ADVANCES IN NEPHROLOGY
From the University of Miami Miller School of Medicine’s 42nd Annual Advances in Medicine
Warren L. Kupin, MD, Associate Professor, Department of Medicine, Division of Nephrology and Hypertension,
University of Miami Miller School of Medicine, and Co-Director, Transplant Nephrology, University of Miami/Jackson
Memorial Hospital, Miami, FL
| NEPHROLOGY: YEAR IN REVIEW
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| New treatment for hyponatremia: vasopressin antagonists new class of drugs (aquaretics); articles on
conivaptan and tolvaptan
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 | Hyponatremia: most common electrolyte abnormality (2%-4% of hospitalized patients); serum Na level
<135 mEq/L; critical levels <120 mEq/L; predictor of mortality in congestive heart failure (CHF) and
cirrhosis; mortality rises with drop in serum Na level
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| Development of hyponatremia: excessive water retention (not salt loss alone); leads to cerebral edema;
acute hyponatremia (serum Na level falls below 35 mEq/L within 48 hr; rare)
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| Chronic hyponatremia: common, eg, serum Na level 129 to 130 mEq/L; considered acceptable in elderly
patients with multiple medical problems; risk of rapid correction—osmotic demyelinating syndrome (formerly
central pontine myelinolysis; patients develop quadriplegia and coma); limit rate of correction to
≤12 mEq per 24 hr
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| Antidiuretic hormone (ADH): overstimulation leads to hyponatremia; ADH (arginine vasopressin) binds to
vasopressin (V) 2 receptor in kidney to insert water channels (aquaporins); aquaretic therapy eliminates
water alone
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| Study of conivaptan: double-blind placebo-controlled multicenter study compared fluid restriction alone to
conivaptan (V2-receptor blocker); results—serum Na level reached normal range in 70% to 80% of patients
treated with conivaptan; effect dose related; <50% with fluid restriction alone
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| Study of risk of chronic hyponatremia: 120 patients with serum Na level 120 to 132 mEq/L compared
to 244 normal controls; results—9-fold higher risk of falls due to gait and balance problems; correction
of sodium levels resulted in steadier gait and better focus
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| Study of tolvaptan: selective oral V2-receptor antagonist; Study of Ascending Levels of Tolvaptan (SALT)
1 and 2 involved 42 centers in United States and 50 in Europe; patients followed for 30 days; results—
significantly improved serum Na at all levels (mild; severe) of hyponatremia and CHF, cirrhosis, or cognitive
deficits, compared to fluid restriction alone; scores on mental and physical surveys found to be improved
(revealing previous levels low)
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| Risk for hypertension in kidney donors: meta-analysis looked at 5000 donors ≈40 yr of age with excellent
kidney function; 7 yr after donation, diastolic and systolic blood pressure (BP) increased ≈5 mm Hg (this
results in 1.5-fold greater risk of cardiovascular disease [CVD] in general population); any donor with prehypertension
likely to develop stage 1 hypertension; no consensus statement on donors with prehypertension;
discuss risk with patients; donors followed annually for rest of lives
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| Effect of statins on albuminuria: meta-analysis found statin therapy alone significantly improved albuminuria;
may result in improved endothelial function; increases nitric oxide; statins may be used as adjunct to
proven therapies for albuminuria
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| Cystatin C new marker for kidney function: chronic kidney disease (CKD) defined as glomerular filtration
rate (GFR) <60 mL/min for 3 mo; CKD may be nonspecific (varies based on age and muscle mass);
body maintains constant level of cystatin C (proteinase; filtered in kidney; increase in level indicates kidney
problem); Cardiovascular Health Study (CHS) findings—elevated cystatin C levels present in 39% of patients
with normal GFR, creatinine levels, and creatinine clearance; elevated cystatin C levels alone
predicted 42% increased risk of cardiovascular disease and mortality and 29% increased risk of stroke
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| Islet cell transplantation for type 1 diabetes: transplantation of whole pancreas problematic, with risk of
complications and rejection; International Trial of Edmonton Protocol for Islet Transplantation—in Canadian experience,
7 patients became insulin independent; pancreas homogenized and islet cells filtered out and infused
into liver, where they live and produce insulin; patients treated with immunosuppressive drugs; 42
centers in United States opened to perform procedure; result—149 patients underwent protocol at
9 centers; ≤3 pancreases required for each patient; 58% of patients became insulin independent; after 2 yr,
only 24% remained off insulin therapy; in 3 centers, no patient ever became insulin independent; kidney
function deteriorated in some patients as result of immunosuppressive therapy
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| ANGIOTENSIN-CONVERTING ENZYME INHIBITOR (ACEI) AND ANGIOTENSIN-RECEPTOR
BLOCKER (ARB) THERAPY IN CHRONIC KIDNEY DISEASE
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| Chronic kidney disease: based on creatinine clearance, not serum creatinine; significant complications start
at stage 3; epidemiology—8 million in United States with stage 3 and above CKD, 350,000 on dialysis; diabetes
and hypertension main risk factors for end-stage renal failure; both can be treated to slow disease progression;
more prevalent among black patients
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| Role of hypertension: part of CKD in 80% of patients, either as cause or result; 70% of people hypertensive
by 70 yr of age; probably most important modifiable factor for progression of renal disease; treatment
objectives—1) reduce rate of progression; 2) affect CVD outcome; not just hemodynamics—hypertension increases
production of angiotensin II locally in blood vessels
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| Angiotensin II: produced in afferent and efferent arterioles of kidney; does more than vasoconstriction;
seeps into interstitium of kidney and increases transforming growth factor (TGF)- β (single most important
agent that causes permanent scarring and injury of kidney); angiotensin II causes inflammation through effects
on cell growth and survival and on oxygen free radical production; works indirectly by binding to receptor
(angiotensin receptor type 1 [AT-1]); sequence—prohormone angiotensinogen transformed into
angiotensin I; angiotensin-converting enzyme (ACE) enables conversion of angiotensin I to angiotensin II;
physiologic effects follow
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| Renin-angiotensin system: important in treatment of patients with kidney disease and hypertension; influences
areas that increase progression of disease
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| Proteinuria: not just marker of kidney injury; independent cause of disease progression; pathophysiology—
any renal injury causes protein to be filtered through glomerulus to proximal tubule, which tries to reabsorb
albumin (body’s natural attempt to reclaim protein); increase of protein in cells leads to inflammation and
scarring in kidney; treatment objective—to reduce proteinuria in order to limit kidney injury
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| Cardiovascular disease: risk of CVD increases with amount of proteinuria (inflammation causes endothelial
damage in kidney and entire body); most patients with advanced kidney disease die of CVD rather
than going on dialysis; treating CKD decreases risk of death from CVD; cardiovascular events increase as
GFR declines
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| Strategy for treating hypertension: slow progression of CKD; reduce proteinuria; prevent CVD (major
goal); Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC)—
guidelines require use of ACEIs and ARBs in treatment of CKD (stage 3 and higher “compelling indication”);
by contrast, several options available for treating hypertension without CKD; treatment goal BP of
130/80 mm Hg; only 27% of CKD patients reach goal; requires >1 drug—≤4 drugs used in large clinical trials;
as GFR goes down, number of antihypertensive drugs goes up; 3 drugs required in average stage 3 CKD
patient; benefits of lowering BP—lowering BP of 140/90 to 130/85 mm Hg adds 4 yr to survival of kidney;
proteinuria—patients with highest levels of proteinuria get greatest benefit from lowering BP (require more
aggressive therapy)
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| Choice of drugs in CKD: avoid—dihydropyridine calcium channel blockers (eg, amlodipine [eg, Norvasc],
nifedipine [eg, Adalat]); peripheral vasodilators; dilate afferent arteriole, increasing pressure in glomerulus,
leading to more filtration and proteinuria; select—ACEIs (decrease intraglomerular pressure); calcium
channel blockers diltiazem and verapamil decrease proteinuria by decreasing BP; studies show that captopril
(ACEI) reduces risk of renal failure in diabetes; no clinical differences among ACEIs (patient compliance
may vary); benefits of starting ACEI in stage 3 kidney disease actually greater than starting earlier in
disease
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| Role of ARBs: all ARBs offer same benefits as ACEIs (reduced rate of disease progression and proteinuria,
improved renal survival)
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| Monitor proteinuria: measure proteinuria when starting drug therapy; after few months, measure proteinuria
again; if no improvement, increase dose; even if BP controlled, unacceptable levels of proteinuria
require raising dose of ACEI or ARB (until clinical consequences occur, eg, cough, hyperkalemia); as in
statin therapy, clinicians now pushing dose higher to achieve lower than normal values; level of risk—much
lower if proteinuria pushed down to 1.5 mg/dL than if allowed to remain substantially higher
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| Potential risk of therapy: ACEI or ARB contraindicated in presence of renal artery stenosis (high-risk patient
with bruits in carotid and abdomen, and claudication); leads to acute renal failure
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| Initial creatinine elevation transient: starting ACEI or ARB lowers pressure in glomerulus, causing rise in
serum creatinine (eg, from 2.5 mg/dL to 3 mg/dL, or 1.8 mg/dL to 2.3 mg/dL); leads many physicians to
withdraw drug; “don’t panic”; renal function declines at first, stabilizes in 2 to 4 wk, then improves over
weeks and months; check creatinine weekly to ensure level stabilizing (undue rise in creatinine occurs in
patients who are volume-depleted or on high-dose diuretics; over-the-counter nonsteroidal anti-inflammatory
drugs may upset autoregulation process); risk of hyperkalemia minimal
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| Advanced kidney failure: in patients taking ACEI, rate of failure lower in stage 4 CKD (GFR 16-30 mL/
min); kidney survival increased 1 to 1.5 yr; risks minimal
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| Summary of key points: renin-angiotensin system intimately involved in progression of kidney disease;
proteinuria independent risk factor for disease progression; drug therapy provides benefits beyond controlling
BP; trial of ACEI or ARB indicated in patients with moderate and advanced renal failure; drug
selection—first, either ACEI or ARB; second, add ACEI or ARB; third, add calcium channel blocker, diuretic,
or other options; creatinine level goes up—then stabilizes after onset of therapy; highest increase in
creatinine often gets most benefit
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Suggested Reading
Agarwal R: Add-on angiotensin receptor blockade with maximize ACE inhibition. Kidney Int 59:2282, 2001;
Bakris GL et al: Rationale and design of a study to evaluate management of proteinuria in patients at high
risk for vascular events: the IMPROVE trial. J Hum Hypertens 20:693, 2006; Barnett A: Prevention of loss of
renal function over time in patients with diabetic nephropathy. Am J Med 119:S40, 2006; Biesenbach G et al:
Rate of decline of GFR and progression of vascular disease in type 2 diabetic patients with diabetic or vascular
nephropathy during the last three years before starting dialysis therapy. Kidney Blood Press Res 29:267,
2006; Chobanian AV et al: Seventh report of the Joint National Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure. Hypertension 42:1206, 2003; Douglas K et al: Meta-analysis:
the effect of statins on albuminuria. Ann Intern Med 145:117, 2006; Ferrari P: Prescribing angiotensin-converting
enzyme inhibitors and angiotensin receptor blockers in chronic kidney disease. Nephrology (Carlton)
12:81, 2007; Ghali JK et al: Efficacy and safety of oral conivaptan: a V1A/V2 vasopressin receptor antagonist,
assessed in a randomized, placebo-controlled trial in patients with euvolemic or hypervolemic hyponatremia.
J Clin Endocrinol Metab 91:2145, 2006; MacKinnon M et al: Combination therapy with an
angiotensin receptor blocker and an ACE inhibitor in proteinuric renal disease: a systematic review of the efficacy
and safety data. Am J Kidney Dis 48:8, 2006; Matos JP et al: Effects of dual blockade of the renin angiotensin
system in hypertensive type 2 diabetic patients with nephropathy. Clin Nephrol 64:180, 2005;
Murussi M et al: Glomerular filtration rate changes in normoalbuminuric and microalbuminuric Type 2 diabetic
patients and normal individuals A 10-year follow-up. J Diabetes Complications 20:210, 2006; Rossing P
et al: Monitoring kidney function in type 2 diabetic patients with incipient and overt diabetic nephropathy.
Diabetes Care 29:1024, 2006; Senior PA et al: Changes in renal function after clinical islet transplantation:
four-year observational study. Am J Transplant 7:91, 2007; Shapiro AM et al: International trial of the Edmonton
protocol for islet transplantation. N Engl J Med 355:1318, 2006; Shlipak MG et al: Cystatin C and
prognosis for cardiovascular and kidney outcomes in elderly persons without chronic kidney disease. Ann Intern
Med 145:237, 2006; Shoda J et al: A five-year comparison of the renal protective effects of angiotensin-
converting enzyme inhibitors and angiotensin receptor blockers in patients with non-diabetic nephropathy.
Intern Med 45:193, 2006; Smith JP et al: Hypertension management: special considerations in chronic kidney
disease patients. Curr Hypertens Rep 6:462, 2004; Sochett EB et al: Impact of renin angiotensin system
modulation on the hyperfiltration state in type 1 diabetes. J Am Soc Nephrol 17:1703, 2006.
Educational Objectives
| The goal of this program is to improve the management of kidney disease. After hearing and assimilating this
program, the clinician will be better able to:
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| 1. Manage therapy for hyponatremia using a new class of drugs.
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| 2. Diagnose kidney disease using cystatin C, a new marker for kidney function.
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| 3. Recognize the role of proteinuria as an independent cause of progression of kidney disease.
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| 4. Include antihypertensives in the treatment of chronic kidney failure for benefits beyond lowering blood
pressure.
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| 5. Institute a trial of angiotensin-converting enzyme inhibitors or angiotensin receptor-blockers in patients
with moderate and advanced kidney disease.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members 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, the faculty reported nothing
to disclose.
Acknowledgements
Dr. Kupin was recorded at 42nd Annual Advances in Medicine, sponsored by the University of Miami Miller
School of Medicine in Miami, FL, January 21-26, 2007. The Audio-Digest Foundation thanks Dr. Kupin and
the University of Miami Miller School of Medicine for their cooperation in the production of this program.
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