WHAT’S NEW IN NEPHROLOGY
From Internal Medicine Update 2006, presented January 21-25, 2006, by University of Miami Miller School of
Medicine
Warren Kupin, MD, Associate Professor of Clinical Medicine, Division of Nephrology, University of Miami Miller
School of Medicine
| SLE NEPHRITIS: THERAPY EASIER AND MORE EFFECTIVE
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| Demographics of systemic lupus erythematosus (SLE): young population, predominantly women; kidney affected in
25% to 50% of patients at time of diagnosis and in 66% of patients over course of disease; black patients with lupus
have higher risk for renal disease than other groups (rates of renal disease also disproportionately higher in black patients
with hypertension, diabetes, and HIV infection); young black women at particularly high risk of developing renal
disease as complication of lupus; hereditary factors contribute to risk
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| Standard treatment: induction phase—chemotherapy with intravenous (IV) cyclophosphamide (Cytoxan) former
standard of treatment to induce remission; high doses given monthly for 6 mo; maintenance phase—long-term therapy
traditionally relied on oral cyclophosphamide or azathioprine ([Imuran]; immunosuppressive agent); treatment
regimen—kidney biopsy necessary to assess severity of disease; aforementioned treatment used in patients with class
III or class IV disease; regimen based on data from National Institutes of Health (NIH), showing superiority of IV cyclophosphamide
over steroids, azathioprine, or oral cyclophosphamide; adverse effects of cyclophosphamide—
infections; hemorrhagic cystitis; malignancy; sterility
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| Mycophenolate (CellCept): oral antiproliferative agent; has replaced Imuran for preventing rejection after kidney
transplantation; potential application for management of autoimmune diseases, including SLE
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 | Induction therapy: study (Ginzler et al, 2005)—large, multicenter trial randomized patients to 6-mo treatment with
IV cyclophosphamide (NIH protocol) or oral mycophenolate (associated with significantly fewer adverse effects);
remission rate—patients receiving mycophenolate 4 times as likely to undergo complete remission, compared to
patients receiving cyclophosphamide; partial remission slightly higher in mycophenolate group; adverse
outcomes—no difference in rates of relapse, renal failure, and mortality; conclusions—successful induction
therapy with oral mycophenolate and its association with fewer infections and lower risk for sterility have
changed clinical approach to lupus; new approach enables office-based practices to perform induction therapy
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| Maintenance therapy: study (Contreras et al, 2004)—remission achieved with IV cyclophosphamide; single-center
study compared azathioprine, mycophenolate, and cyclophosphamide for maintenance therapy; results—patients
in mycophenolate group had lower risk for relapse than patients in other 2 treatment groups (especially
compared to cyclophosphamide group); long-term risk for complications significantly lower in patients receiving
mycophenolate or azathioprine, compared to cyclophosphamide; current practice—oral mycophenolate preferred
for induction as well as maintenance therapy (azathioprine still used in some patients)
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| Renal effects: myeloma kidney (cast nephropathy)—overproduction of kappa and lambda light chains clogs kidney
tubules with formation of casts, resulting in acute renal failure; dehydration and diuretic therapy may exacerbate
problem; other etiologies of renal failure in myeloma patients—hypercalcemia; direct infiltration of plasma cells
into kidney; increased risk for infection; but, myeloma kidney most common cause of acute renal failure in these
patients
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| Plasmapheresis: plasma exchange performed daily or every other day in attempt to remove circulating light chains and
prevent filtration through kidney; study (Clark et al, 2005)—Canadian multicenter trial randomized 104 patients with
proven myeloma and acute renal failure to chemotherapy alone or chemotherapy with plasma exchange (current standard
of care); patient selection—older patients; high levels of serum creatinine; very low glomerular filtration rate
(GFR; stage IV or V acute renal failure); predominance of kappa and lambda light chains; results—no differences in
treatment outcomes; rate of renal recovery not affected by plasmapheresis; conclusion—plasmapheresis no longer recommended
for treatment of myeloma kidney (high viscosity and other syndromes may still necessitate procedure)
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| DOPAMINE AND ACUTE RENAL FAILURE
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| Background: 5% to 7% of hospitalized patients experience acute renal failure; preventing or minimizing renal failure
decreases cost of medical care and risk for complications; 50% of patients with acute renal failure die from infection,
gastrointestinal (GI) hemorrhage, and other complications
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| Treatment: medical interventions for preventing and treating renal failure include loop diuretics, mannitol, atrial
natriuretic peptide (ANP), thyroid hormone, acetylcysteine, and others
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| Dopamine: increases renal blood flow; may increase GFR; increases excretion of sodium and urine output, thereby
slowing progression of disease; influences other receptors, eg, adrenergic receptors; risks—certain doses induce
vasoconstriction and increase inotropic effect, resulting in increased risk for cardiac arrhythmias, myocardial ischemia,
and intestinal ischemia leading to gram-negative sepsis; concern that standard vasodilatory dose of 2.5
µg/kg per minute may cause vasoconstriction in some patients; some studies suggest higher mortality in patients
treated with dopamine
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| Efficacy of dopamine: study (Bellomo et al, 2000)—meta-analysis published in Lancet included 24 studies (involving
800 patients); treatment with dopamine did not reduce mortality, risk for progression, or need for dialysis;
although study clearly showed no benefit of dopamine and recommended stopping its use in patients with
acute renal failure, practice continued in United States; study (Friedrich et al, 2005)—meta-analysis published
in Annals of Internal Medicine included 61 randomized, controlled trials (≈300 patients); etiologies of acute renal
failure included surgery, contrast nephropathy, and drug toxicity; adult and pediatric patients included in
analysis; standard doses used; no benefit found; some studies suggested negative effect of dopamine, compared
to placebo; although patients receiving dopamine had increased urine output on day 1, effect diminished over 24
hr; no benefit for long-term outcome or mortality; conclusion—dopamine has no role in acute renal failure
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| EXPANDING THE SEARCH FOR KIDNEY DONORS
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| Background: organ attrition—cadaver kidneys last 11 to 13 yr; failure results from toxicity of medications and
chronic rejection; kidneys from living family members last ≈20 yr; benefit of transplantation—risk for cardiovascular
disease significantly increases in patients undergoing dialysis; eliminating need for dialysis improves survival
(but lifespan still shorter than average) and quality of life; need for organs—cadaver donors have decreased; number
of living donors has begun to level off; 68,000 patients waiting for kidney transplants in United States; patients
may wait 4 to 10 yr for kidney (increasing number of patients dying while waiting for organs)
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| Paired donor exchange: process matches living unrelated donors and recipients; 2 patients in need of transplant unable
to find compatible match among family members; but, family member (or other potential donor) of each patient
compatible with unrelated patient; family member of patient “A” donates to patient “B”, and family member
of patient “B” donates to patient “A”; 3-way exchanges also possible (patients A, B, and C); paired exchange technique
could provide organs for 7% of kidney transplantations in United States; outcomes—10 paired exchanges
and 2 triple exchanges performed at Johns Hopkins University; no difference in outcomes, compared to transplantations
performed with organs from unrelated cadavers; recommendations—encourage initiation of national program
to match donors and recipients for paired sharing; educate patients about becoming organ donors
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| Expanded criteria for donor organs: traditionally, organs accepted only from healthy individuals (eg, victims of motor
vehicle accidents) without history of diabetes, hypertension, renal dysfunction, or cancer; expanded cadaveric
kidney program approved in United States accepts kidneys from healthy donors >60 yr of age and from younger
donors with history of hypertension (even if death caused by stroke, indicating significant hypertension) or deteriorating
renal function; both kidneys sometimes transplanted into single recipient; recipients—42% of patients waiting
for kidney willing to accept organ from expanded cadaveric program; program currently provides kidneys for
17% of transplantations in United States; outcome—organs expected to function 7 to 8 yr; studies (eg, Merion et
al, 2005) show decreased mortality and risk for cardiovascular disease and increased quality of life, compared to
patients on dialysis; patient selection criteria—program not offered to patients <40 yr of age; patients >60 yr of
age, especially those with diabetes, more likely to benefit
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| AN ADVANCE IN MANAGING DIALYSIS
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| Hyperparathyroidism: increasing level of phosphorus causes corresponding decrease in circulating calcium, which
stimulates production of parathyroid hormone (PTH); management practices have included attempts at lowering
serum levels of phosphorus by increasing levels of calcium and vitamin D (using supplements); concern that addition
of calcium salt may stimulate formation of calcium precipitates and increase risk for vascular disease; screening
for PTH—current guidelines recommend at least quarterly measurement of PTH in all patients with stage III
or IV kidney disease (GFR <60 mL/min); as phosphorus level begins to increase (and calcium level decreases), homeostatic
mechanism involving PTH increases excretion and maintains phosphorus level within normal range; increasing
levels of PTH (required to maintain homeostasis) also affect bone, heart, and vasculature
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| Cinacalcet (Sensipar): new oral agent binds to calcium receptor in parathyroid gland, turning off production of PTH;
studies—2 large multicenter trials in United States and Canada (Lindberg et al, 2005; Charytan et al, 2005) randomized
patients to cinacalcet or placebo; study included patients with stage III or stage IV disease (GFR 15-60
mL/min) not undergoing dialysis; patients had normal levels of phosphorus and calcium but very high levels of
PTH; results—cinacalcet immediately turned off production of PTH; response sustained for duration of study;
PTH significantly decreased in all patients; calcium levels decreased slightly, but significant hypocalcemia did not
develop; studies performed with patients on dialysis (hemodialysis or peritoneal dialysis) found similar results;
conclusion—novel agent has revolutionized treatment of patients with hyperparathyroidism
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| Kidney transplantation: blood group-incompatible kidney transplantation—requires removal of spleen, administration
of high doses of chemotherapy, and regular plasmapheresis; significantly increases cost (≈3 times that of blood
group-compatible transplant); results in lower success rate (60%-70%, compared to 85%-90% for compatible transplants);
upper age limit for kidney transplantation—no set age limit (depends on health of recipient), but survival
benefit disappears in patients >70 yr of age; transplantation still improves quality of life in these patients
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| Target levels for PTH: guidelines allow higher levels of PTH in patients with kidney failure; target range depends on
stage of disease; PTH required for remodeling of bone; risk for fractures increases if PTH decreases below certain
level
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| Paracalcitol (Zemplar): superior to other vitamin D products when given IV; IV Zemplar does not appear to cause
hypercalcemia, as occurs with other agents; oral Zemplar likely equivalent to other oral agents
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Educational Objectives
| The goal of this activity is to review recent clinical research that significantly affects management of patients with renal
dysfunction. After hearing and assimilating this program, the clinician will be better able to:
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| 1. Perform induction and maintenance therapy for patients with systemic lupus erythematosus (SLE).
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| 2. Discuss recent changes in recommendations in the management of acute renal failure in patients with multiple
myeloma.
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| 3. Implement changes in the use of dopamine for managing patients with acute renal failure.
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| 4. Educate patients about expanded programs for organ donation.
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| 5. Identify patients with hyperparathyroidism and discuss recent advances in treatment.
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Discussed on This Program
Acetylcysteine (n-acetylcysteine) [Acetadote, Mucomyst, Mucomyst 10 IV, Mucosil-10, -20]
Azathioprine (AZA) [Imuran]
Cinacalcet HCl [Sensipar]
Cyclophosphamide [Cytoxan, Cytoxan Lyophilized, Neosar]
Dopamine HCl [Intropin, Dopamine HCl in 5% Dextrose]
Mannitol [Osmitrol, Resectisol
Mycophenolate mofetil (MMF) [CellCept]
Paracalcitol [Zemplar]
Suggested Reading
Bellomo R, et al: Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial.
Australian and New Zealand Intensive Care Society (ANZICS). Lancet 356:2139, 2000; Charytan C, et al: Cinacalcet
HCl is an effective treatment for secondary hyperparathyroidism in patients with CKD not receiving dialysis. Am
J Kidney Dis 46:58, 2005; Clark WF, et al: Plasma exchange when myeloma presents as acute renal failure. Ann Intern
Med 143:777, 2005; Contreras G, et al: Sequential therapy for proliferative lupus nephritis. N Engl J Med
350:971, 2004; Dooley MA, Ginzler EM: Newer therapeutic approaches for systemic lupus erythematosus: immunosuppressive
agents. Rheum Dis Clin North Am 32:91, 2006; Friedrich JO, et al: Meta-analysis: low-dose dopamine
increases urine output but does not prevent renal dysfunction or death. Ann Intern Med 142:510, 2005; Ginzler EM,
et al: Mycophenolate mofetil or IV cyclophosphamide for lupus nephritis. N Engl J Med 353:2219, 2005; Gupta A,
Heslin KC: Racial differences in response to cinacalcet as a treatment for uremic hyperparathyroidism. Kidney Int
69:1094, 2006; Lindberg JS, et al: Cinacalcet HCl, an oral calcimimetic agent for the treatment of secondary hyperparathyroidism
in hemodialysis and peritoneal dialysis patients: a randomized, double-blind, multicenter study. J Am
Soc Nephrol 16:800, 2005; Merion RM, et al: Deceased donor characteristics and the survival benefit of kidney transplantation.
JAMA 294:2726, 2005; Montgomery RA, et al: Clinical results from transplanting incompatible live kidney
donor/recipient pairs using kidney paired donation. JAMA 294:1655, 2005; Segev D, et al: Kidney paired
donation and optimizing the use of live donor organs. JAMA 293:1883, 2005; Simforoosh N, et al: Living unrelated
vs living related kidney transplantation: 20 years’ experience with 2155 cases. Transplant Proc 38:422, 2006; Wang
IK, et al: Early prognostic factors in patients with acute renal failure requiring dialysis. Ren Fail 28:43, 2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue,
the faculty reported nothing to disclose.
Dr. Kupin was recorded in Miami at Internal Medicine Update, sponsored by the University of Miami Miller School
of Medicine, and held January 21-25, 2006. The Audio-Digest Foundation thanks Dr. Kupin and University of Miami
Miller School of Medicine for their cooperation in the production of this program.
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