Course Authors

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

Dr. Anees is Senior Chief Renal Fellow, SUNY Health Science Center, Brooklyn, 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 shibboleth is 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 it 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^®, seven myths and shibboleths held as bedrock to the core of Nephrology are explored. In Part II, we will examine six more.

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 1 lists the myths we will examine in Part I and Part II. What follows are the edited responses with my comments.

Myth: Kidney Donation Does Not Jeopardize Function in the Remaining Kidney (contributed by Daniel J Wolde, M.D.)

If results in experiments in rodents were directly translatable to humans, live donor kidney transplantation would have been seriously constrained by the physician's primary mandate of "first do no harm." In some rat strains, reduction in renal mass induces an increase in intraglomerular pressure, hypertension, glomerular hyperfiltration, proteinuria, and ultimately, renal insufficiency. Termed the "Brenner Hypothesis,"(1) these findings cast a pall on the long-term integrity of residual nephrons in kidney donors. First studies of kidney donors indicated a higher rate of proteinuria and hypertension than that of age and gender matched healthy controls. Upon reflection, however, it was appreciated that these donors were family members of an individual who developed kidney disease and thus might themselves be at greater genetic risk for hypertension and proteinuria than the population at large.

All recent reports indicate that in healthy normal individuals, unilateral nephrectomy does not cause progressive renal dysfunction. Overall health of donors was scored at least as high as age and gender matched controls. Accordingly, abundant(2),(3),(4),(5),(6),(7) evidence sustains kidney donation as safe and without an enhanced risk of kidney disease.

Conclusion: Kidney donation is safe.

Myth: Hypertension Imposes a Risk of Chronic Kidney Failure (contributed by Mervat Mansour, M.D.)

Previously argued in Cyberounds^®, questioning the widely held consensus view that hypertension imposes a risk of end-stage renal disease (ESRD) is taken by some as an attack on conventional wisdom and baseline knowledge. Without question, untreated malignant hypertension can be complicated by ESRD. Although neither prospective nor controlled, ample evidence sustains the direct progression from normal renal function to the abrupt onset of renal failure in a syndrome encompassing grade IV hypertensive retinopathy, proteinuria, fibrinoid necrosis and hyalinization of small arteries and arterioles.

Beyond this sequence, investigators have had difficulty employing retrospective analyses of patient charts to link hypertension in the absence of intrinsic kidney disease to progressive renal insufficiency. For example, the Baltimore Longitudinal Study on Aging (BLSA) reported 446 patients in whom five or more determination of creatinine clearance were made over a 13-year period. While hypertensive patients lost renal function at a faster rate with aging than did normotensive subjects, the difference between groups was small and unlikely to result in ESRD. In the BLSA, as in other observational prospective studies, it was not established whether hypertension caused the slightly accelerated rate of decline in renal function or was the result of undiagnosed renal disease.

Also non-helpful to the inquiry is the Hypertension Detection and Follow Up Program (HDFP). Data from this study show that hypertensive patients with an abnormally high serum creatinine at entry sustain increased mortality and further decline in glomerular filtration rate but did not provide evidence that hypertension per se causes ESRD. Because patients with underlying renal disease were not excluded, it is likely that many patients that presented with an abnormal serum creatinine had a primary renal disease that caused both the hypertension and the higher mortality.

Rostand et al. explored the relationship between hypertension and renal disease by retrospectively reviewing the records of 181 patients with hypertension. Increased risk of developing a decline in renal function was noted in blacks, elderly patients and those with a higher number of missed office visits. Unexpectedly, an equivalent decline in renal function was observed in patients whose blood pressure was controlled as in those whose blood pressure was not well controlled. This finding was echoed by Weisstuch and Dworkin who after a literature review in 1992 remarked: "Although an increase in serum creatinine or decline in clearance has been reported, progression to ESRD has not been documented."

Ideally, proof that essential hypertension causes ESRD requires prospective analysis of a large cohort of patients with well-documented essential hypertension and normal renal function at presentation who then followed until a significant number of individuals develop renal failure. Unfortunately, such data are unavailable. For the present, therefore, the frequency with which essential hypertension leads to ESRD remains speculative fitting the definition of a myth.

Conclusion: Hypertension per se does not lead to ESRD.

Myth: Angiotensin Converting Enzyme Inhibitors (ACEi) Are Superior to Other Antihypertensive Drugs Because of Their Renoprotective Properties (contributed by Moro O. Salifu, M.D.)

Animal models suggest that proteinuria upregulates inflammatory cytokines, resulting in both interstitial and glomerular fibrosis. Also, angiotensin II (AGII) upregulates cytokines, promoting mesangial matrix deposition, while altering glomerular hemodynamics and basement membrane pore size distribution. In the absence of similar studies in humans, it has been inferred that the effect of ACEi on AgII and proteinuria is 'renoprotective'. In actuality, support for the superiority of ACEi over other antihypertensives in humans is anecdotal.

Favoring ACEi. In diabetic nephropathy, the Collaborative Study Group of angiotensin converting enzyme inhibition in diabetic nephropathy, a multicenter, prospective, randomized, double-blind study, compared 409 patients with type 1 diabetes who had protein excretion over 500 mg/24h and a serum creatinine level less than 2.5 mg/dl treated with captopril or other agents. Captopril treatment attained a 50% reduction in patients reaching end points of death, dialysis, and transplantation or doubling of serum creatinine, independent of degree of blood pressure control.

In non-diabetic nephropathy, the Ramipril Efficacy in Nephropathy (REIN) study was a prospective randomized, double blinded comparison of ACEi with conventional therapy in 352 patients with proteinuria of either 1-3 g/24h or >3 g/24h randomly assigned to 1.25 mg of ramipril or placebo. Ramipril was increased to keep diastolic BP to < 90 mmHg. A slower decline in glomerular filtration rate (GFR) was noted in the ramipril group. For the same degree of blood pressure control, ramipril decreased the risk of ESRD by 56% and the risk of progression to overt nephropathy by 52%.

No advantage to ACEi. Parving clearly demonstrated the effect of blood pressure control on proteinuria and GFR in 11 type 1 diabetics observed for six years in Denmark, in 1987. Patients served as their own controls comparing an initial pretreatment period (~32 months) with treatment (~72 months) using metoprolol, hydralazine and furosemide. Only one patient received alphamethyl dopa. Mean decline in GFR was 0.94 ml/min/month before entry. After three years of intensive blood pressure control, mean blood pressure dropped from 143/96 mm Hg to 129/84 mmHg. The mean rate of fall of GFR dropped to 0.29 ml/min/month after three years and to 0.1 ml/min/month after six years. This corresponds to 88% reduction in GFR decline at six years. Decline in proteinuria was significant. The key point is that this remarkable preservation of kidney function (renoprotection) was achieved without ACEi.

From the evidence in hand, blood pressure reduction appears to be the key factor in renoprotection. Caution should be exercised in extrapolating animal studies to humans before concluding that ACEi are superior to conventional therapy in renoprotection.

Conclusion: ACEi are not proven to be superior to other antihypertensive drugs.

Myth: Dietary Protein Restriction Slows Progression of Renal Insufficiency (contributed by Margaret Brunson, P.A.)

According to Mitch, low-protein diets alleviate uremic symptoms and some complications of chronic renal failure (CRF). Low-protein diets are viewed as nutritionally sound in CRF patients because they activate compensatory mechanisms that conserve body muscle mass. In a prospective, randomized study of the efficacy of protein restriction in slowing the rate of progression of renal impairment Ihle et al. found that ESRD developed in nine of 33 patients on unmodified diets as compared with only two of 31 patients on a protein-restricted diet.

Similarly, Fraga et al. studied seven patients on a low-protein diet for six months noting that after a transitory increase in plasma creatinine concentration, there was a fall in plasma urea concentration while mean systolic and diastolic arterial blood pressure remained stable. On an ad-libitum diet, 4/7 patients evinced progressive loss of renal function while the other three were stable. Protein restriction decreased progression of chronic renal failure in the four patients with previous disease perhaps due to suppression of compensatory hyperfiltration. A low-protein and phosphorus restricted diet distinctly improved uremic symptoms, secondary hyperparathyroidism and metabolic acidosis in patients with chronic renal failure in a study by Maroni and Mitch.

Bakris et al. stress the importance of appropriate end-points in any trial designed to slow the course of renal disease whether by dietary protein restriction or use of antihypertensive drugs. No reported trial clearly demonstrates the value of dietary protein restriction in retarding the course of kidney disease. As noted by Marcantoni et al. the risk of progression of renal disease can be minimized by lowering both blood pressure and proteinuria with ACEi but not by diet alone.

Of all the evaluations of dietary protein restriction, the Modification of Diet in Renal Disease (MDRD) Study showed no conclusive benefit. True, in patients with moderate renal insufficiency, a slower decline in renal function began four months after starting a low-protein diet, but in patients with severe renal insufficiency, a low-protein diet did not significantly slow progression. Also inferred from the MDRD Study is the inference that not all renal diseases respond similarly to interventions and that future studies should focus more narrowly on types of patients or specific renal diseases that may be worsening through common mechanisms.

At one extreme, Mehrotra et al. conclude that low-protein diets have only a beneficial effect on hyperphosphatemia with no proven benefit on other aspects of the uremic syndrome. Overall, the impact of dietary protein restriction or preservation of GFR in nondiabetic renal disease is small and of no clinical relevance. Furthermore, noting that subjects of the MDRD study developed subclinical signs of malnutrition and that compliance with the regimen is inconstant supports the conclusion. It was concluded from this study that low-protein diets are not necessary in chronic renal failure.

Conclusion: Dietary protein restriction is unsubstantiated in progressive kidney disease.

Myth: Plasmapheresis Is Beneficial in Some Renal Disorders (contributed by Leila J. Macey, P.A.)

Membrane-based plasmapheresis was performed on April 9, 1979 in Germany purportedly improving the course of a 21-year-old woman with myasthenia gravis. Between 1979 and 1994, a total of 824 articles on plasmapheresis and renal disease were published, including 529 papers limited to humans reported in the English language. Diseases in which plasmapheresis has been used as therapy, either alone or in combination with other agents, are:

• Advanced renal failure in antineutrophil cytoplasmic antibody (ANCA) - associated renal vasculitides.
• Rapidly progressive glomerulonephritis
• Idiopathic atypical hemolytic uremic syndrome (HUS)
• Cryoglobulinemia Type II
• Renal failure associated with multiple myeloma
• Pauci-immune crescentic glomerulonephritis
• Henoch-Schonlein purpura nephritis
• Acute renal failure
• Lupus nephritis
• Idiopathic IgA nephropathy
• Recurrent focal segmental glomerular sclerosis (FSGS) following kidney transplantation
• Recurrent idiopathic membranoproliferative glomerulonephritis (MPGN) type I following renal transplantation
• Recurrent nephrotic syndrome post renal transplantation in children.
• Given the multiplicity of applications, there are few reports of large series of patients and nearly none that are controlled trials of plasmapheresis.

Positive Reports

1. Harada et al. in 17 patients with RPGN employing plasmapheresis as an adjunct to immunosuppressive therapy, 10 patients stabilized renal function for 1-3 years, two patients progressed to ESRD requiring hemodialysis, two patients showed no improvement in renal function and the outcome was not stated for the remaining three patients.
2. Similarly, Hattori et al. reported that in nine nephrotic children with Henoch-Schonlein purpura who had decreased GFR and crescentic glomeruli who were treated solely with plasmapheresis, four patients had complete recovery, two patients had microscopic hematuria but with alleviation of symptoms, improvement in GFR and reduction of proteinuria. The remaining three patients after an initial improvement in clinical status had a rebound of proteinuria and two of these remaining three progressed to hemodialysis.
3. Of 11 adults with biopsy proven focal and segmental glomerulosclerosis (FSGS) and nephrotic syndrome, resistant to steroids and cytotoxic drugs, plasmapheresis, oral prednisolone and intravenous cyclophosphamide after six months resulted in complete or partial clinical remission in six (54.5%) patients.
4. In 11 adult recipients of kidney transplants with a pre-transplant diagnosis of FSGS, three received pretransplant plasmapheresis and did not have recurrent disease. Of the eight who did not receive pre-transplant plasmapheresis, four lost their grafts due to recurrent FSGS; two patients continued to be stable; one had proteinuria with FSGS on biopsy specimen and underwent plasmapheresis once/month for two years with good renal function and controlled FSGS.

Negative reports:

1. In a prospective French study of 62 children with SLE, 37 were followed for five years, of whom 13 (35%) were in remission; seven (19%) had urinary abnormalities or nephrotic syndrome; four (11%) had moderate renal failure; seven (19%) had chronic renal failure and six (16%) had hypertension. Medical treatment did not always prevent development of severe renal failure. Plasmapheresis failed to avert death in one patient and progression to chronic renal failure in two others.
2. Of 26 patients with biopsy-proven RPGN (crescentic), Glockner et al. randomized 12 patients treated with immunosuppressants alone, compared with 14 patients who received plasmapheresis in addition to the same immunosuppressive regimen. After eight weeks, 73% and 69% of patients in each respective group showed a substantial fall in serum creatinine levels.
3. Similarly, a randomized, multicenter controlled clinical trial of 86 patients with lupus nephritis compared prednisone and cyclophosphamide with the same regimen plus plasmapheresis. There was no difference in clinical outcome between the two therapeutic regimens.
4. It is concluded that plasmapheresis does not improve the clinical outcome in patients with lupus nephritis or non-autoantibody induced rapidly progressive glomrulonephritis because the literature substantiated this with clinically sound trials.

Conclusion: Plasmapheresis is of unproven worth in kidney transplant recipients evincing recurrence of FSGS or in antibody associated glomerular nephritides.

Myth: Urinary Tract Infection Is More Prevalent in Diabetes (contributed by Iram Anees, M.D.)

Variables in selecting populations at risk may override actual differences in outcome when screening for bacteriuria. For example, in a study of 1,072 women in Canada, 85 (7.9%) were found to have bacteriuria and this subset was more likely to have type 2 diabetes. In Singapore, of 287 diabetic patients with urinary infections Klebsiella species were significantly more common than in nondiabetic individuals with urinary infections. A prospective study of 1,458 adult inpatients in Boston noted 136 urinary tract infections in 1,474 indwelling bladder catheterizations with diabetes and a serum creatinine above 2.0 mg/dl as separate risk factors. When 148 diabetic patients were compared with 1488 nondiabetic patients in Spain, urinary tract infections had an incidence nearly twice as high in the group with diabetes (26.8/1000 admissions) versus those without diabetes (15.5/1000 admissions) p<0.001.

By contrast, in an epidemiologic comparison of diabetic patients with urinary tract infection to nondiabetic patients with similar infections, no significant differences in epidemiological, clinical or microbiological features were discerned between the two groups. Similarly, a Scandinavian study of urinary tract infection in 304 girls and 337 boys with type 1 diabetes discerned no difference in incidence or prevalence from the rate in healthy young people without diabetes.

An evidence based answer to the question posed must equivocate until further trials are completed. Clinical experience strongly suggests that all infections including urinary tract infection are more likely to be severe and life threatening in a diabetic patient.

Conclusion: An epidemiologic case for greater incidence and/prevalence of urinary tract infections due to diabetes is still unproven.

Myth: Urinary Tract Infection Can Lead to ESRD (contributed by Iram Anees, M.D.)

Starting with the discovery in the 1950s that bacterial infection of the urinary tract may be asymptomatic and indolent, this finding was cast in a sinister and foreboding light. Coupled with an inability to explain a rising incidence of ESRD, both hypertension (vide supra) and bacteriuria were viewed as risk factors for progressive renal injury. But is there evidence to support such a presumption?

Pros

Reviewing 55 literature reports through 1991, Kallen linked urinary tract infections, in association with ureteral reflux or dysperistalsis, to progressive kidney scarring that may result in "inexorable progression of glomerular sclerosis in patients destined to progress to end-stage renal disease." There were no reports of renal damage after long-term observation of urinary infections in the absence of confounding coincident risk factors such as anatomic abnormalities or systemic disorders including diabetes (vide supra).

Cons

The case against the conclusion that urinary infections per se may be harmful has strong support by consensus and specific observational study. Infants, previously thought to have incurred kidney damage after an infection, actually sustained congenital renal injury, according to Hellerstein. After reviewing the charts of 102 children who developed ESRD between 1986 and 1995, only one eight-year-old girl who had ureteral reimplantations was thought to have had urinary infection as a significant contributing factor.

A similar retrospective study of 481 ESRD patients disclosed eight patients, five women and three men, in whom so called chronic pyelonephritis was listed as the cause of uremia. Anatomic or metabolic (calculi) explanations were found in six patients, sustaining the inference that isolated urinary infection was only rarely associated with ESRD. Kunin put the argument clearly: "Although urinary tract infections can severely impair renal function, this is rare in the absence of a major predisposing factor such as obstruction, calculus, reflux, abnormalities of the voiding mechanism, or diabetes."

Support for this position was afforded by Murray and Goldberg who attributed none of 101 cases of chronic interstitial nephritis to urinary infection. Consistent with this view is the 12-year observational study by Freedman and Andriole of 250 women with urinary infections, none of whom had deterioration in renal function. Also, Asscher et al. noted that none of 107 women with bacteriuria had progressive renal dysfunction when untreated in the absence of hypertension or obstructive uropathy. Lastly, in 249 men with bacteriuria, followed by Freeman et al. for up to a decade, no loss of renal function was evidenced in the absence of severe urologic disease or concomitant noninfectious renal disease.

Conclusion: Whether or not urinary infection leads to ESRD is pure speculation