Nephrology Hypertension

Diabetic Kidney Disease: General management

Does this patient have diabetic kidney disease?

History, signs and symptoms

The two chief signs of diabetic kidney disease (DKD) are increased urinary albumin excretion and reduced kidney function, as measured by estimated glomerular filtration rate (eGFR) based on serum creatinine.

Urine albumin excretion: Higher levels of urine albumin excretion are continuously correlated with severity of kidney disease, but thresholds are commonly used to categorize DKD (Table 1). Microalbuminuria, defined as an albumin-to-creatinine ratio (ACR) of 30-300 mg/g, occurs in 20-30% of diabetics after 5-15 years of disease. Macroalbuminuria, defined as an ACR >300 mg/g, is usually seen after approximately 10 years of disease and gradually increases with time.

Table 1.

Classification of urine albumin excretion
Albumin-creatinine ratio (ACR) Albumin excretion rate (AER)
Normal < 30 mg/g < 30 mg/24hr
Microalbuminuria 30-299 mg/g 30/299 mg/24hr
Macroalbuminuria ≥ 300 mg/g ≥ 300 mg/24hr

Glomerular filtration rate: GFR is estimated from serum creatinine concentration (eGFR). Impaired GFR, usually defined as eGFR < 60 m/min/1.73m2, represents a measure of kidney damage that is complementary to albuminuria. While it was previously thought that DKD generally manifested first with abnormal urine albumin excretion rate, it is now shown that in a subset of diabetics, it presents by a reduction in GFR in setting of normal urine albumin excretion.

Hypertension: In people with type 1 diabetes, increase in urine albumin excretion is closely correlated with the onset of hypertension. The blood pressure begins to rise around the time microalbuminuria develops and continues to rise with worsening kidney function. In comparison, approximately 40% of people with type 2 diabetes are hypertensive at diagnosis of diabetes and in nearly half of these patients, hypertension predates microalbuminuria. Furthermore, among people with type 2 diabetes, hypertension is strongly associated with obesity. For more details on signs and symptoms, please see section below, "Does the patient have diabetic kidney disease?."

Other kidney diseases in differential

Differential diagnoses of proteinuric kidney disease in diabetic patients includes other proteinuric glomerular diseases, such as focal segmental glomerulosclerosis, IgA nephropathy, membranous glomerulonephritis, minimal change disease, amyloid kidney disease, lupus nephritis, HIV nephropathy, HCV/HBV-associated kidney disease, etc.

Differential diagnosis for non-proteinuric kidney disease falls along pre-renal, renal and post-renal categories, as detailed in the section on diagnosis of acute kidney injury. However, a few conditions that are frequently responsible for acute increases in serum creatinine in diabetic patients include volume depletion (e.g. due to diuretics), particularly in the setting of RAAS blockade; urinary obstruction; and adverse effects of medications (eg, NSAIDs, medications causing allergic interstitial nephritis).

Red flags suggesting non-DKD etiologies for kidney disease in diabetic patients

  • Albuminuria <5 yrs after the onset of type 1 diabetes

  • Nephrotic-range proteinuria (albumin-creatinine ratio [ACR] > 3g/g or albumin excretion rate [AER] >3g/24hr)

  • Acute drop in GFR or rise in urine albumin excretion

  • Refractory hypertension

  • Hematuria or otherwise active urine sediment , eg, dysmorphic red blood cells [RBCs] and cellular casts

  • Absence of diabetic retinopathy (DR) in type 1 diabetics (DKD is seen in absence of DR in as many as half of type 2 diabetic patients in small series)

  • >30% GFR drop in 2-3 months after renin-angiotensin-aldosterone system (RAAS) blockade

  • Signs/symptoms of other systemic disease

Other microvascular complications (retinopathy, neuropathy): Most type 1 diabetics with DKD have DR, which usually precedes kidney disease (reverse is not the case, ie, most DR patients do not have DKD). Association between DR and DKD is less certain in type 2 diabetes. There is a close association between DR and presence of Kimmelstiel-Wilson nodules on kidney biopsy. Type 2 diabetics with DR and proteinuria are most likely to have DKD, while ~30% of type 2 diabetics without DR may have kidney disease due to other etiology.

Pathology

  • Class I- GBM thickening. No mesangial expansion, increased mesangial matrix or global glomerulosclerosis in >50% of glomeruli

  • Class II- Mild (IIa) or severe (IIb) mesangial expansion.

  • Class III- >1 Kimmelstiel-Wilson lesion (nodular intercapillary glomerulosclerosis), but less than 50% glomerulosclerosis

  • Class IV- advanced sclerosis. >50% glomerulosclerosis attributable to DKD.

What tests to perform?

Urine albumin excretion

Urine albumin excretion should be measured annually in all diabetic patients, starting at diagnosis for type 2 diabetics and 5 years after diabetes onset in type 1 diabetics. Urine albumin excretion should be measured using an albumin-to-creatinine ratio (ACR) in a random urine sample. Urine dipstick is not an appropriate test because it only detects urine albumin excretion exceeding 300-500 mg/L and is susceptible to error due to urine volume and dilution.

ACR indexes urine albumin to urine creatinine concentration, which corrects for changes in urine dilution. ACR is also preferable to albumin excretion rate as the latter requires a timed urine collection, which is cumbersome and error-prone. ACR can be transiently increased in setting of fever, exercise, poor glycemic control, uncontrolled hypertension, decompensated congestive heart failure, high dietary protein intake and in presence of urinary tract infections. Therefore, an abnormal urine albumin excretion should be confirmed by 2-3 repeat ACRs over the subsequent 3-6 months.

Please refer to section above, "Does the patient have diabetic kidney disease?"for limitations of the above recommendations.

Glomerular filtration rate

Serum creatinine should be measured yearly starting at diagnosis of type 2 diabetes and 5 years after diabetes onset of type 1 diabetes, with changes to medications known to affect or be affected by kidney disease, and with acute illness. Serum creatinine should be used to estimate GFR using a validated estimating equation (currently Modification of Diet in Renal Disease [MDRD]), which also incorporates patient age, sex, and race. Estimated GFR < 60 mL/min/1.73m2 is abnormal and is used to grade severity of DKD (Table Y- CKD section).

The MDRD-estimated GFR is imprecise and less useful in the “normal” range (≥ 60 mL/min/1.73m2). Approaches using serum cystatin C have been suggested as a more precise alternative to estimating GFR in the “normal” range, but at this time the role of cystatin C in clinical care is poorly defined and cystatin C is not routinely available in clinical laboratories.

Urinalysis

Urinalysis is an informative, non-invasive and inexpensive test and should be performed in all patients with kidney disease (albuminuria or impaired eGFR). Relevant information gleaned from urinalysis includes presence of hematuria (red urinary pellet, RBC in microscopy), urinary tract infections (white blood cell count (WBC), bacteria, leukocyte esterase, etc), crystals and an active urine sediment (cellular casts, dysmorphic red blood cells).

Kidney imaging

Renal ultrasound is advisable if rise in serum creatinine is suspected to be due to urinary tract obstruction. It is also helpful for evaluation of baseline kidney size and disease chronicity. For example, small echogenic kidneys with high resistive indices suggest chronic irreversible disease. Ultrasound with Doppler is used to evaluate renal vascular flow, for example if deterioration of renal function is suspected to be due to renal arterial stenosis (eg, rapid rise in serum creatinine with RAAS blockade).

Retinopathy evaluation

In type 1 diabetics, prevalence of other microvascular diabetic complications such as retinopathy and neuropathy correlates with the presence of albuminuria. For example, proliferative retinopathy was reported in 12%, 28% and 58% of patients with normo-, micro- and macroalbuminuria, respectively. Presence of DR also corroborates the diabetic etiology of kidney disease. Patients with DKD attributable to type 2 diabetes have retinopathy in only approximately 50% of cases; the presence of diabetic retinopathy in this group increases the likelihood that kidney disease is due to diabetes, but the absence of retinopathy does not rule out kidney disease due to diabetes. Therefore, concomitant retinopathy evaluation is prudent in both type 1 and type 2 diabetic patients.

Referral to nephrologist

Per K/DOQI guidelines, patients should be referred to a nephrologist if their clinical course is not consistent with DKD or if they display signs of other causes of kidney disease (see red flags in section above, "Does the patient have diabetic kidney disease?"). Patients with eGFR below 30 ml/min should be referred to a nephrologist for education and planning for renal replacement therapy and close management of chronic kidney disease complications even if the clinical course is consistent with DKD.

Kidney biopsy: Kidney biopsy is not commonly performed in diabetic patients with kidney disease unless their clinical course is not consistent with DKD (eg, acute loss of kidney function or rise in proteinuria) or if they display signs of other causes of kidney disease (eg, hematuria, an active urinary sediment). Some of the relative contraindications for kidney biopsy are small hyperechoic kidneys (<9cm) which suggest chronic irreversible disease (and likely fibrosed and pathologically uninformative tissue), solitary native kidney, severe hypertension and uncorrectable bleeding diatheses.

Limitations:

The ideal time for measuring albumin-to-creatinine ratio is not certain. As such and in light of clinical convenience, ACR measurement is recommended in random voided urine samples.

Accurate conversion of ACR to absolute daily albumin excretion depends on the assumption of daily creatinine excretion of ~1g. Therefore, extreme departures from the 1g daily creatinine excretion tends to over- or under-estimate daily albumin excretion in individuals with much lower or higher daily creatinine excretion, respectively (eg, a cachectic older woman vs. a heavily muscular young man).

There are racial/ethnic- and gender-based differences in albumin and creatinine excretion. Daily creatinine excretion in higher in men compared to women and in African Americans and Mexicans compared to non-hispanic whites. However, these differences are less important in clinical practice where relative change in individual patients over time affects management more than small differences in absolute albumin excretion at a given time.

How should patients with diabetic kidney disease be managed?

Blood pressure control (see chapter on diabetes and blood pressure management for more details)

Blood pressure is one of the most important factors influencing progression of diabetic kidney disease and therefore should be aggressively controlled. In patients with diabetes or kidney disease, JNC-7 recommends treating patients to a blood pressure of <130/80mm Hg. The first agent of choice should be an ACE-Inhibitor (type 1 diabetes) or Angiotensin Receptor Antagonist (ARB) (type 1 or 2 diabetes).

Using multiple agents/Combination Therapy

The majority of hypertensive patients with diabetes require more than one agent to control blood pressure to the recommended target level. We recommend adding diuretics or/and calcium channel blockers to ACE-Inhibitors or Angiotensin Receptor Antagonists. More detailed information on specific classes of antihypertensive agents is given below

Inhibition of the renin-angiotensin system

The RAAS plays a central role in the pathogenesis and progression of diabetic kidney disease. Therefore inhibition of this system with ACE-Inhibitors or ARBs is one of the most important steps in the treatment of DKD.

  • All hypertensive patients with diabetes should be treated with an ACE-Inhibitor or ARB.

  • Normotensive patients with microalbuminuria or macroalbuminuria may benefit from treatment with an ACE-Inhibitors or Angiotensin Receptor Antagonists. From a kidney perspective there is no data to support treatment of normotensive, normoalbuminuric patients with ACE-I or ARBs, although there may be some benefit for retinopathy.

  • Patients who are intolerant to ACE inhibitors due to cough usually tolerate an ARB. While angioedema has also been reported with ARBs, it is a rarely seen side effect and much less common that with ACE-Inhibitors.

  • Aldosterone antagonists (spironolactone, epleronone) and direct renin inhibitors (aliskerin) reduce proteinuria in short-term studies but have not been demonstrated to prevent the development or progression of DKD or cardiovascular disease.

  • Dual RAAS blockade (see section on Antihypertensive agents, below)

Blood glucose control (see chapter on glycemic control for more details)

Blood glucose control plays an important role in the prevention and progression of DKD and other microvascular diabetes complications. Therefore, good glycemic control is critical for the management of these patients. In general, the ADA recommends a HbA1C goal of <7%.However, many patients with CKD are at increased risk of hypoglycemia and should be considered for higher glycemic targets.

Lipid control

Hyperlipidemia is common in diabetic patients with renal disease. Treatment with a statin reduces cardiovascular disease risk and may reduce albuminuria and risk of GFR loss in chronic kidney disease. Therapy with a Statin should be considered if the LDL cholesterol is > 100mg/dl with an LDL treatment goal of <100mg/dl. An LDL treatment goal of <70mg/dl is optional.

Dietary considerations

For diabetics with chronic kidney disease, a moderate protein restriction of 0.8 g/kg body weight per day has been shown to reduce the risk of progression of albuminuria/proteinuria and loss of GFR. For other dietary interventions in patients with chronic kidney disease please see the chapter on chronic kidney disease.

Lifestyle Changes

Smoking has been demonstrated to contribute to the rapidity of GFR loss in diabetic patients with kidney disease. Therefore smoking cessation should be strongly considered for any diabetic patient. Regular exercise can lead to weight loss, reduction in creatinine and albuminuria and should be encouraged. Normalization of the BMI (18.5-14.9) should be a treatment goal.

Antihypertensive agents

Consider adding an antihypertensive agent to ACE inhibitors or ARBs for treatment of hypertension among patients with diabetes:

  • Dihydropyridine calcium channel blockers (CCBs). Dihydropyridine CCBs (eg, amlodipine, felodipine) as a sole agent have been shown to increase proteinuria in the IDNT study but are thought to be safe if used in combination with an ACE-Inhibitor or ARB. In fact, the ACCOMPLISH study has demonstrated superiority with regards to progression of chronic kidney disease of the combination of an ACE-Inhibitor with a dihydropyridine CCB as compared to the ACE-Inhibitor combined with hydrochlorothiazide.

  • Diuretics. Diuretics and RAAS inhibitors are synergistic in terms of effect on BP, ie, the combined effect of agents from these classes on BP is equal to or greater than the sum of individual effects of each medication. Patients with diabetes and normal or near-normal GFR usually respond to thiazide-type diuretics. In the diabetic subgroup of ALLHAT, chlorthalidone reduced the primary endpoint of fatal coronary heart disease and myocardial infarction to the same degree as lisinopril or amlodipine and was superior for prevention of heart failure.

  • Non-dihydropyridine calcium channel blockers (CCBs). Non-dihydropyridine CCBs (eg, diltiazem, verapamil) reduce proteinuria in short-term studies but have not been demonstrated to prevent the development or progression of DKD or cardiovascular disease. Non-dihydropyridine CCBs tend to have less potent effects on BP than dihydropyridine CCBs.

  • Beta blockers. Beta blockers have proven benefit for comorbidities that often accompany diabetes, including coronary artery disease, stroke, and congestive heart failure, and are often indicated for these conditions. In the absence of these conditions, the utility of beta blockers for BP control in diabetes is not clear. Beta blockers and RAAS inhibitors are not synergistic in terms of effect on BP, ie, the combined effect of agents from these classes on BP is often less than the sum of individual effects of each medication.

  • Dual RAAS blockade. For patients with significant proteinuria (> 1 gram on a fully dosed ACE-I or ARB) some experts recommend various combinations of ACE-Inhibitors with Angiotensin Receptor Antagonists, Aldosterone Antagonists and/or Renin Inhibitors for further antiproteinuric effect. While small, short-term, surrogate outcomes studies have demonstrated a further reduction in proteinuria with dual RAAS blockade (blocking the Renin Angiotensin System at various levels), no longterm studies have shown any additional renoprotective effect.

    On the contrary, the ON TARGET trial, while not a trial designed to investigate diabetic kidney disease, has raised a safety concern for the combination of ACE-Inhibitors and ARBs with an increased incidence of renal failure. In a post hoc analysis of the ON TARGET trial even in patients with macroalbuminuria and a eGFR < 60 mls/min (80% of which were diabetic) there was concern for harm with dual RAAS blockade. A short-term (6 months) study has demonstrated additional albuminuria reduction by roughly 20% with the addition of a Renin antagonist to a full-dose ARB. Nevertheless long-term outcome studies with hard outcomes are lacking and this therapy can therefore not be recommended in routine care.

  • Intensive glucose control. While targeting HbA1c <6-6.5% reduced the risk of albuminuria development and progression, but it also increased risk of severe hypoglycemia and may increase the risk of mortality. Intensive glucose control to this degree is not currently recommended. In fact, many diabetic patients with CKD should be considered for target HbA1c levels >7% because of their greatly increased risk for hypoglycemia.

  • HbA1c in DKD. Chronic kidney disease, end stage kidney disease (ESRD) and treatment with erythropoiesis stimulating agents (ESAs) have been shown to be associated with decreased red blood cell survival or an increase in red blood cell production/turnover, thereby causing artificially low HbA1C levels in some of these patients. Other reports have shown an increase of HbA1C in CKD through possibly carbamylation of hemoglobin or acidosis. As a result HbA1C levels may not be as accurate in assessing glycemic control in patients with CKD or ESRD.

  • Effects of DKD on glucose control. With advanced GFR loss, typically <20 mL/min/1.73m2 or ESRD, insulin catabolism is diminished and gluconeogenic capacity by the kidney is impaired. Therefore glucose-lowering therapy often requires reduction to avoid hypoglycemia.

What happens to patients with diabetic kidney disease?

Progression of albuminuria

DKD is traditionally characterized by progressively rising urine albumin excretion. Higher levels of urine albumin excretion, particularly above 300 mg/g creatinine or 300 mg/d (“macroalbuminuria”), usually represent progressive parenchymal kidney damage and identify individuals at high risk of GFR loss. Modifiable risk factors for worsening albuminuria include poor glycemic control, high blood pressure, dyslipidemia, obesity, and smoking. Intensive glycemic control and RAAS antagonists have been proven in clinical trials to reduce the risk of albuminuria progression in types 1 and 2 diabetes.

Regression of albuminuria

Not all patients with DKD progress, and many patients with “microalbuminuria” (30-299 mg/g creatinine or 30-299 mg/d), even if persistent, will subsequently “regress” to normal urine albumin excretion (< 30 mg/g creatinine or 30 mg/d). Regression may occur in up to half of patients with type 1 diabetes and microalbuminuria, while rates in type 2 diabetes are less clear. Regression may occur spontaneously or as a result of medications, eg, RAAS inhibitors.

Regression is more common with better glycemic control, lower blood pressure, and more favorable circulating cholesterol levels. In kidney biopsies of persons with type 1 diabetes, lesions of diabetic glomerulopathy have been demonstrated to regress with normalization of glycemia via pancreas transplantation.

GFR loss

Rate of GFR loss is closely tied to level of albuminuria. GFR loss occurs with normal urine albumin excretion and microalbuminuria, though rate of loss tends to be relatively slow (usually < 3-5 mL/min/1.73m2/yr) and this can be difficult to detect in the “normal” range of GFR (≥ 60 mL/min/1.73m2). GFR loss with “macroalbuminuria” averages up to 5-10 mL/min/1.73m2/yr and can exceed this range in some cases. GFR loss leads to metabolic complications of chronic kidney disease (see chapter x) and ESRD.

End stage renal disease

ESRD requiring renal replacement therapy is a severe complication of diabetes. Most patients with DKD will not progress to ESRD within their lifetime, but those who do progress experience substantial personal hardship. Renal replacement therapies are time- and resource-intensive and are associated with adverse effects and complications. 5-year survival after reaching ESRD is < 40%. Preparing for ESRD and options for renal replacement therapy are discussed in chapter x.

Cardiovascular disease

Patients with DKD are at particularly high risk of cardiovascular disease. Among patients with diabetes, the presence of albuminuria and low GFR (< 60 mL/min/1.73m2) each increase risks of cardiovascular events and death by at least 50%. Patients with DKD are up to 11 times more likely to die, often of cardiovascular disease, than to progress to ESRD. Therefore, prevention and treatment of cardiovascular disease should be a major focus for all patients with DKD.

How to utilize team care?

Care of the diabetic patient can be complex and challenging and may require the involvement of a whole team of healthcare providers. Team composition will vary according to patient needs, patient load, clinical setting and professional skills. In general team care requires at least a “core” team, which involves a physician, nurse and dietician, at least one of whom is a certified diabetes educator.

Many other healthcare professionals can and need to be team members or collaborative consultants if needed. The team can minimize the patient’s health risk by assessment, intervention and surveillance to prevent and identify problems early and start treatment.

  • Registered Nurses play a central role in the “core team” and can lead the administration of protocol based care. With medical direction a nurse can make management decision about glucose, lipid, anemia and hypertension management and can also provide valuable education for the patient.

  • Registered Dieticians can provide medical nutrition therapy that has been shown to improve outcomes and save money in the care of diabetic patients. For the patient with diabetic kidney disease dieticians are invaluable in guiding salt, phosphorus, protein, potassium and caloric restriction as deemed appropriate by the physician.

  • Clinical Pharmacists can provide important medication counseling, diabetes education, insulin initiation and adjustment, help with insulin pumps and glucose sensors and also help with blood pressure treatment and adjustment of antihypertensive management.

  • Important other team members or consultants include nephrologists, endocrinologists, ophthalmologists, podiatrists, psychologists, social workers, vascular surgeons, cardiologists, neurologists, physical therapists, and obstetricians.

Are there clinical practice guidelines to inform decision making?

  • KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis 49:S12-S154, 2007.

  • KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, cCassification, and Dtratification. Am J Kidney Dis 39:S1-266, 2002

Other considerations

NA

What is the evidence?

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Hovind, P, Tarnow, L, Rossing, P, Jensen, BR, Graae, M, Torp, I, Binder, C, Parving, HH. "Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: inception cohort study". Bmj. vol. 328. 2004. pp. 1105.

Warram, JH, Gearin, G, Laffel, L, Krolewski, AS. "Effect of duration of type I diabetes on the prevalence of stages of diabetic nephropathy defined by urinary albumin/creatinine ratio". J Am Soc Nephrol. vol. 7. 1996. pp. 930-937.

Krolewski, AS, Warram, JH, Christlieb, AR, Busick, EJ, Kahn, CR. "The changing natural history of nephropathy in type I diabetes". Am J Med. vol. 78. 1985. pp. 785-794.

Fioretto, P, Mauer, M, Brocco, E, Velussi, M, Frigato, F, Muollo, B, Sambataro, M, Abaterusso, C, Baggio, B, Crepaldi, G, Nosadini, R. "Patterns of renal injury in NIDDM patients with microalbuminuria". Diabetologia. vol. 39. 1996. pp. 1569-1576.

Lane, PH, Steffes, MW, Mauer, SM. "Glomerular structure in IDDM women with low glomerular filtration rate and normal urinary albumin excretion". Diabetes. vol. 41. 1992. pp. 581-586.

Perkins, BA, Ficociello, LH, Ostrander, BE, Silva, KH, Weinberg, J, Warram, JH, Krolewski, AS. "Microalbuminuria and the risk for early progressive renal function decline in type 1 diabetes". J Am Soc Nephrol. vol. 18. 2007. pp. 1353-1361.

Parving, HH, Hommel, E, Mathiesen, E, Skott, P, Edsberg, B, Bahnsen, M, Lauritzen, M, Hougaard, P, Lauritzen, E. "Prevalence of microalbuminuria, arterial hypertension, retinopathy and neuropathy in patients with insulin dependent diabetes". Br Med J (Clin Res Ed). vol. 296. 1988. pp. 156-160.

"KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease". Am J Kidney Dis. vol. 49. 2007. pp. S12-S154.

de Boer, IH, Rue, TC, Cleary, PA, Lachin, JM, Molitch, ME, Steffes, MW, Sun, W, Zinman, B, Brunzell, JD. "Long-term Renal Outcomes of Patients With Type 1 Diabetes Mellitus and Microalbuminuria: An Analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Cohort". Archives of internal medicine. vol. 171. 2011. pp. 412-420.

de Boer, IH, Katz, R, Cao, JJ, Fried, LF, Kestenbaum, B, Mukamal, K, Rifkin, DE, Sarnak, MJ, Shlipak, MG, Siscovick, DS. "Cystatin C, albuminuria, and mortality among older adults with diabetes". Diabetes Care. vol. 32. 2009. pp. 1833-1838.

Ninomiya, T, Perkovic, V, de Galan, BE, Zoungas, S, Pillai, A, Jardine, M, Patel, A, Cass, A, Neal, B, Poulter, N, Mogensen, CE, Cooper, M, Marre, M, Williams, B, Hamet, P, Mancia, G, Woodward, M, Macmahon, S, Chalmers, J. "Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes". J Am Soc Nephrol. vol. 20. 2009. pp. 1813-1821.

Foley, RN, Murray, AM, Li, S, Herzog, CA, McBean, AM, Eggers, PW, Collins, AJ. "Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999". J Am Soc Nephrol. vol. 16. 2005. pp. 489-495.

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. vol. 164. 2004. pp. 659-663.

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