google Scholar Assessment of microalbuminuria is particularly important in diagnosing DKD because low levels of dipstick-negative albuminuria are an early clinical manifestation of diabetic nephropathy that may present several years before development of a diminished glomerular filtration rate (GFR). Spot urine samples have replaced the need for timed urine collections and can be used to easily identify patients with elevated albumin excretion rates by measuring the albumin-to-creatinine ratio (ACR). Once an elevated ACR has been detected, interventions should be initiated to slow the progression of DKD and possibly minimize the increased cardiovascular risk associated with DKD, a risk that exists even in the early stages of DKD. Although DM has long been identified as a cardiovascular disease (CVD) risk equivalent, only recently has CKD been more widely recognized by primary care physicians in the United States as an independent risk factor for CVD and all-cause mortality.8Kidney Disease Outcomes Quality Initiative (K/DOQI) K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease.Am J Kidney Dis. 2004 May; 43: S1-S290PubMed Google Scholar, 9Levey AS Coresh J Balk E et al.National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification.Ann Intern Med. 2003; 139: 137-147Crossref PubMed Scopus (3671) Google Scholar, 10Weiner DE Tighiouart H Stark PC et al.Kidney disease as a risk factor for recurrent cardiovascular disease and mortality.Am J Kidney Dis. 2004; 44: 198-206Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar, 11Go AS Chertow GM Fan D McCulloch CE Hsu CY Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (8986) Google Scholar In a study of more than 1 million ambulatory adult patients, the risk of a cardiovascular event and death due to any cause increased at every level of CKD below a GFR of 60 mL/min per 1.73 m2, with a nearly 3.5-fold increased risk of a cardiovascular event and a 6-fold increased risk of death for those with a GFR of less than 15 mL/min per 1.73 m2 (ie, CKD stage 5).11Go AS Chertow GM Fan D McCulloch CE Hsu CY Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (8986) Google Scholar Furthermore, microalbuminuria alone has been associated with an increased risk of cardiovascular disease, both in patients with and without DM.12Klausen 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 Jul 6; 110 (Epub 2004 Jun 21.): 32-35Crossref PubMed Scopus (569) Google Scholar, 13Gerstein HC Mann JFE Yi Q HOPE Study Investigators et al.Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals.JAMA. 2001; 286: 421-426Crossref PubMed Scopus (2053) Google Scholar, 14Dinneen SF Gerstein HC The association of microalbuminuria and mortality in non-insulin-dependent diabetes mellitus: a systematic overview of the literature.Arch Intern Med. 1997; 157: 1413-1418Crossref PubMed Google Scholar Therefore, in patients with DKD, the cardiovascular risks of DM and CKD are additive and increase as the kidney disease progresses.15Adler AI Stevens RJ Manley SE Bilous RW Cull CA Holman RR UKPDS Group Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64).Kidney Int. 2003; 63: 225-232Crossref PubMed Scopus (1366) Google Scholar, 16Miettinen H Haffner SM Lehto S Rönnemaa T Pyörälä K Laakso M Proteinuria predicts stroke and other atherosclerotic vascular disease events in nondiabetic and non-insulin-dependent diabetic subjects.Stroke. 1996; 27: 2033-2039Crossref PubMed Scopus (242) Google Scholar, 17Valmadrid CT Klein R Moss SE Klein BE The risk of cardiovascular disease mortality associated with microalbuminuria and gross proteinuria in persons with older-onset diabetes mellitus.Arch Intern Med. 2000; 160: 1093-1100Crossref PubMed Scopus (395) Google ScholarThe current article presents results of a literature review conducted to clarify the rationale and strategies for early detection and management of DKD. The National Library of Medicine's PubMed database was used to conduct a review of literature published between January 1976 and June 2008. The following key terms were used in the search: diabetes, kidney disease, microalbuminuria, glomerular filtration rate, and diabetic nephropathy. The kidneys receive 25% of the cardiac output of blood. Although 20% of renal plasma flow (ie, approximately 180 L) is filtered through the glomerulus, only small amounts of protein can be detected in the urine.18Jefferson JA Shankland SJ Pichler RH Proteinuria in diabetic kidney disease: a mechanistic viewpoint.Kidney Int. 2008 Jul; 74 (Epub 2008 Apr 16.): 22-36Crossref PubMed Scopus (305) Google Scholar Several plasma proteins are freely filtered, whereas others are prevented from crossing the glomerular filtration barrier, based on the proteins' molecular size and charge. The existence of several restrictive pores and of a glomerular charge barrier has been proposed to explain why the glomerulus is relatively impermeable to proteins of greater molecular weight (ie, >100 kDa) and to negatively charged proteins (eg, albumin).18Jefferson JA Shankland SJ Pichler RH Proteinuria in diabetic kidney disease: a mechanistic viewpoint.Kidney Int. 2008 Jul; 74 (Epub 2008 Apr 16.): 22-36Crossref PubMed Scopus (305) Google Scholar More recently, it has been suggested that, under normal conditions, a substantial amount of plasma protein, possibly at nephrotic levels, is filtered through the glomerulus, but proteinuria is prevented because of proximal tubule cell retrieval.19Russo LM Sandoval RM McKee M et al.The normal kidney filters nephrotic levels of albumin retrieved by proximal tubule cells: retrieval is disrupted in nephrotic states.Kidney Int. 2007 Mar; 71 (Epub 2007 Jan 17.): 504-513Crossref PubMed Scopus (329) Google Scholar According to this idea, damage that disrupts the glomerular filtration barrier, or possibly the proximal tubular system, allows larger, negatively charged proteins that are normally contained within the serum to pass into the urine. The presence of such proteins, typically albumin, in the urine is an abnormal condition and is often one of the first signs of various forms of CKD, including DKD. Chronic kidney disease is defined as kidney damage identified by proteinuria or by a GFR of less than 60 mL/min per 1.73 m2 body surface area (with or without evidence of kidney damage) for 3 months or longer.8Kidney Disease Outcomes Quality Initiative (K/DOQI) K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease.Am J Kidney Dis. 2004 May; 43: S1-S290PubMed Google Scholar, 9Levey AS Coresh J Balk E et al.National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification.Ann Intern Med. 2003; 139: 137-147Crossref PubMed Scopus (3671) Google Scholar Table 1 shows the stages of CKD and the recommended treatments at each stage. In patients with DKD, the disease process begins with renal hypertrophy and hyperfiltration resulting from elevated renal plasma flow. In patients with type 1 DM and type 2 DM, hyperglycemia leads to increases in GFR of approximately 5% to 10%.20Christiansen JS Frandsen M Parving HH Effect of intravenous glucose infusion on renal function in normal man and in insulin-dependent diabetics.Diabetologia. 1981; 21: 368-373Crossref PubMed Scopus (106) Google Scholar, 21Remuzzi A Viberti G Ruggenenti P Battaglia C Pagni R Remuzzi G Glomerular response to hyperglycemia in human diabetic nephropathy.Am J Physiol. 1990; 259: F545-F552PubMed Google Scholar, 22Skøtt P Vaag A Hother-Nielsen O et al.Effects of hyperglycaemia on kidney function, atrial natriuretic factor and plasma renin in patients with insulin-dependent diabetes mellitus.Scand J Clin Lab Invest. 1991; 51: 715-727Crossref PubMed Scopus (40) Google Scholar, 23Christensen PK Lund S Parving HH The impact of glycaemic control on autoregulation of glomerular filtration rate in patients with non-insulin dependent diabetes.Scand J Clin Lab Invest. 2001; 61: 43-50Crossref PubMed Scopus (29) Google Scholar Although the mechanism is not completely understood, a correlation exists between glycosylated hemoglobin (HbA1c) and GFR, and normalization of blood sugar levels has been shown to normalize GFR.24Rigalleau V Lasseur C Raffaitin C et al.Glucose control influences glomerular filtration rate and its prediction in diabetic subjects.Diabetes Care. 2006; 29: 1491-1495Crossref PubMed Scopus (42) Google Scholar, 25Vora JP Dolben J Williams JD Peters JR Owens DR Impact of initial treatment on renal function in newly-diagnosed type 2 (non-insulin-dependent) diabetes mellitus.Diabetologia. 1993; 36: 734-740Crossref PubMed Scopus (42) Google Scholar Other factors that influence hyperfiltration include increased ketone concentration, increased activity of the growth hormone/insulin-like growth factor system,26Cingel-Ristíc V Flyvbjerg A Drop SL The physiological and pathophysiological roles of the GH/IGF-axis in the kidney: lessons from experimental rodent models.Growth Horm IGF Res. 2004; 14: 418-430Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar and disturbances in renal prostaglandins and the kallikrein-kinin system. In early-stage CKD, these abnormalities are frequently associated with enlarged kidneys.27Trevisan R Viberti G Pathophysiology of diabetic nephropathy.in: LeRoith D Taylor SI Olefsky JM Diabetes Mellitus: A Fundamental and Clinical Text. 2nd ed. Lippincott Williams & Wilkins, Philadelphia, PA2000: 898-909Google ScholarTABLE 1Stages of Chronic Kidney Disease and Recommended TreatmentaACR = albumin-to-creatinine ratio; CVD = cardiovascular disease; ESA = erythropoietic stimulating agent; ESRD = end-stage renal disease; GFR = glomerular filtration rate; MDRD = Modification of Diet in Renal Disease.Data from Ann Intern Med.9Levey AS Coresh J Balk E et al.National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification.Ann Intern Med. 2003; 139: 137-147Crossref PubMed Scopus (3671) Google ScholarStageDescriptionGFR (mL/min per 1.73 m2)TreatmentbIncludes treatments from preceding stages.1Kidney damagecDefined as abnormalities on pathologic, urine, blood, or imaging tests. with normal or elevated GFR≥90Manage comorbid conditions, slow progressiondGlycemie control plus angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker., reduce CVD risk2Kidney damagecDefined as abnormalities on pathologic, urine, blood, or imaging tests. with mildly reduced GFR60-89Estimate progression as follows: compare serial estimated GFRs using serum creatinine and MDRD calculation, track ACR3Moderately reduced GFR30-59Evaluate and manage complications as follows: (1) measure serum phosphorus level, consider use of phosphate binders and low-phosphorus diet; (2) measure vitamin D and parathyroid hormone levels, consider use of vitamin D supplementation; (3) measure hemoglobin, consider use of ESA4Severely reduced GFR15-29Prepare for kidney replacement therapy5Kidney failure (ESRD)<15 or dialysisKidney replacement (if uremia present)a ACR = albumin-to-creatinine ratio; CVD = cardiovascular disease; ESA = erythropoietic stimulating agent; ESRD = end-stage renal disease; GFR = glomerular filtration rate; MDRD = Modification of Diet in Renal Disease.b Includes treatments from preceding stages.c Defined as abnormalities on pathologic, urine, blood, or imaging tests.d Glycemie control plus angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker. Open table in a new tab Hyperfiltration is typically followed by the loss of the negatively charged glomerular filtration barrier, allowing for negatively charged proteins, such as albumin, to pass through the glomerulus and into the urinary space. The presence of these proteins in the urinary space elevates urinary albumin excretion and produces microalbuminuria.27Trevisan R Viberti G Pathophysiology of diabetic nephropathy.in: LeRoith D Taylor SI Olefsky JM Diabetes Mellitus: A Fundamental and Clinical Text. 2nd ed. Lippincott Williams & Wilkins, Philadelphia, PA2000: 898-909Google Scholar Microalbuminuria is defined as an albumin excretion rate between 30 and 300 mg per 24 hours, a range higher than the normal rate (<30 mg per 24 hours) but below the rate detectable by the standard urine dipstick method.8Kidney Disease Outcomes Quality Initiative (K/DOQI) K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease.Am J Kidney Dis. 2004 May; 43: S1-S290PubMed Google Scholar Overexcretion of albumin typically increases at a rate of 15% per year28Feldt-Rasmussen B Mathiesen ER Deckert T Effect of two years of strict metabolic control on progression of incipient nephropathy in insulin-dependent diabetes.Lancet. 1986; 2: 1300-1304Abstract PubMed Scopus (373) Google Scholar and can result in macroalbuminuria (>300 mg per 24 hours) or even nephrotic-range proteinuria (>3.5 g per 24 hours). In general, once macroalbuminuria (frank proteinuria) sets in, GFR begins to decline.29Nelson RG Bennett PH Beck GJ Diabetic Renal Disease Study Group et al.Development and progression of renal disease in Pima Indians with noninsulin-dependent diabetes mellitus.N Engl J Med. 1996; 335: 1636-1642Crossref PubMed Scopus (403) Google Scholar Progressive mesangial and interstitial capillary occlusion then occur, restricting the glomerular filtration surface and leading to a further decrease in GFR. Some proteins are reabsorbed by the renal tubules and accumulate in tubular epithelial cells. This accumulation induces the release of vasoactive and inflammatory cytokines, which damage the renal tubules and lead to tubular atrophy and interstitial fibrosis.30Gruden G Gnudi L Viberti G Pathogenesis of diabetic nephropathy.in: LeRoith D Taylor SI Olefsky JM Diabetes Mellitus: A Fundamental and Clinical Text. 3rd ed. Lippincott Williams & Wilkins, Philadelphia, PA2004: 1315-1330Google Scholar A negative feedback loop is thereby initiated, wherein increased proteinuria leads to increased tubulointerstitial injury and renal scarring, both of which further reduce GFR.30Gruden G Gnudi L Viberti G Pathogenesis of diabetic nephropathy.in: LeRoith D Taylor SI Olefsky JM Diabetes Mellitus: A Fundamental and Clinical Text. 3rd ed. Lippincott Williams & Wilkins, Philadelphia, PA2004: 1315-1330Google Scholar Both hypertension and hyperglycemia are important in the development and progression of microalbuminuria and DKD. Table 2 presents a list of disorders associated with microalbuminuria. Several studies have shown that blood pressure elevations either precede or occur in conjunction with microalbuminuria in patients with both type 1 DM and type 2 DM.29Nelson RG Bennett PH Beck GJ Diabetic Renal Disease Study Group et al.Development and progression of renal disease in Pima Indians with noninsulin-dependent diabetes mellitus.N Engl J Med. 1996; 335: 1636-1642Crossref PubMed Scopus (403) Google Scholar, 31Poulsen PL Hansen KW Mogensen CE Ambulatory blood pressure in the transition from normo- to microalbuminuria: a longitudinal study in IDDM patients.Diabetes. 1994; 43: 1248-1253Crossref PubMed Google Scholar, 32Microalbuminuria Collaborative Study Group, United KingdomRisk factors for development of microalbuminuria in insulin dependent diabetic patients: a cohort study.BMJ. 1993; 306: 1235-1239Crossref PubMed Google Scholar Among patients with type 1 DM and DKD, those with increased urinary albumin excretion were found to be prehypertensive (120-139/80-89 mm Hg) at baseline, and their blood pressure and albuminuria levels increased in synch thereafter.31Poulsen PL Hansen KW Mogensen CE Ambulatory blood pressure in the transition from normo- to microalbuminuria: a longitudinal study in IDDM patients.Diabetes. 1994; 43: 1248-1253Crossref PubMed Google Scholar, 32Microalbuminuria Collaborative Study Group, United KingdomRisk factors for development of microalbuminuria in insulin dependent diabetic patients: a cohort study.BMJ. 1993; 306: 1235-1239Crossref PubMed Google Scholar These elevations happened even though overt hypertension was not present before the onset of microalbuminuria. In patients with type 1 DM and DKD, blood pressure elevations before the onset of DM correlated with the future development of microalbuminuria.33Nelson RG Pettitt DJ Baird HR et al.Pre-diabetic blood pressure predicts urinary albumin excretion after the onset of type 2 (non-insulin-dependent) diabetes mellitus in Pima Indians.Diabetologia. 1993; 36: 998-1001Crossref PubMed Scopus (100) Google ScholarTABLE 2Disorders Associated With Microalbuminuria Elevated blood pressureDyslipidemiaElevated fibrinogen and plasminogen activator inhibitor 1Increased insulin resistanceIncreased sodium disorders and related disordersIncreased transcapillary escape rate of albuminImpaired basal endothelium-dependent vasorelaxationIncreased left ventricular volumeDiabetic retinopathyDiabetic neuropathyPeripheral vascular diseaseSilent ischemie heart disease Open table in a new tab As previously mentioned, hyperglycemia can affect GFR and is necessary for the development of DKD. Likely mechanisms by which elevated glucose levels cause kidney damage include accumulation of advanced glycation end products, glucose-induced growth factor expression, and increased expression of inflammatory factors. However, hyperglycemia alone is insufficient to cause renal dysfunction.30Gruden G Gnudi L Viberti G Pathogenesis of diabetic nephropathy.in: LeRoith D Taylor SI Olefsky JM Diabetes Mellitus: A Fundamental and Clinical Text. 3rd ed. Lippincott Williams & Wilkins, Philadelphia, PA2004: 1315-1330Google Scholar Most patients with DM never have clinically evident DKD, despite poor glycemic control. The absence of DKD in these patients suggests a genetic predisposition for DKD. The existence of such a predisposition is supported by studies showing an increased risk of nephropathy among people with a family history of the disorder.34Seaquist ER Goetz FC Rich S Barbosa J Familial clustering of diabetic kidney disease: evidence for genetic susceptibility to diabetic nephropathy.N Engl J Med. 1989; 320: 1161-1165Crossref PubMed Scopus (906) Google Scholar, 35Pettitt DJ Saad MF Bennett PH Nelson RG Knowler WC Familial predisposition to renal disease in two generations of Pima Indians with type 2 (non-insulin-dependent) diabetes mellitus.Diabetologia. 1990; 33: 438-443Crossref PubMed Scopus (372) Google Scholar, 36Harjutsalo V Katoh S Sarti C Tajima N Tuomilehto J Population-based assessment of familial clustering of diabetic nephropathy in type 1 diabetes.Diabetes. 2004; 53: 2449-2454Crossref PubMed Scopus (82) Google Scholar Nevertheless, in susceptible individuals, hyperglycemia plays a crucial role in the progression of DKD from microalbuminuria to renal insufficiency and ESRD, as shown in type 1 DM by the Diabetes Control and Complications Trial37Diabetes Control and Complications Trial Research Group The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.N Engl J Med. 1993; 329: 977-986Crossref PubMed Scopus (22708) Google Scholar and in type 2 DM by the United Kingdom Prospective Diabetes Study.38UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet. 1998; 352: 837-853Abstract Full Text Full Text PDF PubMed Scopus (18950) Google Scholar Both these studies conclusively showed that the development and progression of DKD are strongly correlated with deficiencies in glucosecontrol, verifying that glycemic control remains one of the cornerstones of treatment of DKD. The ADA recommends that both microalbuminuria and serum creatinine levels be assessed annually in patients with DM to screen for DKD.3American Diabetes Association Standards of medical care in diabetes—2007.Diabetes Care. 2007; 30: S4-S41Crossref PubMed Scopus (1524) Google Scholar For patients with type 1 DM, screening should begin 5 years after diagnosis because it takes at least that long for signs of nephropathy to develop. For patients with type 2 DM, screening should begin immediately at diagnosis because the precise onset of DM is often less clear, and the kidneys may have already sustained damage from years of undiagnosed hyperglycemia and/or hypertension. After evidence of DKD has been detected, ongoing evaluations should be based on measurements of GFR.3American Diabetes Association Standards of medical care in diabetes—2007.Diabetes Care. 2007; 30: S4-S41Crossref PubMed Scopus (1524) Google Scholar However, in clinical practice, albuminuria is also typically measured to monitor disease progression and optimize therapy. The following sections review the various methods used to measure GFR and albuminuria, focusing on the benefits and limitations of each. Glomerular Filtration Rate. An index of functioning renal mass, GFR assessment is the most reliable method of detecting and monitoring renal impairment. Glomerular filtration rate can be measured directly or it can be estimated indirectly using the Modification of Diet in Renal Disease (MDRD) or Cockcroft-Gault equations. Simple measurement of serum creatinine is not recommended as an estimate of GFR because creatinine levels are greatly influenced by an individual's muscle mass, and thus simple measurements may overestimate or underestimate true GFR. Another reason that serum creatinine measurements may lead to an overestimation of GFR is that creatinine is cleared via secretion by the proximal tubule, and extrarenal excretion of creatinine is common in patients with more advanced CKD.3American Diabetes Association Standards of medical care in diabetes—2007.Diabetes Care. 2007; 30: S4-S41Crossref PubMed Scopus (1524) Google Scholar, 8Kidney Disease Outcomes Quality Initiative (K/DOQI) K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease.Am J Kidney Dis. 2004 May; 43: S1-S290PubMed Google Scholar, 9Levey AS Coresh J Balk E et al.National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification.Ann Intern Med. 2003; 139: 137-147Crossref PubMed Scopus (3671) Google Scholar Direct measurement of the fractional excretion of inulin, a fructose polysaccharide, is considered the criterion standard for GFR measurement. Inulin is inert, freely filtered at the glomerulus, and neither secreted, reabsorbed, synthesized, nor metabolized by the kidneys. However, using inulin infusion to measure GFR is expensive, cumbersome, and not widely available. An alternative method for measuring GFR involves