KIDNEY DISEASE: CURRENT CONCEPTS
From the University of Miami Miller School of Medicine’s Advances in Medicine Warren L. Kupin, MD, Associate
Professor of Medicine, University of Miami Miller School of Medicine, Miami, FL
Educational Objectives
| The goal of this program is to provide up-to-date advice on managing patients with kidney disease. After hearing and assimilating
this program, the clinician will be better able to:
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 | 1. Manage congestive heart failure in patients with kidney disease.
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| 2. Prevent hospital-acquired hyponatremia.
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| 3. Prescribe angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers for management of proteinuria.
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| 4. Use cystatin C as a marker for renal function.
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| 5. Recognize the prevalence of chronic kidney disease and the regulations governing kidney transplantation in the
United States.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the
planning committee to disclose relevant financial relationships within the past 12 months that might create any personal
conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes
quality in health care and not a proprietary business or commercial interest. For this program, Dr. Kupin and the planning
committee reported nothing to disclose.
Acknowledgements
Dr. Kupin was recorded at Advances in Medicine, sponsored by the University of Miami Miller School of Medicine, on
January 14-18, 2008, in Miami, FL. The Audio-Digest Foundation thanks the speaker and the sponsor for their cooperation
in the production of this program.
| Congestive heart failure (CHF): kidney failure leads to heart disease (cardiorenal syndrome); CHF cost health
care system $33 billion in 2007, mainly due to acute CHF exacerbations (eg, dyspnea, pulmonary edema); no
treatment alters long-term outcome
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| Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST): major prospective,
international, multicenter trial; Food and Drug Administration (FDA) approval sought for tolvaptan as treatment
for worsening CHF and hyponatremia; tolvaptan vasopressin receptor antagonist that inhibits action of
antidiuretic hormone, causing water loss (aquaresis); diuretic causes natriuresis (sodium and water loss); patients
received tolvaptan along with standard CHF therapy
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| Current CHF options: diuretics; nesiritide (Natrecor); intravenous (IV) nitroglycerin; dopamine; dobutamine; milrinone;
all have short-term efficacy, but none alters natural history and mortality of CHF
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| Antidiuretic hormone (ADH): extremely high in CHF; stimulates aquaporans (water channels) in kidney, leading to
increased water reabsorption, fluid overload, and edema, along with diminished circulating volume; mechanism
counterproductive but logical (because of low ejection fraction, baroreceptors in heart demand more volume); inhibition
of ADH designed to impede vicious cycle of sodium and water reabsorption by binding of vasopressin to
V2 receptor in kidney (target of tolvaptan [vasopressin antagonist])
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| Results of study: no difference in all-cause or cardiovascular mortality; tolvaptan benefits as add-on agent—faster
reduction in body weight (fluid overload); faster resolution of dyspnea; better correction of serum sodium level;
no effect on short- and long-term morbidity and mortality; no significant side effects; recommendation—
tolvaptan as immediate therapy along with standard modalities for acute exacerbations of CHF
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| Ultrafiltration for CHF: Ultrafiltration vs Intravenous Diuretics for Patients Hospitalized for Acute Decompensated
Heart Failure (UNLOAD) study designed to test whether dialysis-like machine used to remove fluid alone
more effective than diuretic; patients with significant CHF treated with angiotensin-converting enzyme (ACE) inhibitors,
angiotensin-receptor blockers (ARBs) and β-blockers; one group also received twice outpatient dose of
IV diuretics; in other group, diuretics stopped and replaced with portable ultrafiltration device 25% size of standard
dialysis device that continuously removes plasma volume; unlike with diuretics, rate of removal can be controlled;
unlike standard dialysis machine, patient ambulatory
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| Results of study: greater weight and fluid loss; rate of rehospitalization reduced 50%; no significant side effects; no
data on long-term benefits and mortality; why better than diuretics—removes plasma volume slowly and predictably
with no effect on kidney function; rehospitalization significantly less than with other treatments; removes
more sodium per liter
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| Hospital-acquired hyponatremia: occurs in ≤33% of hospitalized patients; Na levels of ≤130 mEq/L impair
cognitive functioning (at ≤120 mEq/L, risk of seizure)
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| Hypotonic fluids: 0.45% saline (half normal) with 20 mEq KCl commonly used; same Na level as perspiration and
urine; thought that giving 0.9% saline (normal saline) leads to fluid overload; in hospitalized patients, nonosmotic
stimuli (eg, pain, infection, surgery) lead to high levels of ADH that impair ability to regulate fluids and
eliminate hypotonic fluid
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| Cellular response: diluting Na to ≈129 mEq/L causes water to rush into cell; cellular swelling leads to risk of cerebral
edema; ≈48 hr required before enough K removed and cell begins to shrink; body then metabolizes or extrudes
organic molecules (myoinositol) and cell shrinks to normal size
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| Cerebral edema: causes nausea, malaise, and headache; risk of falls, accidents, and hip fractures in elderly
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| Osmotic myelinating syndrome: caused by too rapid correction of hyponatremia
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| Increased risk of hyponatremia and cerebral edema: premenopausal women; children (greater ratio of brain volume
to cranium); traumatic brain injury; pulmonary disease; pneumonia; CHF; chronic kidney disease (CKD); vomiting;
nausea; all conditions that increase ADH
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| Recommendations for hospitalized patients: abandon use of hypotonic fluids (lactated Ringer’s solution has Na
concentration of 130 meq/L and results in hyponatremia); use normal saline as fluid of choice and control rate of
administration, based on insensible losses
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| ACE inhibitor and ARB combination therapy: nephrologists consider renin-angiotensin system toxic molecular
pathway; angiotensin stimulates cardiac and kidney fibrosis; aldosterone also stimulates fibrosis;
proteinuria—important risk factor for progression of kidney disease; microalbuminuria indicates early diabetic
renal disease; albumin itself toxic molecule, ie, not only marker for progression of CKD, but also promotes progression
independently of original cause
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| Pathogenesis of nephrotic syndrome: excess protein in urine filtered through damaged glomerulus; tubules try to reabsorb
extra protein, activating intracellular pathways, causing scarring; increased protein load causes oxidative
stress and increased cytokine activity that directly damages kidney
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| Achieving therapeutic goal: monitor proteinuria for response to ACE-ARB therapy
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| Meta-analysis of combination therapy: class effect—no difference in effectiveness among different ACE inhibitors
or different ARBs; ACE inhibitors and ARBs equally effective; both more effective than calcium-channel blockers
in reducing proteinuria; combining ACE inhibitor and ARB more effective in reduction of proteinuria; ACE
inhibitors and ARBs target different areas of pathway
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| Recommendations: ACE inhibitor and ARBs first-line therapy for proteinuria; begin with drug of either class;
when therapy fails to reduce proteinuria to <0.5 g/day, double dose; if still no reduction, double dose again until
cough or other complications appear; expect creatinine to increase 0.3 to 0.5 mg/dL, then stabilize; if proteinuria
still >0.5 g/day, add second agent of other class; risk concerns—contraindicated in women of childbearing age
(teratogenic; risk for fetal loss); low percentage of angioedema and hyperkalemia
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| Cystatin C as marker for CKD: better marker than creatinine for renal function
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| Creatinine: reflects muscle mass and age; may be deceptively low, eg, in patient with small muscle mass; CKD
classification based on glomerular filtration rate (GFR); risk for mortality from cardiovascular disease (CVD;
not going on dialysis) chief concern in patients with stage-3 or stage 4 kidney disease; creatinine upper limit
of normal (ULN) 1.2 mg/dL in women, 1.5 mg/dL in men; creatinine low in cirrhosis and pregnancy (kidney
failure possible with creatinine of 0.8 or 0.9 mg/dL); creatinine increases exponentially, and 15% secreted, so
GFR always overestimated; poor marker for kidney function; in pregnancy, cirrhosis, and extremes of age,
patients may be in kidney failure with normal creatinine
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| Advantage of cystatin C: constantly produced by body; level unaffected by other functions; cleared completely by
kidney; minor rise in cystatin C level indicates diminished GFR; large study representative of overall population
showed linear correlation between measured GFR and cystatin C; ULN cystatin C known; laboratory reports
identify elevated cystatin C level; cystatin C superior to creatinine and estimated or measured GFR in predicting
CVD and event rates
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| Statin use in hospitalized patients: reduces risk of sepsis in hospitalized patients with CKD; sepsis major cause
of mortality in CKD; statins may inhibit bacterial growth; study findings—based on 1000 subjects in 19 states and
81 dialysis clinics; ≈30% of patients black; major reduction in risk of infection with patients on statins across all
population groups; statin effects—reduce cytokine production; mitigate vasodilation that causes shock; some organisms
naturally produce statins for survival benefits; statin benefits go beyond cholesterol management
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| Prevalence of CKD: long-running National Health and Nutritional Examination Surveys (NHANES) found
significant rise in incidence of diabetes, hypertension, obesity (body mass index [BMI] >30), and albuminuria
in general population; associated with large increase in patients with stage-2 CKD (GFR 60-90 mg/dL) and
stage-3 CKD; slight increase in stage 4; elderly at highest risk for CKD; patient awareness of CKD declined
(need to educate patients on meaning of GFR); 26 million with CKD (13% of US population); place CKD on
patient’s problem list and indicate stage and measures being taken to target risk factors
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| Systemic lupus erythematosus (SLE): rare cause of kidney failure but important in certain urban populations;
traditionally cyclophosphamide (Cytoxan) for induction and azathioprine (Imuran) for maintenance; mycophenolate
(CellCept)—replaced azathioprine for maintenance; now used for induction therapy; toxicity risks—
cyclophosphamide (hemorrhagic cystitis; infertility); mycophenolate (leukopenia; bone marrow effects; gastrointestinal
disturbance; seemingly less severe degree of systemic complications); studies found—mycophenolate
superior to cyclophosphamide in inducing remission of lupus nephritis, with fewer side effects
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| THE INTERNIST’S ROLE IN KIDNEY TRANSPLANTATION
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| Introduction: expect patients to ask about issue; 483,000 patients with stage-5 CKD; 314,000 patients on hemodialysis
and 2500 on peritoneal dialysis; ≈17% of those on dialysis listed for transplantation (low percentage disappointing;
indicates physician uncertainty about kidney transplantation)
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| National Organ Transplant Act: central computer database; 258 designated transplant centers in United States;
organ procurement organizations (OPOs) responsible for harvesting organs; OPOs determine which hospitals in
their geographic area receive organ; 17,000 kidney transplants in 2007
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| Kidney perfusion device: enables preservation for ≤2 days; most kidneys transplanted between 24 and 30 hr
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| Source of kidneys: cadaver donors (≈60%); living donors (≈40%); donation policy “required request” in United States
(families must be asked; turn down request 80% of time); “presumed consent” in other countries (citizens presumed
to have agreed to donate organs); recent increase in—spouses and friends donating kidneys
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| Waiting time unfair: depends on state of residence; time varies—7 to 10 yr in California; 3 yr in Florida; 5 to 7 yr in
Michigan; moving to another state for shorter wait allowed under national guidelines
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| Survival: transplantation improves function but it does not return to normal; transplantation superior to dialysis (4 to -
5-yr survival advantage in 70-yr-old)
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| Message for internists: prevent development of CKD; treat blood pressure early; prevent progression of diabetes; posttransplantation
management—underlying causes of CKD remain, eg, atherosclerosis, DNA changes, bone disease; patients
have stage-2 to stage-3 CKD; survival remains significantly lower; aggressively manage risk factors; recommend
to patients—transplantation as alternative to dialysis
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Suggested Reading
Coresh J et al: Prevalence of chronic kidney disease in the United States. JAMA 298:2038, 2007; Costanzo MR
et al: Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am
Coll Cardiol 49:675, 2007; Epub 2007 Jan 26. Erratum in: J Am Coll Cardiol. 2007 Mar 13;49:1136. Gupta R et al:
Statin use and sepsis events [corrected] in patients with chronic kidney disease. JAMA 297:1455, 2007; Erratum in:
JAMA. 2008 Feb 20;299:765; Konstam MA et al: Effects of oral tolvaptan in patients hospitalized for worsening
heart failure: the EVEREST Outcome Trial. JAMA 297:1319, 2007; Kunz R et al: Meta-analysis: effect of monotherapy
and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann
Intern Med 148:30, 2008; Epub 2007 Nov 5; Menon V et al: Cystatin C as a risk factor for outcomes in chronic kidney
disease. Ann Intern Med 147:19, 2007; Molitoris BA et al: Improving outcomes of acute kidney injury: report
of an initiative. Nat Clin Pract Nephrol 3:439, 2007; Walsh M et al: Mycophenolate mofetil for induction therapy of
lupus nephritis: a systematic review and meta-analysis. Clin J Am Soc Nephrol 2:968, 2007.
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