During her first encounter, a 58-year-old woman with long-standing diabetes mellitus and hypertension has a BP of 142/92 mm Hg, weighs 115 lb, and stands 5 ft 3 in tall. She is taking hydrochlorothiazide and amlodipine for hypertension. Her serum creatinine is 1.3 mg/dL (lab reference range 0.4-1.4), and urine dipstick reveals 2+ protein. You add losartan to her regimen and continue to monitor her for the next four years. During that time, her serum creatinine levels never exceed 1.9.

Is this patient suffering from chronic kidney disease (CKD)? Kidney function has traditionally been assessed by serum creatinine level. Both diet and muscle mass influence generation of creatinine, however, making it an inaccurate indicator of renal function. Lower serum creatinine levels are typically observed with older age, female gender, vegetarian diet, and muscle-wasting states, while higher values are associated with muscular habitus and a high-protein diet.

The best index of kidney function is the glomerular filtration rate (GFR), and the case above, in which the patient is a thin, older female, exemplifies how serum creatinine level can underestimate kidney disease.

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Until recently, doctors would commonly “watch” patients who have a serum creatinine in the high-normal range. This case shows that while the patient’s serum creatinine stayed between 1.3 and 1.9 over five years, her GFR declined from 45 to 28 mL/min/1.73 m2 (Table 1), or from stage 3 to stage 4 CKD. Both stages reflect moderately advanced kidney disease.

The growing rates of CKD in the general population represent an epidemic of enormous proportions. Aggressive strategies are required to retard progression of the disease and to prevent and treat cardiovascular disease (CVD), a common comorbidity. It is evident that as the burden of CKD in the United States expands, primary-care clinicians will play an increasingly important role in the care of afflicted patients.

Is it really CKD?

The National Kidney Foundation defines CKD as the presence of kidney damage and/or reduced GFR for three or more months. Markers of kidney damage include proteinuria, abnormal urine sediment, abnormalities of blood or urine chemistries, or abnormalities seen on radiologic studies. CKD can also be diagnosed if the GFR is <60 for three months or more in the absence of overt structural damage. CKD is now staged according to GFR level (Table 2).1

Determining the GFR isn’t always easy, however. The most precise method is to measure iothalamate or inulin clearance. While these techniques are the gold standard for investigative studies, routine use in clinical practice is impractical and expensive. The 24-hour urine creatinine clearance is an alternative test that requires a simultaneous serum creatinine measurement for the calculation. This method is inconvenient and tedious, and it relies on patients’ ability to follow collection instructions.

Recently, the Modification of Diet in Renal Disease (MDRD) equation has been recommended by the National Kidney Foundation to more accurately estimate GFR. Besides serum creatinine, the MDRD GFR requires input of patient age, gender, and ethnicity.

The MDRD GFR is routinely reported by several commercial laboratories and may also be computed at innumerable Internet sites. While the MDRD GFR provides a fairly accurate estimation for patients with kidney disease, it has not been validated for all populations, including patients older than 70, individuals with normal renal function, patients at extremes of weight, pregnant women, and kidney-transplant recipients. In these cases, 24-hour urine collection may be necessary to estimate GFR.

Trying to keep CKD in check

Contrary to popular belief, progression to end-stage renal disease (ESRD) and dialysis is not the likeliest outcome in patients with CKD: They are more likely to die than to start dialysis.2 It is now evident that CKD is a major risk factor for death from CVD and that this risk increases with worsening CKD stage.3

Primary-care clinicians need to focus their attention on preventing CKD progression, maximizing CVD risk reduction, and aggressively treating comorbidities associated with CKD. These comorbid conditions, many of which predispose to CVD in their own right, include anemia, volume overload, abnormal calcium phosphate homeostasis, hypertension, dyslipidemia, and metabolic syndrome.

Strategies that delay CKD progression require an understanding of the physiologic mechanisms of normal glomerular hemodynamics, as well as what impedes function. The GFR in an individual nephron is influenced by glomerular capillary hydrostatic pressure (Pgc), which in turn is determined largely by blood flow through and resistance in the afferent and efferent arterioles of the glomerulus.

The GFR in diseased nephrons declines because of reduced blood flow and lower Pgc. In an effort to counteract this decrease in function, Pgc (and therefore GFR) is augmented in the remaining healthy nephrons by efferent arteriolar vasoconstriction. Angiotensin II, through activation of the renin-angiotensin-aldosterone system (RAAS), mediates this adaptive response. Over time, this RAAS-dependent compensatory mechanism leads to hyperfiltration-mediated injury and increased proteinuria, culminating in progressive glomerulosclerosis, fibrosis, and further loss of kidney function.

Blockade of the RAAS prevents efferent arteriolar vasoconstriction, reduces Pgc, and mitigates the above cascade of events. For this reason, ACE inhibitors and angiotensin receptor blockers (ARBs) play a central role in retarding progression of CKD, particularly in the presence of proteinuria. Since RAAS blockade may be associated with GFR decline and hyperkalemia, these drug classes must be used with caution.

RAAS blockade is strongly advised for patients who have stage 1-4 CKD with proteinuria (Table 3). We recommend initiating ACE inhibitors or ARBs at low doses, with blood chemistries checked one to three weeks later or with any subsequent dose increment. This is necessary to monitor for changes in serum potassium and creatinine. We accept up to a 25% increase in serum creatinine after RAAS blockade is started, as long as serum creatinine stabilizes; a continued rise warrants discontinuation of this therapy.

An ACE inhibitor and an ARB used in combination are more powerful than either agent individually and may be effective, provided the patient does not have hyperkalemia or unacceptable serum creatinine elevation.

Since increasing proteinuria predicts progression to ESRD,4 an additional therapeutic goal is to reduce urine protein excretion, if present, to <500-1,000 mg/day (spot urine protein-to-creatinine ratio <0.5-1.0). Evidence is emerging that aldosterone also promotes kidney injury; therapies that block the effect of aldosterone are being increasingly incorporated into clinical practice.5

Dealing with tough complications

Nephrologists and primary-care clinicians co-manage the plethora of CKD-related complications and comorbidities. The risk factors that predispose to CVD, such as dyslipidemia, metabolic syndrome, obesity, and elevated glucose, need to be aggressively managed, usually by primary-care clinicians. Complications requiring the involvement of a nephrologist include hypertension, anemia, and mineral metabolism.

Hypertension. The goals of antihypertensive therapy are to lower BP, retard CKD progression, and reduce CVD risk. Most patients with CKD require a multidrug regimen to reach target BP levels, defined as <120/75 for patients with proteinuria and <130/80 for others by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and the Kidney Disease Outcome and Quality Initiative (KDOQI).1,6

Once RAAS blockade has been maximized in terms of efficacy or tolerability, additional antihypertensive therapy may be needed. Diuretics are particularly useful when volume overload is contributing to hypertension. Loop diuretics can also be used to avoid or treat hyperkalemia. For patients with persistent proteinuria, therapy with a non-dihydropyridine (non-DHP) calcium channel blocker should be considered next in the armamentarium. In addition to BP-lowering effects, the non-DHP calcium channel blockers may reduce proteinuria and confer an additive effect when used together with an ACE inhibitor.

Beta blockers can also be used if hypertension is not controlled and the patient is euvolemic.

Anemia. Anemia of CKD has been associated with complications, including adverse cardiovascular outcomes, cognitive impairment, decreased quality of life, and overall mortality. Current KDOQI guidelines recommend that you consider using erythropoietic-stimulating agents when hemoglobin levels fall below 11.0 g/dL in CKD patients, regardless of stage.7

These agents are typically administered as subcutaneous injections. A complete blood count with red cell indices, iron, transferrin, ferritin, and reticulocyte count should be included in the anemia workup. Nephrologists may order IV iron compounds to replenish iron stores in patients on erythropoietin therapy. Finally, rule out other causes of anemia not related to CKD.

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Mineral metabolism. The disorders in the mineral metabolism of CKD require careful management of calcium, phosphate, and parathyroid hormone (PTH) levels. Worsening kidney function results in reduced levels of 1,25-dihydroxycholecalciferol, hyperphosphatemia, hypocalcemia, and, consequently, the development of secondary hyperparathyroidism. Much of the excess morbidity and mortality from abnormal mineral metabolism has to do with CVD, bone disease, and soft-tissue calcification. All patients with CKD stages 3-5 should have their calcium, phosphate, and PTH levels checked at regular intervals, according to KDOQI guidelines.8

Managing worsening CKD

Most CKD patients need to begin dialysis once their GFR has dropped to around 10-15. Patients who are prepared medically and emotionally for this eventuality achieve better long-term outcomes than those who are unprepared.

Preparation for renal replacement therapy typically commences when a patient’s GFR reaches 25. Primary-care clinicians can play a significant role in initiating and providing support through the multitiered process of education required. Patients need information about dialysis and its modality options (hemodialysis vs. peritoneal dialysis), access placement, nutrition and lifestyle modification, as well as the evaluation process for kidney transplant.

Ideally, patients who plan to do hemodialysis should have an arteriovenous fistula or graft placed and usable prior to the start of therapy. This can avoid the need for an indwelling, IV dialysis catheter with its attendant risks of many complications, including infection. Close nephrologic follow-up should aid in determining when to initiate renal replacement therapy.

Evaluation for kidney transplantation is as important as dialysis preparation for patients with advanced CKD. For those identified as suitable candidates, kidney transplantation is the treatment of choice, providing a substantially greater quality-of-life and longevity benefit, compared with remaining on dialysis.

Patients may receive kidneys from either living or deceased donors. Living kidney transplantation is recommended, wherever possible, as outcomes and kidney-graft function are better than observed following deceased-donor transplantation.9 The other major advantage of living-donor transplantation is that it may avoid the lengthy wait required for recipients of deceased-donor kidneys, currently between three and four years in the United States and rising as the CKD epidemic grows.

A team approach works bestThe best treatment of CKD is accomplished with a multidisciplinary approach built around a close collaboration between the primary-care clinician and the nephrologist but frequently requiring additional input of care from diabetologists, cardiologists, and other specialists. We recommend that patients be referred for nephrology evaluation when GFR ranges between 30 and 60. Once GFR falls below 30, patients should receive regular nephrologic follow-up. CVD, the major complication of CKD, is attributable to many of the comorbid conditions and complications of kidney dysfunction.

Dr. Bloom is associate professor of medicine at the Hospital of the University of Pennsylvania in Philadelphia, where Dr. Bress is a fellow.


1. NKF-K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis. 2002;39(2 Suppl 1):S1-S266.

2. Keith DS, Nichols GA, Gullion CM, et al. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med. 2004;164:659-663.

3. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-1305.

4. Iseki K, Ikemiya Y, Iseki C, Takishita S. Proteinuria and the risk of developing end-stage renal disease. Kidney Int. 2003;63:1468-1474.

5. Epstein M. Aldosterone blockade: an emerging strategy for abrogating progressive renal disease. Am J Med. 2006;119:912-919.

6. NKF-K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004;4(5 Suppl 1)3:S1-S290.

7. KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis. 2006;47(5 Suppl 3):S11-S145.

8. NKF-K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42:S1-S201.

9. Cecka JM. The UNOS Scientific Renal Transplant Registry—2000. Clin Transpl. 2000;:1-18.