Course Authors

Eli A. Friedman, M.D., and Iram Anees, M.D.

Dr. Anees is Senior Chief Renal Fellow, SUNY Health Science Center, New York.

Within the past three years, Dr. Friedman has received grant/research support from Alteon. Dr. Anees reports no commercial conflict of interest.

Estimated course time: 1 hour(s).

Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

 

Learning Objectives

Upon completion of this Cyberounds^®, you should be able to:

• Discuss the use of evidence based medicine in nephrology

• List and examine some core beliefs of nephrology

• Assess supporting literature citations with respect to challenging core beliefs held.

 

Webster's New Collegiate Dictionary defines a myth as a traditional story, popular belief or notion explaining a practice or natural phenomenon that may be unfounded or false. Similarly, a shibbolethis a commonplace idea or saying that is a criterion for distinguishing a custom or usage.

Medicine is filled with myths and shibboleths, some of which, though the foundation of clinical practice, are at best unsubstantiated and at worst false. It should be noted, however, that broadly held (consensus-based) approaches to medical diagnosis and treatment may be valid and appropriate even when not based on experimental evidence or clinical trials.

In this two-part Cyberounds^®, we hope to distinguish what we know as "proven" from what we believe based on well meaning but unsubstantiated bias. As an example of an unproven though universally accepted effective therapy, realize that the life-sustaining regimen of maintenance hemodialysis has never been tested in a prospective, alternate case trial against a control group of undialyzed patients given optimized conservative care. Indeed, no Institutional Review Board would approve such a trial in 2001. Similarly, the stroke-preventive value of lowering blood pressure in malignant hypertension is inferred from historical controls rather than a concurrent cohort of untreated hypertensive controls. Common sense dictates that not every treatment premise can or should be subjected to experimental testing. Nevertheless, it is beneficial to segregate what is from what we wish might be.

Our Renal Disease Division, at SUNY Health Science Center, Brooklyn, New York, conducts a thrice weekly morning report exercise to foster review of patient care, research initiatives and any other subject that trainees (fellows, elective residents, medical students) opt to raise based on their interaction with patients. For this Cyberounds^® Nephrology, Part II, we will look at the remaining six myths and shibboleths held as bedrock to the core of nephrology.

In collaboration with our senior fellow, Dr. Iram Anees, topical issues that qualified as either a myth or shibboleth were assigned to fellows, house staff and medical students with the request that the evidence supporting and denying the prevalent belief be assessed and an independent conclusion proffered. Table I lists the myths we examine in Part I and Part II. What follows are the edited responses with my comments.

Myth: Type 1 Diabetes Is More Likely Than Type 2 Diabetes to Lead to Nephropathy and ESRD (contributed by Moyna Kapoor, M.D.)

The natural history of diabetes is continuously changing as a result of:

1. the growing pandemic of type 2 diabetes that now accounts for 90+% of prevalent diagnosed cases of diabetes;
2. effective treatment regimens including antihypertensive and oral hypoglycemic drugs that slow the course of complications;
3. recognition of varieties of type 2 diabetes that formerly were confused for type 1 diabetes including Flatbush Diabetes, J-Type Diabetes and Maturity Onset Diabetes in Young Non-obese Japanese Adults. Illustrating the flawed view of diabetic nephropathy portrayed in the literature are more than a decade of registry reports generated by the United States Renal Data System that over-represented the number of type 1 diabetic ESRD patients relative to type 2 diabetic patients because insulin use was interpreted as insulin dependence.

Epidemiologic assessments of diabetic nephropathy have afforded a changing perspective of the proportion of individuals that manifest nephropathy and ultimately develop ESRD. Recognition that microalbuminuria (daily urinary albumin excretion of 30-300 mg) was a predictor of subsequent clinical nephropathy (urinary albumin excretion >300 mg/day) provided a marker for long-term observational studies. Initial prospective studies of nephropathy in type 1 disease discerned an approximately 80% rate of progression from microalbumniuria to proteinuria. Microalbuminuria appeared to be an ominous and inexorable sign of impending renal failure. More recently, this conception has changed for the better with only a 30-45% risk of progression of microalbuminuria to proteinuria over 10 years,(1) while, surprisingly, about 30% became normalbuminuric and the remainder continued microalbuminuric.(2) For undefined reasons, the incidence of type 1 diabetes is declining while the proportion that progress to clinical nephropathy is also decreasing.(3),(4),(5),(6),(7),(8)

By contrast the incidence and prevalence of nephropathy and ESRD in those with type 2 diabetes has grown to what Ritz et al have termed "A medical catastrophe of world wide proportions."(8) Explanations for the explosion of type 2 diabetic nephropathy include the aging and increased obesity in industrialized nations thereby permitting expression of a "thrifty gene" that permitted survival of our Paleolithic ancestors during periods of food deprivation. Few studies compare cohorts of type 1 and type 2 diabetes under the same conditions of observation. Of those that do, the renal risk when comparing the interval from onset of diabetes to proteinuria and ultimately ESRD is equivalent.(10),(11),(12),(13)

Thus, the question as to which type of diabetes is more nephropathic is unanswered. A key restriction on timing complications with duration of type 2 diabetes is the lack of precision in establishing the onset of diabetes. Accordingly, judgments of progression that may be precise in type 1 diabetes are blurred in type 2 disease. One conclusion that is inescapable is that type 2 diabetes is not a mild disorder.

Conclusion: The relative renal complication rates in type 1 and type 2 diabetes are not established.

Myth: Pharmacological Strategies May Prevent Acute Tubular Necrosis (ATN) (contributed by Bharat Patel, M.D.)

Although furosemide and other loop diuretics, mannitol and dopamine are frequently used for prevention and/or treatment of ATN, clinical studies supporting this view have not been convincing. Other drugs with theoretical value, specifically atrial natriuretic peptide analogues, adenosine blockers and calcium antagonists, have been insufficiently studied to recommend use. Ensuring adequate intravascular fluid volume remains the only approach to managing ATN which can be considered relatively effective and safe. Perhaps the best studied clinical circumstance in which ATN is risked is exposure to radiocontrast-induced nephropathy.

Solomon et al. found that, in patients with chronic renal insufficiency who are undergoing cardiac angiography, hydration with 0.45 percent saline provides better protection against acute decreases in renal function induced by radiocontrast agents than does hydration with 0.45 percent saline plus mannitol or furosemide. A "modest benefit" in preempting radiocontrast nephropathy was found by Stevens et al. in a prospective randomized trial of prevention measures that included forced diuresis with intravenous crystalloid, furosemide and mannitol. On the other hand, renal function actually deteriorated in a cohort of patients given furosemide to protect against radiocontrast nephropathy. The use of atrial natriuretic peptide to prevent radiocontrast nephropathy was disappointing in patients with preexisting renal insufficiency, with or without diabetes.

Conclusion: Prevailing evidence does not sustain the value of pharmacologic intervention in preventing ATN. In other words, this myth is just an unconfirmed hopeful anticipation of success. A bright note on the horizon, however, is the recent application of acetylcysteine as a highly effective tool in preventing radiocontrast nephropathy. Confirmatory studies are awaited with enthusiasm.

Myth: Intravenous Iron May Be Hazardous in Infected Hemodialysis Patients (contributed by Dhiren M. Haria, M.D.)

Iron is decreased in ESRD patients on hemodialysis due to a variety of reasons. Iron deficiency is assessed by measuring serum ferritin, serum iron, and/or transferrin TSAT (Transferrin saturation = Total Iron/TIBC*100). Free iron is not detectable in vivo as long as transferrin is less than fully saturated. Serum ferritin is a labile marker affected by chronic infection and inflammation. Also generally speaking, serum ferritin is a more useful gauge of iron status at lower values than at higher ones. A high serum ferritin level is associated with altered chemotactic and phagocytic properties of neutrophils, thereby reducing their ability to kill invading pathogens. However, unanswered is the question of whether serum ferritin levels are elevated due to increased iron stores or infection. Infection per se may elevate serum ferritin levels inducing neutrophil dysfuntion. When studies control for covariates, such as use of catheters and previous infections, the purported infectious risk associated with iron administration or elevated serum ferritin levels is reduced or eliminated.

A recent report from Hoen et al.assessed the risk factors for developing at least one bacteremic episode in an erythropoietin-treated hemodialysis population and reiterated that the dominant risk factors for infection were presence of a dialysis catheter and prior bacteremia. There is concern that high levels of serum iron may promote replication and dissemination of bacterial pathogens that require iron as a growth factor. In vitro, the absence of free iron is crucial for proper phagocytosis and killing but stored bodily iron is unlikely to render an organism more virulent. Any putative effect of stored iron would likely proceed through mechanisms involving neutrophil dysfuntion after release of free iron from storage.

Conclusion: A link between iron and infection in hemodialysis patients is a rational concern. Iron is important for bacterial virulence/growth; both lack of iron and excess iron might impair leukocyte function. Firm evidence linking iron and clinical infectious is minimal. For the present, withholding iron supplementation from infected hemodialysis patients who are anemic and depleted of iron stores cannot be advocated.

Myth: Peritoneal Dialysis Is Equivalent to Hemodialysis (contributed by Jasmohan Bajaj, M.D.)

Although renal transplantation is regarded by consensus to be the best available renal replacement therapy ,most patients with end stage renal disease(ESRD) are sustained by dialytic therapy either as a bridge to transplant or as their only treatment. Peritoneal(PD) or Hemodialysis(HD) are the two preferred forms of maintenance dialysis provided in industrialized countries. Whether they are equivalent in outcome and complications is the subject of controversy. Comparison has been made in various headings:

1. Mortality: Pro HD. The United States Renal Data System (USRDS) report for 2000 study indicates that all cause mortality is marginally higher in CAPD/CCPD (230.5 vs. 227.2/1000 patient years at risk), but there was a substantial increase in mortality with increasing age, especially in patients above 65 years of age on PD than those on HD (414.5 vs. 339.4). The causes of mortality, however are similar for both modalities. Pro PD: Large scale studies comparing mortality report an increased risk of early mortality in patients on HD (possibly due to the acuity of their presentation) which equalizes that on PD at three- and six-month periods in Canada.(26) Fenton et al.(28) demonstrated an overall lower PD mortality risk in Canadian patients 1990-94.
2. Hospitalizations: Pro HD. USRDS 2000 data shows more hospital days required in PD than in HD (15 vs. 13/patient year at risk). Studies done in 1990(31) also found that there was a higher rate of hospitalization in PD with a RR 1.33 though the reasons for admission were different and the length of the stay was greater in HD (due to greater baseline comorbid conditions).
3. Pro HD. While dialysis related admissions were greater in PD but admissions for cardiovascular disease and non-dialysis related infectious illness were higher in HD.(32)
Quality of Life: PD=HD. The majority of studies suggest an equivalence for the two methods as far as symptomatic improvement of uremia and nutritional status, but t HD patients are thought better adjusted to their disease burden than PD patients,(40) perhaps attributable to support and medical staff attention
4. Patient Choice: Pro PD. Ahlmen et al.(41) found that the majority of patients with ESRD chose PD over HD after receiving adequate information.
5. Renal Transplant success: PD=HD. Kang et al.(37) detected no significant difference in outcomes after renal transplant in patients previously treated with HD or PD.
6. Socioeconomic: Pro PD. Increased use of PD is of greater socioeconomic benefit.

Conclusion: HD has lower mortality benefits than PD in the USA but not in Canada. The disparity between modalities increases with increasing age. PD and HD are equivalent as far as quality of life, subsequent kidney transplant survival and morbidity. HD is the preferred acute renal replacement therapy but PD is more cost effective in all settings. There persists an unresolved concern that patients with large body mass may require more than four daily PD exchanges to attain sufficient solute removal, especially as their residual renal function falls to zero.

Myth: Rationing of ESRD Treatment Is an Unavoidable Reality (contributed by Sidartha Pani, M.D.)

Rationing means the implicit or explicit denial of beneficial or marginally beneficial medical treatment as a result of insufficient resources to provide treatment to all. A growing demand for solid organ transplantation, coupled with a static supply of organs, results in an excess demand crisis. While it is only in the arena of transplantation that the United States medical community presently confronts a true rationing dilemma, the remainder of the world is forced to cope with insufficient funding for treatment of all potentially treatable ESRD patients. It follows that a cohesive rationing policy should manage both the demand for ESRD therapy as well as the fair allocation of transplantable organs.

Despite what appears an inescapable conclusion -- rationing of expensive health services must be applied at some point in every economy, there are still social planners who deny that rich nations will ever need to deny any therapy to any appropriately selected patient.

Conclusion: Although the premise is unproven, it is probable that every nation will practice rationing of health services. Rationing according to social worth, ability to pay or age, while ethically debatable, may be justified by the stark reality of limited funding.

Myth: Tacrolimus Is Superior to Cyclosporine in Renal Transplantation (contributed by Melad G. Benyamine, M.D.)

Courses of therapy devised to immunosuppress organ transplant recipients evolved from trial and error and drug-by-drug trials, with few prospective randomized comparisons of combination "a" versus combination "b". Unless treatment cohorts are equivalent, analyses of immunosuppressive drug studies in kidney transplantation may be skewed by inequity in study groups including: donor-recipient compatibility, induction with monoclonal antibody antilymphocyte products, timing and dose of corticosteroids, choice of one of four main immunosuppressive drugs (azathioprine, cyclosporine, tacrolimus, mycophenolate), subsequent dosage and frequency of selected drugs.

When cyclosporine was introduced (at substantially greater cost), richer nations largely abandoned the relatively inexpensive azathioprine. Now that a choice of principal immunosuppressive agents is marketed, clinicians face difficulty in drug selection, emulating the stress engendered when selecting antihypertensive or antimicrobial regimens.

The prevailing and growing myth is that tacrolimus proffers advantages over cyclosporine:

1. Tacrolimus significantly reduced duration of delayed graft function in non-heart-beating donors and is preferred over cyclosporine when this complication is probable as in: recipients with a low pretransplant mean arterial blood pressure, female donor to a male recipient and after prolonged ischemia time.(49) While as safe and effective as cyclosporine in cadaveric renal transplantation, tacrolimus has a similar side-effect profile.(50)
2. Immunosuppression with tacrolimus after renal transplantation significantly reduces the incidence of acute rejection, compared with cyclosporine(51) in both African American and Caucasian,(52) and at one year permits greater graft survival than cyclosporine.(53) Significantly lower serum creatinine and cholesterol levels are reported in black recipients of primary cadaveric renal transplants.(54)
3. Compared with cyclosporine, tacrolimus induced less acute rejection, resulted in lower serum creatinine concentration at one and two years, reduced the use of muromonab-CD3 or antilymphocyte globulin and had less frequent conversion to mycophenolate mofetil.(55)
4. The superior efficacy of tacrolimus in the prevention of acute rejection is not associated with an increased risk of either CMV(56) or posttransplant lymphoproliferative disease, compared with cyclosporine.(57)
5. Tacrolimus plus mycophenolate mofetil induced the lowest rate of steroid rejection requiring anti lymphocyte therapy.(58)
6. After three years, a U.S. multicenter trial demonstrated a significant decrease of graft loss in tacrolimus treated patients compared to cyclosporine patients.(59)

Suggestive evidence exists indicating that tacrolimus is not superior to cyclosporine:

1. Posttransplant diabetes is more common with tacrolimus than with cyclosporine.(60)
2. Conversion from tacrolimus to cyclosporine in stable renal transplant recipients was associated with a small rise in blood cholesterol levels.(61)
3. In a series of combined pancreas plus kidney transplants, there was less rejection, but more infection, in recipients treated with tacrolimus, compared with cyclosporine.(62)

In summary, tacrolimus holds short term advantage over cyclosporine in kidney transplants. How the greater risk of posttransplant diabetes may impact on long-term patient and allograft integrity remains to be established.

Conclusion: Though tacrolimus holds advantages over cyclosporine, its ultimate place in immunosuppression is unestablished.