CKD

Anemia often develops early in the course of chronic kidney disease (CKD), well before the onset of end-stage renal disease, and then worsens as CKD progresses.

Anemia & Chronic Kidney Disease

Anemia is a common complication of chronic kidney disease (CKD), develops early, and worsens as CKD progresses. CKD-related anemia has multiple adverse consequences, affecting quality of life, cognitive function, exercise capacity, immune response, and heart function. Early identification and treatment of CKD-related anemia to prevent serious consequences is an idea promoted as the Renal Anemia Management Period (RAMP) by concerned nephrologists. Benefits of anemia correction in patients with CKD include decreased morbidity, hospitalization, and mortality; and improvement in quality of life, exercise capacity, cognitive function, and sexual function.

CKD: An Insidious Disease

Chronic kidney disease (CKD) is an insidious disease that gradually impairs kidney function. In its earliest stages, patients may be unaware they have the disease, but over a period ranging from several years to several decades, CKD will often progress to end-stage renal disease (ESRD), requiring renal replacement therapy (dialysis or kidney transplantation) to sustain life.

CKD arises as a consequence of diabetes mellitus, hypertensive nephrosclerosis, chronic glomerulonephritis, polycystic kidney disease, and a host of other disorders.1 Diabetes and hypertension are the two leading causes of ESRD, accounting for approximately 43% and 27% of all new ESRD cases, respectively.2

Staging and Prevalence of CKD

While the terminology of the formal literature has been inconsistent and confusing, this monograph has adopted the CKD staging terminology recently proposed by the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) and uses the term chronic kidney disease to encompass the entire spectrum of kidney disease, from its earliest stages through ESRD.3,4

As serum creatinine (SCr) levels are an imperfect indicator of the severity of kidney disease, the NKF-K/DOQI staging and prevalence estimates are based on glomerular filtration rates (GFRs) derived using a formula developed by Levey and colleagues5 from data in the Modification of Diet in Renal Disease Study.

The resulting estimated total of 19.5 million people in the United States who have CKD marks the disease as a major public health concern, affecting more than the number of Americans with diabetes (estimated at 17 million)8 and nearly half the number of those with hypertension (estimated at 50 million).9 Because CKD typically progresses to its most severe form, ESRD, the public health concern is underscored by the most recent data from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD). The combined 1995 to 1999 prevalence of ESRD patients was 392,847 on dialysis and 8,287 with transplants.2 Expecting this alarming trend to continue, the NIDDKD has estimated that the prevalence of ESRD will reach over half a million by 2010.10

The NKF-K/DOQI prevalence estimates, together with the high costs associated with CKD, prompted the National Institutes of Health to establish the National Kidney Disease Education Program (NKDEP), an aggressive public education campaign currently underway. The NKDEP initiative likely will recommend interventions based on this K/DOQI staging. For patients first diagnosed with CKD, a primary goal will

be to slow progression through the

use of angiotensin-converting enzyme inhibitors, blood pressure control, and, in patients with diabetes, blood sugar control. Emphasis will be given to preventive and therapeutic approaches related to uremic complications, malnutrition, anemia, bone disease, acidosis, and medical comorbidities, such as cardiovascular disease.

Anemia Common in CKD

Anemia is a common complication of CKD, mainly due to the inability of the kidneys to secrete enough erythropoietin to stimulate adequate hematopoiesis. Additional factors that may cause or contribute to CKD-related anemia include iron deficiency,11 severe hyperparathyroidism,12 acute and chronic inflammatory conditions,13 aluminum toxicity,14 folate deficiency,15 shortened red blood cell survival,16 hypothyroidism,17 and hemoglobinopathies such as a-thalassemia.18

Anemia often develops early in the course of CKD, well before the onset of ESRD (stage 5, on dialysis),10,12,14,18-21 and then worsens as CKD progresses. Anemia is thus an important clinical factor for millions of Americans with CKD stages 3 through 5.

Hb/Hct levels in dialysis patients (stage 5, on dialysis) are meticulously followed by the Medicare system, and detailed analyses of these levels and treatment results are readily available. Less is known, however, regarding Hb/Hct levels in the millions of Americans with CKD not requiring dialysis.

One frequently cited paper that sheds light on the prevalence of anemia in CKD patients prior to ESRD—and the quality of their care—is a retrospective analysis by Obrador and colleagues21 of more than 130,000 US patients initiating dialysis between April 1995 and June 1997. Sixty-eight percent of these patients had a Hct value <30%, considered to indicate severe anemia, and 51% had a Hct value <28% immediately before starting dialysis. Of those with Hct <28%, epoetin had not been prescribed for 80%.

Obrador and colleagues based their analysis on information collected on Medicare’s Medical Evidence Form (MEF). A recent comparison of MEF data to actual Medicare claims22 (n = 89,193) suggests that the MEF overestimates epoetin use in CKD patients prior to ESRD. The percentage of untreated patients suggested by Obrador and colleagues, therefore, may be even higher. In any event, the evidence is clear that anemia related to CKD stages 1 through 4 is underrecognized and undertreated in the United States.

Consequences of CKD-Related Anemia

The clinical consequences of anemia have been studied more in CKD than in any other disease state. The condition affects almost every organ system. In addition to contributing to the development of left ventricular hypertrophy (LVH), as described below, anemia impairs cognitive function,23 decreases exercise capacity,24 erodes quality of life,25 and may weaken immune responses.26 In patients with ESRD, severe anemia is associated with increases in hospitalization,27 health care costs,28,29 and mortality.30-32

Cardiovascular disease (CVD) is the cause of death in nearly half of dialysis patients.33 Many of the risk factors for CVD are also risk factors for CKD, including hypertension, diabetes, and male gender. Complications of CKD

create additional cardiovascular risk factors, such as volume overload, anemia, increased oxidant stress, hypoalbuminemia, divalent ion abnormalities, hypokalemia and hyperkalemia, and metabolic acidosis.34

LVH is a common finding in patients with CKD,35-37 resulting from alterations in left ventricular wall stress caused, at least in part, by hypertension and anemia.35,36 It has been shown to progress with the degree of CKD. LVH is a significant risk factor for cardiovascular events independent of blood pressure in hypertensive men,38 and for cardiac and all-cause mortality in patients who require dialysis or kidney transplant.