Manual of Nephrology. Diagnosis and Therapy 6e
Editors: Schrier, Robert W.
Title: Manual of Nephrology, 6th Edition
Copyright 2005 Lippincott Williams & Wilkins
> Table of Contents > 11 - The Patient with Chronic Kidney Disease
11
The Patient with Chronic Kidney Disease
Michael Conchol
David M. Spiegel
Patients with end-stage renal disease (ESRD) have decreased quality of life, high morbidity, and an annual mortality of about 22%. The number of persons with kidney failure who are treated with dialysis and transplantation is projected to increase from 340,000 in 1999 to 651,000 in 2010 (1). The high morbidity and mortality seen in dialysis patients may decrease significantly if patients were healthier at the time of initiating renal replacement therapy.
This chapter presents an overview of the current recommendations designed to retard the progression of chronic kidney disease (CKD); to optimize the medical management of comorbid medical conditions, such as cardiovascular disease (CVD), diabetes, and lipid disorders; and to decrease the complications secondary to progression of kidney disease, including hypertension, anemia, secondary hyperparathyroidism, and malnutrition. These recommendations are derived from the recent clinical practice guidelines published by the Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation (NKF) (2).
Definition and staging of chronic kidney disease. The definition of chronic kidney disease (CKD) is:
Kidney damage for 3 months or longer, as defined by structural or functional abnormalities of the kidney, with or without decreased glomerular filtration rate (GFR), manifest by either:
Pathological abnormalities; or
Markers of kidney damage, including abnormalities in the composition of the blood or urine, or abnormalities in imaging tests
GFR of less than 60 mL per minute per 1.73 m2 for 3 months or longer, with or without kidney damage.
In a recent NKF report, CKD was divided into stages of severity (Table 11-1.) Importantly, the staging system is based on calculated GFR and not on the measurement of serum creatinine. Stage 1 CKD is recognized by the presence of kidney damage at a time when GFR is conserved; this includes patients with albuminuria or abnormal imaging studies. For example, a patient with type II diabetes and normal GFR, but with microalbuminuria, is classified as Stage 1 CKD. The definition for microalbuminuria is 30 to 300 mg per day (24-hour excretion) and for clinical proteinuria: more than 300 mg per day (24-hour excretion). Stage 2 CKD takes into account patients with evidence of kidney damage with decreased GFR (60 to 89 mL per minute per 1.73 m2). Last, all patients with a GFR of less than 60 mL per minute per 1.73 m2are classified as having CKD irrespective of whether kidney damage is present.
Table 11-1. National Kidney Foundation Kidney Disease Outcomes Quality Initiative Classification, Prevalence, and Action Plan for Stages of Chronic Kidney Disease2
Stage Description GFR, mL per min per 1.73 m Prevalence, n (%) Action At increased risk 60 (with chronic kidney disease risk factors) Screening: chronic kidney disease risk reduction 1 Kidney damage with normal or increased GFR 90 5,900,000 (3.3) Diagnosis and treatment; treatment of comorbid conditions; slowing progression; CVD risk reduction 2 Kidney damage with slightly decreased GFR 60 89 5,300,000 (3.0) Estimating progression 3 Moderately decreased GFR 30 59 7,600,000 (4.3) Evaluating and treating complications 4 Severely decreased GFR 15 29 400,000 (0.2) Preparation for kidney replacement therapy 5 Kidney failure 15 (or dialysis) 300,000 (0.1) Kidney replacement (if uremia present) 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 The staging of chronic kidney disease is useful because it endorses a model in which primary physicians and specialists share responsibility for the care of patients with CKD. This classification also offers a common language for patients and the practitioners involved in the treatment of CKD. For each stage of CKD, K/DOQI provides recommendations for a clinical action plan (Table 11-1).
An essential requirement for the classification and monitoring of CKD is the measurement or estimation of GFR. Serum creatinine is not an ideal marker of GFR, because it is both filtered at the glomerulus and secreted by the proximal tubule. Creatinine clearance (CrCl) is known to overestimate GFR by as much as 40% in normal individuals and by even more in
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patients with CKD (3). Estimates of GFR based on 24-hour CrCL require timed urine collections, which are difficult to obtain and often involve errors in collection. Classic methods for measurements of GFR, including the gold-standard inulin clearance, are cumbersome, require an intravenous infusion and timed urine collections, and are not clinically feasible. In adults, the normal GFR based on inulin clearance and adjusted to a standard body surface area of 1.73 m2 is 127 mL per minute per 1.73 m2 for men and 118 mL per minute per 1.73 m2 for women, with a standard deviation of approximately 20 mL per minute per 1.73 m2. After age 30, the average decrease in GFR is 1 mL per minute per 1.73 m2 per year (2).Equations based on serum creatinine but factored for gender, age, and ethnicity are the best alternative for estimation of GFR. The most commonly used formula is the Cockcroft-Gault equation. This equation was developed to predict CrCl, but has been used to estimate GFR (4):
The Modification of Diet in Renal Disease (MDRD) Study equation was derived on the basis of data from more than 500 patients with a wide variety of kidney diseases and GFRs up to 90 mL per minute per 1.73 m2. Thus, the abbreviated MDRD equation is recommended for routine use and requires only serum creatinine, age, gender, and race (2):
The calculations can be made using available web-based and downloadable medical calculators (www.kdoqi.com).
The MDRD study equation has many advantages. It is more accurate and precise than the Cockcroft-Gault equation for persons with a GFR of less than approximately 90 mL per minute per 1.73 m2. This equation predicts GFR as measured by using an accepted method (urinary clearance of 125I-iothalamate). It does not require height or weight and has been validated in kidney transplant recipients and African-Americans with nephrosclerosis. It has not been validated in diabetic kidney disease, in patients with serious comorbid conditions, in normal persons, or in individuals older than 70 years of age (2).
Prevalence of CKD. The Third National Health and Nutrition Examination Survey (NHANES III) included 15,625 participants age 20 years or older and was conducted, between 1988 to 1994, by the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention. The goal of this survey was to provide nationally representative data on the health and nutritional status of the civilian, noninstitutionalized United States (U.S.) population. The results, when extrapolated to the U.S. population of adults age older than 20 years (n = 177 million), revealed the following findings relevant to CKD (5):
6.2 million individuals had a serum creatinine equal to or greater than 1.5 mg per dL, which is a 30-fold higher prevalence of reduced kidney function compared with the prevalence of treated ESRD during the same time interval.
2.5 million individuals had a serum creatinine equal to or greater than 1.7 mg per dL.
800,000 individuals had a serum creatinine equal to or greater than 2.0 mg per dL.
Of individuals with elevated serum creatinine, 70% have hypertension.
Only 75% of patients with hypertension and elevated serum creatinine received treatment, with only 27% having a blood pressure (BP) reading
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lower than 140/90 mm Hg and 11% having their BP reduced to lower than 130/85 mm Hg.In a further analysis of NHANES III data, estimated GFR was calculated from the serum creatinine using the MDRD study equation (2). The prevalence of the different stages of CKD clearly shows that the CKD population is several times larger than the ESRD population. The challenge for the medical community is to identify earlier stages of CKD and institute correct treatment strategies to decrease complications and slow the progression to ESRD.
Mechanism of kidney disease progression. Diabetes and hypertension are responsible for the largest proportion of ESRD. Glomerulonephritis represents the third most common cause of ESRD. Despite the many diseases that can initiate kidney injury, a limited number of common pathways are available for kidney disease progression (6). A general theme of many of these pathways is that adaptive changes in the nephron lead to maladaptive consequences. One of the best developed of these themes is the hyperfiltration that occurs in remaining nephrons after loss of renal mass. Elevated glomerular pressures drive this hyperfiltration. Glomerular hyperfiltration has initial adaptive effects by maintaining GFR, but later may lead to glomerular injury. Abnormal glomerular permeability is common in glomerular disorders, with proteinuria being the clinical consequence. Evidence has accumulated that this proteinuria might be a factor inciting tubulointerstitial disease (6). The extent of tubulointerstitial damage is a prime risk factor for subsequent renal disease progression in all forms of glomerular diseases studied (7). In experimental models and in humans trials, an association has been consistently demonstrated between the reduction of proteinuria and renoprotection.
Risk factors for progression to ESRD. The quantity of protein excreted in the urine is one of the strongest predictors of renal disease progression and response to antihypertensive therapy in almost all studies of CKD (8). Thus, the greater the proteinuria, the higher the risk for progression.
As described in the previous section, an important risk factor for most glomerular diseases is the extent of tubulointerstitial disease on renal biopsy (7).
Ethnicity is a risk factor for many renal diseases. For example, African-American patients with diabetes have a twofold to threefold higher risk for developing ESRD compared with white patients (9). Some of this increased risk is attributable to such modifiable factors as suboptimal health behaviors, suboptimal glucose and BP control, and lower socioeconomic status (9). Human immunodeficiency virus (HIV)-associated nephropathy is also more common in African-American patients compared with white patients.
Gender is an additional risk factor for the development and progression of certain types of renal disease. Overall, the incidence of ESRD is greater in males than females.
Smoking has been associated with proteinuria and renal disease progression in both type 1 and 2 diabetes, as well as in IgA nephropathy, lupus nephritis, and polycystic kidney disease. Smoking cessation has been associated with a slower rate of progression of renal failure in type 1 diabetic patients (10).
Finally, heavy consumption of non-narcotic analgesics, particularly phenacetin, has been associated with an increased risk of CKD.
Retarding progression to ESRD
Anti-hypertensive therapy. Hypertension is a risk factor for the progression of kidney disease, and it is the second most common cause of ESRD. The opinion of the seventh report of the Joint National Committee (JNC VII) recommended that blood pressure be lowered to levels below 130/80 mm Hg in patients with diabetes or chronic kidney disease (11).
An increasing amount of evidence has demonstrated that the inhibition of the renin-angiotensin system by either inhibiting angiotensin II
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generation with angiotensin converting enzyme (ACE) inhibitors, or blocking the angiotensin type 1 A receptor with angiotensin receptor blockers (ARBs) has renoprotective effects above and beyond the effects of these therapies on reducing blood pressure.Studies in patients with diabetic kidney disease with established nephropathy
Type 1 diabetic patients with established nephropathy
A pronounced benefit of ACE inhibitors in type I diabetics who already had overt nephropathy has been demonstrated in the largest study to date. Four hundred and nine patients with overt proteinuria and a plasma creatinine concentration equal to or greater than 2.5 mg per dL were randomized to therapy with either captopril or placebo. Further antihypertensive drugs were then added as necessary, although calcium channel blockers and other ACE-inhibitors were excluded. At approximately 4 years of nearly equivalent BP control, patients treated with captopril had a slower rate of increase in the plasma creatinine concentration and a lesser likelihood of progressing to ESRD or death (12).
Type 2 diabetic patients with established nephropathy
The Reduction of Endpoints in type 2 diabetes with the Angiotensin II Antagonist Losartan (RENAAL) study examined the effects of losartan versus non-ACE inhibitors or ARB antihypertensive therapy in 1,513 patients with type 2 diabetes and nephropathy, followed for a mean of 3.4 years (13). The results of this study demonstrated a beneficial effect of losartan, beyond its effects on lowering BP, on the time to doubling of serum creatinine concentration and onset of ESRD.
In the Irbesartan Diabetic Nephropathy Trial (IDNT), 1,715 patients with nephropathy secondary to type 2 diabetes were randomly assigned to receive irbesartan, amlodipine, or placebo. The mean duration of follow up was 2.6 years. This study revealed that patients assigned to irbesartan had a 33% reduction of risk for the doubling of serum creatinine compared with placebo and a 37% decrease compared with patients on amlodipine (14).
Studies in patients with diabetic kidney disease with microalbuminuria
Meta-analysis of published trials. Diabetic nephropathy trialists have examined 12 selected studies involving 698 patients to compare the effects of ACE inhibitors versus placebo in type 1 diabetic patients with microalbuminuria and normal BP (15). Results showed that ACE inhibitors were more likely associated with regression of microalbuminuria. This effect persisted despite adjustment for any changes in blood pressure.
The United Kingdom Prospective Diabetes Study (UKPDS) examined the efficacy of atenolol and captopril in reducing the risk of both macrovascular and microvascular complications in type 2 diabetic patients with hypertension. This study found that both captopril and atenolol were equivalent in reducing the renal endpoints of progression of albuminuria, overt nephropathy, a twofold increase in serum creatinine, and the development of ESRD (16).
The Appropriate Blood Pressure Control in Diabetics (ABCD) trial was a prospective randomized trial of 950 type 2 diabetic patients examining whether intensive versus moderate BP control affected the incidence of progression of type 2 diabetic complications (17). The hypertensive patients (n = 470) were randomized to intensive BP control (DBP goal of 75 mm Hg) versus moderate blood pressure control (DBP goal of 80 to 89 mm Hg) and
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to either nisoldipine or enalapril as the initial antihypertensive medication. Blood pressure control of 138/86 or 132/78 mm Hg with either nisoldipine or enalapril as the initial antihypertensive medication appeared to stabilize renal function in hypertensive type 2 diabetic patients without overt albuminuria over a 5-year period. The enalapril-treated patients had significantly fewer heart attacks than the nisoldipine-treated patients. The more intensive BP control decreased all cause mortality. The effects of intensive versus moderate diastolic BP control were also studied in 480 normotensive type 2 diabetic patients (18). Over a 5-year follow-up period, intensive (approximately 128/75 mm Hg) BP control in normotensive type 2 diabetic patients: (a) slowed the progression to incipient and overt diabetic nephropathy; (b) decreased the progression of diabetic retinopathy; and (c) diminished the incidence of stroke. Cardiovascular events occurred more commonly in the nisoldipine group (19).The Heart Outcomes Prevention Evaluation (HOPE) study included 3,577 people with diabetes (20). Of the patients recruited in the study, 1,120 had microalbuminuria. Patients were randomized to the ACE inhibitor ramipril or placebo. Patients treated with ramipril had a 25% reduction in myocardial infarction, stroke, or cardiovascular death. In the ramipril group, the risk of developing overt nephropathy decreased by 24%.
Irbesartan Microalbuminuria Study. The effects of the ARB irbesartan were examined in 590 hypertensive patients with type 2 diabetes and microalbuminuria (21). The primary endpoint was time from baseline visit to the first detection of overt nephropathy. This study revealed that irbesartan had a renoprotective effect independent of its BP lowering effect.
Studies in patients with nondiabetic kidney disease
The African-American Study of Kidney Disease and Hypertension (AASK) was designed to study the effect on progression of hypertensive kidney disease of: (a) two different mean arterial pressure goals usual (MAP: 102 to 107 mm Hg) and lower (MAP: equal to below 92 mm Hg) and (b) treatment with three different antihypertensive drug classes: an ACE inhibitor (ramipril), a dihydropyridine calcium channel blocker (amlodipine), and a betablocker (metoprolol) (22). This study concluded that lowering BP below the achieved 141/85 mm Hg was not associated with added beneficial effects and that ACE inhibitors are more effective antihypertensives in slowing the progression of hypertensive nephrosclerosis.
In the Ramipril Efficacy in Nephropathy (REIN) study, patients were stratified before randomization by the level of 24 hour urinary protein, with stratum 1 having 1 or more and less than 3 g per 24 hour proteinuria, and stratum 2 having 3 or more g per 24 hour proteinuria (23). The patients were then randomized to receive ramipril or placebo, with other medications added to achieve a target diastolic blood pressure (DBP) of lower than 90 mm Hg. An analysis of the results of this study demonstrated a beneficial effect of ramipril on slowing GFR decline that was more than expected from the reduction in BP.
The care of diabetic and nondiabetic renal disease has been significantly advanced by this series of controlled trials. The results of these studies clearly demonstrate the renoprotective effects of ACE inhibitors and ARBs in both reducing proteinuria and slowing the progression of renal disease. The effects of these medications may be related to decreases in glomerular capillary pressure or other effects of angiotensin II on fibrosis
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and growth. These agents should be considered the drugs of first choice in patients with CKD, and the BP goal should be lower than 130/80 mm Hg.
Combined therapy with ACE inhibitors and ARBs in nondiabetic renal disease
COOPERATE study. This study was a randomized, double-blind study designed to test the efficacy and safety of combination therapy with an ACE inhibitor (trandolapril) and an angiotensin receptor blocker (losartan), compared with monotherapy with each drug in 263 patients with nondiabetic kidney disease (24). Combination therapy was associated with a marked antiproteinuric effect, and fewer patients reached the combined primary endpoint of time to doubling of serum creatinine or ESRD compared with either of the monotherapy groups.
Combined therapy with ACE inhibitors and ARBs in diabetic renal disease
In the Candesartan and Lisinopril Microalbuminuria (CALM) study, the effects of candesartan or lisinopril or both on BP or urinary albumin excretion was examined in patients with microalbuminuria, hypertension, and type 2 diabetes (25).
Combination therapy reduced BP and albumin excretion more than either agent alone.
In summary, these studies provide some evidence that combining an ACE inhibitor with an ARB may be more effective than either agent alone in reducing proteinuria and improving renal survival. An increase in adverse events does not appear to exist with combination therapy. However, at present, it is not clear in some studies whether maximizing the dose of either agent is better than the combination or whether the effect of combination therapy is independent of BP reduction.
Managing complications of chronic kidney disease
Anemia. The anemia of chronic renal failure develops during the course of CKD. The degree of anemia is better evaluated using hemoglobin values rather than hematocrit. A direct correlation exists between the level of hemoglobin and GFR. In the NHANES III data, this association exists at GFR levels of less than 90 mL per minute per 1.73 m2, but was most marked when the GFR was less than 60 mL per minute (2). The etiology of the anemia of CKD is multifactorial, with the major factor being a decline in erythropoietin synthesis by the kidneys. Anemia is associated with worse outcomes in CKD patients. Low hemoglobin levels have been associated with an increase in cardiovascular morbidity and mortality. The increase in cardiovascular endpoints is likely related to the association between low hemoglobin and increased left ventricular mass index. Hemoglobin has been shown to be one of the most important predictors of left ventricular hypertrophy. In the RENAAL study, after control of BP in type 2 diabetic patients, anemia was recognized as one of the independent risk factors that predicted renal outcomes (26). K/DOQI guidelines recommend patients with CKD be evaluated for anemia when the GFR is less than 60 mL per minute per 1.73 m2. Erythropoietin levels are not helpful in assessing the anemia of renal disease. The iron status of patients should be assessed, including measurements of serum ferritin, iron, and transferrin saturation (2). Transferrin saturations and ferritin levels should exceed 20% and 100 ng per mL, respectively, to optimize erythropoiesis. Early treatment with erythropoietin (EPO) can prevent severe anemia and may improve the long-term survival of patients with ESRD. The ideal hemoglobin for CKD patients has not been definitively determined. NKF-DOQI guidelines recommend a target hemoglobin of 11 to 12 g per dL.
Phosphate control. Phosphate control in CKD is important to preserve the bone mineral content and avoid hyperparathyroidism. Calcium-containing
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phosphate binders should be instituted when the GFR falls below 30 to 50 mL per minute. The use of vitamin D analogs, primarily 1,25, dihydroxy-vitamin D3, is more controversial. These analogues can clearly help suppress parathyroid gland overactivity, but often at the expense of higher serum phosphate levels and the risk of hypercalcemia, both of which can worsen extraskeletal calcifications. Recommendations for patients with CKD include (2):Maintain serum phosphorus between 3.0 and 4.6 mg per dL
Restrict dietary phosphorus to 800 to 1,000 mg per day when serum phosphorus is greater than 4.6 mg per dL
Restrict dietary phosphorus to 800 to 1,000 mg per day when serum levels of intact PTH are greater than 65 mg per mL
Monitor serum phosphorus every 3 months if patients are on a phosphorus restricted diet
The target range for corrected serum calcium (for every 1 g decrease in serum albumin, the serum calcium should be corrected by 0.8 mg) is 8.8 to 9.5 mg per dL
If serum calcium is greater than 10.2 mg per dL, reduce or discontinue vitamin D, and/or switch to a noncalcium-based phosphate binder
Serum calcium-phosphorus product should be less than 55 mg2 per dL2
Acid-base control. Acidosis is common in almost all forms of CKD. The main mechanism responsible for the acidosis is a decrease in total ammonia excretion, leading to a decrease net hydrogen secretion and a fall in serum bicarbonate. This net positive acid balance results in dissolution of bone, ultimately worsening uremic osteodystrophy. Other adverse consequences of metabolic acidosis include protein malnutrition and the suppression of albumin synthesis. Early treatment of acidosis with oral bicarbonate therapy may help prevent some of the bone disease of chronic uremia. K/DOQI recommends maintaining a serum bicarbonate level of greater than 22 mEq per L (2). Care must be taken, however, not to precipitate or worsen hypertension with the added sodium intake.
Managing cardiovascular comorbidity. Cardiovascular disease remains the most common cause of death in patients with ESRD, and CKD patients are more likely to die from cardiovascular disease than are expected to progress to ESRD. The CKD population has a higher incidence of traditional cardiovascular risk factors, including diabetes, hypertension, and dyslipidemias. In addition, overwhelming scientific evidence has shown that decreased GFR and proteinuria are independent risk factors for cardiovascular disease. Consensus exists in the nephrology community that the CKD population should undergo aggressive risk factor management. This includes strict control of BP and lipids, as well as smoking cessation. K/DOQI clinical practice guidelines on the management of dyslipidemias in CKD have recommended drug therapy for patients with a low-density lipoprotein (LDL) level equal to or greater than 100 mg per dL after 3 months of therapeutic lifestyle changes. Statins are recommended as initial drug therapy for high LDL, and fibrates (e.g., gemfibrozil) are recommended for an elevated fasting triglyceride.
When to refer to a nephrologist. Several studies have shown that delayed referral to a nephrologist is common and is associated with adverse consequences, including greater morbidity and mortality, more severe uremia, increased use of percutaneous vascular access with associated morbidity, reduced use of the preferred arteriovenous fistula for vascular access, restricted patient choice of treatment modality, prolonged and more costly hospitalization at initiation of dialysis, and higher rates of emotional and socioeconomic problems. An early referral allows the patient to develop an effective relationship with a multidisplinary team consisting of a nephrologist, vascular surgeon, nurse, dietitian, social worker, and mental health professional. This relationship allows for a more informed consideration by patients of renal replacement options including transplantation, initiation of renal replacement
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therapy to maintain optimal patient health, timely placement of a dialysis access, supervision of dietary modification, and support services regarding unmet psychological, social, and financial needs. A nephrologist should participate in the care of patients with a GFR of less than 30 mL per minnute per 1.73 m2.
References
United States Renal Data System. Excerpts from the 2000 U.S. Renal Data System Annual Data Report: Atlas of End Stage Renal Disease in the United States. Am J Kidney Dis 2000;36:S1 S279.
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.
Shemesh O, Golbetz H, Kriss JP, Myers BD. Limitations of creatinine as a filtration marker in glomerulopathic patients. Kidney Int 1985;28:830 838.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31 41.
Jones C GM, Kusek JW, et al. Serum creatinine levels in the US population: Third National Health and Nutrition Examination Survey. Am J Kidney Disease 1998;32:992 999.
Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies. N Engl J Med 1998;339:1448 1456.
Nath K. The tubulointerstitium in progressive renal disease. Kidney Int 1998;54:992 994.
Keane W. Proteinuria: its clinical importance and role in progressive renal disease. Am J Kidney Dis 2000;35:S97 S105.
Krop J, Coresh J, Chambless L, et al. A community-based study of explanatory factors for the excess risk for early renal function decline in blacks vs. whites with diabetes. Arch Intern Med 1999;159:1777 1783.
FOrth SR, Ritz E, Schrier RW. The renal risks of smoking. Kidney Int 2003;51:1669 1677.
The JNC 7 Report. JAMA 2003;289:2560 2572.
Lewis EJ, et al. Effect of ACE inhibition on nephropathy in type 1 diabetes. N Engl J Med 1993;329:1456 1462.
Brenner BM, Cooper ME, De Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861 869.
Lewis EJ, Hunsiker LG, Clarke WR, et al. Renoprotective effect of the angiotensin receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851 860.
Kshirsagar AV, Joy MS, Hogan SL, et al. Effect of ACE inhibitors in diabetic and nondiabetic chronic renal disease: a systematic overview of randomized placebo-controlled trials. Am J Kidney Dis 2000;35:695 707.
UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducng risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. Br Med J 1998;317:713 720.
Estacio R, Jeffers B, Gifford N, Schrier RW. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care 2000;23 suppl 2:B54 64.
Schrier RW, Estacio R, Esler A, Mehler P. Effect of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int 2002;61:1086 1097.
Estacio R, Jeffers B, Gifford N, et al. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. N Engl J Med 1998;338:645 652.
Mann JF, Gestein H, Pogue J, et al. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Int Med 2001;134:629 636.
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Parving HH, Lehnert H, Brochner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870 878.
Wright JT, Bakris G, Greene T, et al. Effect of blood pressure lowering and anti-hypertensive drug class on progression of hypertensive kidney disease. Results from the AASK Trial. JAMA 2002;288:2421 2431.
The GISEN Group: randomized placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997;349:1857 1863.
Nakao N, Yoshimura A, Morita H, et al. Combination treatment of angiotensin II receptor blocker and angiotensin-converting enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomized controlled trial. Lancet 2003;361:117 124.
Mogensen CE, Neldam S, Tikkanen I, et al. Randomized controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesatan and lisinopril microalbuminuria (CALM) study. Br Med J 2000;321:1440 1444.
Keane WF, Brenner BM, de Zeeuw D, et al. The risk of developing end stage renal disease in patients with type 2 diabetes and nephropathy: the RENAAL study. Kidney Int 2003;63:1499 1507.