Course Authors
Eli A. Friedman, M.D.
Release Date: 04/02/2003
Upon completion of this Cyberounds®, you should be able to:
Discuss the incidence and prevalence of end-stage renal disease in the United States including an awareness of the dominance of hypertension and diabetes as precipitating causes
Discuss the impact of race on the incidence of kidney failure with associated presentation of the puzzle of why African American, Hispanic, and Native American ESRD patients have better survival during maintenance hemodialysis than do whites
Define and describe the concept of renoprotection as the detection and proactive treatment of the broad based population of those destined to deteriorate into ESRD.
The present-day introduction and broad utilization of effective kidney transplantation and maintenance hemodialysis transformed nephrology from a research subdivision of physiology departments into a meaningful clinical subspecialty of internal medicine. Once it became possible to sustain life in individuals who have irreversibly lost native kidney function, the specialty now termed nephrology was born.
In this, and the next Cyberounds®, we will examine the enormous changes in health care induced by our ability to treat kidney failure. National recognition, by award of the 2002 Albert Lasker Prize to the 1943 inventor of the artificial kidney, Dr. Willem J. Kolff, and to the 1960 innovator who, devised maintenance hemodialysis, Dr. Belding H. Scribner, underscores the transformation of uremia therapy from a sad exercise in futility to an exciting challenge in cost and personnel efficiency. Recently, Kolff received (February 2003) the Ross Prize from the National Academy of Engineering, while the American Association of Kidney Patients conferred their Medal of Excellence on Kolff and Scribner (March 2003).
Nephrology Dialysis Duo Wins Prestigious 2002 Albert Lasker Award. Willem J. Kolff, M.D., (left), fabricated the first artificial kidney during World War II in German Occupied Holland in 1943. Now, at the age of 93, and as adjunct professor of medicine at New York's Downstate Medical Center, Kolff is hard at work devising an artificial lung. Belding H. Scribner, (right), new Chief of Nephrology at the University of Washington, conceived and applied repetitive hemodialysis in 1960 as a chronic therapy that now sustains more than 400,000 kidney failure patients worldwide. Photo by Eli A. Friedman, M.D.
As we celebrate the 50thanniversary of the momentous unraveling of the structure of DNA by Watson and Crick, it is appropriate to pause and assess what the therapeutic gift of Kolff and Scribner might mean. At the least, uremia therapy foreshadows an era of evolving medicine in which bionic devices will sustain millions who might otherwise have died from failed vital organs. Artificial (implantable) hearts, lungs, intestines, livers, endocrine glands and reproductive organs are likely to be in hand as near term as the close of this decade. Preliminary trials of totally implantable hearts have already made the front pages of our key newspapers.
In this context, it seems worthwhile to step back and evaluate what appears to be an incredible forward motion in changing medicine from a cult and priesthood to a science. Together with the broad application of advances in molecular biology, that have, for example, made chronic myelogenous leukemia, and HIV infection treatable (curable) diseases rather than relentless afflictions, bionics-based medicine of 2025 will be unrecognizable to the graduate of 2003.
Superimposed on the wondrous ability to delay death from vital organ failure is the ethical issue of defining the limits of our interventions. Are there not many of our patients who should be permitted to die comfortable deaths after disabling strokes or multiorgan disorders that preempt any return to what might be termed acceptable life quality? If so, who should decide which bionic device is applied to which patient? The complexity of selecting candidates for evolving and extremely expensive treatments will tax the souls and innovative ability of all health care workers as an increasing burden. Let us begin our inspection of the evolving changes imposed by bionic medicine with an examination of contemporary treatment for kidney failure in two prototypical patients:
Case 1: Advanced Kidney Failure Too Late for Renaoprotection
A 51-year-old African American attorney, admitted for a "pathologic" right hip fracture, is found to have autosomal polycystic kidney disease with a blood pressure of 179/116 mm Hg, a serum creatinine concentration of 9 mg/dl, a serum albumin of 4.2 g/dl, a calcium of 6.8 mg/dl, a serum phosphorous of 7.5 mg/dl and a hematocrit of 26%. The patient's mother died of infectious complications of polycystic kidney disease and a brother and sister (of four siblings) have functioning kidney transplants. While under the care of a general practitioner, the patient had annual blood counts and chemical screens but was not treated for hypertension or anemia. A consulting nephrologists urged immediate initiation of hemodialysis via a femoral cannula, and construction of an arteriovenous graft fistula was scheduled for the next day following placement of a hip prosthesis. Planned studies include magnetic imaging of cerebral blood vessels, renal sonography, a dobutamine coronary stress test, and tissue typing as a prelude to listing for a kidney transplant.
Comment
This patient should have had an internal radial arteriovenous fistula created some time (months) earlier, as well as been started on treatment with synthetic vitamin D and erythropoietin. Antihypertensive therapy with either an ACEi, a beta blocker, a calcium channel blocker, or an angiontensin receptor blocker was called for as soon as hypertension was detected. Characterized as a "late referral," this patient will be subjected to both higher morbidity and increased risk of early death compared with.the prognosis for an age, race, gender and renal diagnosis matched patient who begins ESRD therapy with a well developed vascular access, normal blood pressure and a hematocrit of 35-39% induced by treatment with recombinant human erythropoietin. Tissue typing and wait listing for a kidney transplant, had it been done when the serum creatinine reached approximately 5 mg/dl, would have given the patient the chance (admittedly small) to receive a kidney transplant before the life sustaining need for renal replacement therapy became urgent. Additionally, the hip fracture, a component of renal bone disease due to secondary hyperparathyroidism, could have been prevented by treatment with a vitamin D analogue and a phosphate binder. It is now too late in the course to attempt a renoprotective regimen. The patient's management did not reach an acceptable standard.
Case 2: An Ideal Candidate for Renoprotection
A 24-year-old unmarried white female sales clerk, under evaluation for asymptomatic proteinuria, (1.1 g/24 hr) detected at a yearly employee examination, is found to have idiopathic membranous glomerulonephritis by percutaneous renal biopsy of normal sized kidneys. There was no history of exposure to nephrotoxins. Tests for collagen diseases, malignancy, and indolent viral infections including HIV were negative. The blood pressure was 119/71 mm Hg and the physical examination was normal. Screening blood counts and chemistries including the serum creatinine, serum albumin and serum calcium and serum phosphorous concentrations were normal. A urine culture was sterile. The endogenous creatinine clearance was 134 ml/min.
Comment
While about one-third of patients with idiopathic membranous glomerulonephritis will progress to ESRD despite treatment with corticosteroids or immunosuppressive drugs, the majority will either improve or remain stable over five years of observation. Despite substantive proteinuria, the normal glomerular filtration rate excludes this patient from the ranks of those with CRD for which the defining requirement is reduction of GFR with or without azotemia. A trial of mycophenolate mofetil might improve or arrest the proteinuria. Normotension and the absence of urinary infection are reasons to forego any other treatment of the renal disorder.
Part 1: Present Management of Renal Failure in the U.S.
Where We Stand: Renal Failure Is a Growing Economic Burden
According to the United States Renal Data System's (USRDS) 2002 Annual Data Report (ADR), in 2000, the latest year for which data are available, there were 378,862 patients undergoing treatment for end-stage renal disease (ESRD).(1)
The extraordinary growth of diabetes as the leading cause of irreversible kidney failure throughout the industrialized world has previously been explored in Cyberounds®. Indeed, while the incident rate for all other diseases has stabilized, diabetes constitutes a pandemic that will soon account for more than 60 percent of all ESRD cases before this decade ends. There is controversy as to whether hypertension, per se, is an actual cause of kidney failure or only an accelerant for other etiologies of renal disease as explored in Cyberounds® Myths.
Of these, 275,053 were sustained by peritoneal or hemodialysis while 103,809 had a functioning kidney transplant. During 2000, 96,192 new patients began ESRD treatment, of whom 7,765 received a donor kidney while 3,983 received a living donor kidney.
Dialysis is the predominant therapy for ESRD worldwide. Economic forces, however, modulate the proportion of patients assigned to peritoneal versus hemodialysis. In Mexico, for example, peritoneal dialysis predominates and is applied to over 80 per cent of ESRD patients while in the US, hemodialysis was utilized for 83,648 of 92,486 (90.4 percent) of incident ESRD patients in 2,000.
There were 72,342 deaths of ESRD patients during the year while new patients began therapy at a rate of 334 per million population. The cost of ESRD was assumed almost entirely by Medicare ($13.8 billion) while non-Medicare costs amounted to $5.5 billion of which patients were billed $3.1 billion. On a per patient basis, Medicare spending amounted to $46,045 per year with a kidney transplant costing much less ($17,227) than either hemodialysis ($54,917) or peritoneal dialysis ($46,121).
The Mystery of Racial Impact on ESRD Survival
Of all the questions raised by the careful, continuous monitoring of the quality of ESRD care in the US, none is more vexing than the difference in survival between races purportedly treated equally. Recording all incident and prevalent ESRD patients documented the clinical impression that colored races (African American and Hispanic) are at greater risk of renal failure, primarily because of a higher incidence of diabetes and hypertension. As shown in Figure 3, in 2000, African Americans had an ESRD incidence of 777 per million contrasted with an incidence in whites of 269 per million.
Surprisingly, the incidence in Hispanics was only slightly higher than in whites, though Native Americans, because of an exceptional attack rate of type 2 diabetes, had an incidence of 501 per million. It was postulated that lower annual income dictated suboptimal care of hypertension and diabetes and resulted in a greater rate of renal functional deterioration among African Americans.
But why should the relative prevalence of ESRD rise continuously in African Americans throughout their years of ESRD treatment thereby progressively exaggerating the African American-white difference at onset? Illustrating this point are data indicating that in 2000, the ESRD prevalence rate in African Americans was 3,407 per million compared with 986 pre million in whites, 1,005 in Hispanics, and 2,378 in Native Americans. If poverty induced inferior management of diabetes and hypertension was the reason for higher incident rates of ESRD, would it not be expected that the death rate during dialytic therapy or after a kidney transplant would be higher for African Americans and Hispanics than for whites.
Actual survival statistics during maintenance hemodialysis, and after a kidney transplant, again reveal the unexpected. As shown in Figure 4, pooling survival results on peritoneal dialysis and hemodialysis, African Americans and Hispanics actually have a sharply better outcome once begun on dialysis.
Figure 4. US Dialysis Survival by Race, No Hispanic Data After 2 Years.
For example, USRDS statistics show that after two years of dialysis, 71.3 percent of African Americans, and 71.9 percent of Hispanics, but only 61.2 percent of whites are alive. How can this be?
Some hypotheses attribute the better survival of colored races to greater muscle mass leading to mistaken creatinine-based premature diagnosis of ESRD or obscure survival genes. Data are insufficient to explain the course of Native Americans in whom wide variation of diabetes prevalence has been noted depending on the tribe of the individual. As an illustration, 12.3 percent of Native Americans over 19 years old suffer type 2 diabetes, reaching epidemic proportions, as about 6 percent of the general population has diabetes. New York's Mohawk Tribe has a diabetes rate approximately one-third that of the Pima Tribe in Arizona in whom more than 50 percent of adults ages 30 to 64 have diabetes.
The National Diabetes Data Group compared U.S. diabetes rates in the 1987-1982 National Health Interview Survey noting wide disparity in Native American subraces.(2) Similarly, the age-adjusted prevalence of diabetes in Canadian Mohawk Indians is 48.8/1000, two times the U.S. rate.(3)
Deepening the confusion over interpreting the impact of race on ESRD therapy outcome are the confusing and contrary results reported for survival following cadaver donor kidney transplantation. When compared to whites, African American and Hispanic kidney transplant recipients, (unlike their greater survival during peritoneal dialysis or hemodialysis), have no survival advantage when given cadaver donor kidneys, as shown in Figure 5.
Figure 5. Cadaver Donor Kidney Transplant Survival by Race, No Hispanic Data After 2 Years.
African Americans receive fewer donor kidneys in relation to the number of African Americans waiting for a kidney transplant than do whites. To adjust for what has been interpreted as an inadequate allotment of donor kidneys to African Americans, one proposal is to dispense with tissue typing because African Americans appear to be at an allotment disadvantage when this system of organ distribution is followed. By contrast, one retrospective review indicates that suspending tissue typing for African American recipients might drastically lower kidney survival.(4)
In sum, the racial enigma of ESRD therapy outcome is unresolved. Until truly detailed matched cohorts of African American, white and Hispanic ESRD patients beginning treatment are studied, what can be stated is that African Americans are not disadvantaged, in terms of survival, by dialysis as practiced in the U.S..
The Problem: Can Progressive Renal Disease Be Prevented?
It has been projected that by 2010, the incidence of ESRD will increase to 172,667, while the prevalence will grow to 661,330, at a Medicare cost of $39.35 billion. We can estimate the proportion of Americans with chronic renal disease (CRD) from data clarified by the Third National Health and Nutrition Examination Survey (NHANES III) that measured both serum creatinine and urine albumin.(5) Using a nationally representative sample of 15,625 non-institutionalized adults aged 20 years and older, the prevalence of CKD in US adults was 11% (19.2 million).
NHANES III attempted to stage the severity of prevalent CKD, estimating that 5.9 million individuals (3.3%) had Stage 1 [persistent albuminuria with a normal derived glomerular filtration rate (GFR)], 5.3 million (3.0%) had Stage 2 (persistent albuminuria with a GFR of 60 to 89 mL/min/1.73 m2, 7.6 million (4.3%) had Stage 3 (GFR, 30 to 59 mL/min/1.73 m2, 400,000 individuals (0.2%) had Stage 4 (GFR, 15 to 29 mL/min/1.73 m2, and 300,000 individuals (0.2%) had Stage 5, or ESRD. Clearly, the quest for strategies that might slow progression of CRD will afford economic as well as fiscal benefit.
Objective data show the economic impact of retarding CRD. According to Trivedi et al. who employed a mathematical model in which deterioration of renal function to ESRD is slowed by 10%, 20%, and 30%, relying on USRDS projections for incidence and prevalence, in which the rate of decline in renal function, as measured by glomerular filtration rate, is slowed by 10%, 20%, and 30% cumulative direct healthcare savings through 2010 would amount to approximately $18.56, $39.02, and $60.61 billion.(6) These researchers interpreted their findings to indicate that the cumulative economic impact of slowing progression of CRD, "by as little as 10%, would be staggering."
The Plan: Identify Key Interventions That Will Retard Progressive Renal Injury
Because there is a large prevalent population with CRD, the next step in coping with prevention of renal failure is to list possible approaches to modulating the previously thought inevitable march toward ESRD. Lessons learned from treatment of diabetic nephropathy(7) and hypertensive renal disease(8),(9) lent support to the thesis that aggressive proactive treatment of CRD would blunt the slope of the curve of renal functional decline.
As listed in Table 1, interventions that might be applied to delay ESRD (Renoprotection) are now in various stages of clinical trial. The next installment of Cyberounds® Nephrology will weigh the benefits of each component of what is now termed "Renoprotection". Illustrative patients will be presented as guides to your practice approach to patients with compromised renal function.
Table 1. Proactive Protective Measures Entailed in Renoprotection.
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