Disorders of Sodium, Water, and ADH - UCSF · PDF fileDisorders of Sodium, Water, and ADH ... – Guidelines for hyponatremia in neurosurgical patients ... Diagnostic Algorithm: CSW

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Department of Medicine

Disorders of Sodium, Water, and ADH

Advances in Endocrinology and Metabolism Marines’ Memorial Club and Hotel 609 Sutter St San Francisco, CA March 19, 2010

Kerry Cho, MD

Division of Nephrology


Objectives

•  Hyponatremia –  Predictor of poor outcomes –  Vaptans –  Overly rapid correction of hyponatremia

•  Use of ddAVP to reinduce hyponatremia

–  Cerebral Salt Wasting –  Guidelines for hyponatremia in neurosurgical patients –  Nephrogenic Syndrome of Inappropriate Antidiuresis

•  Diabetes Insipidus •  ADH


•  Good review of SIAD •  “There are no professional guidelines for evaluating

and treating SIAD.”

Ellison DH, Berl T. NEJM 2007:356:2064-2072.

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Electrolyte-free Water Clearance

•  CeH20: electrolyte-free water clearance

•  V: 24 hour urine volume •  UNa: urine sodium •  UK: urine potassium •  PNa: plasma sodium



Free Water Restriction in SIAD



•  OPTIMIZE-HF registry of 48612 pts in 259 hospitals •  Hyponatremic pts increased risk of in-hospital death

(19.5%), follow-up mortality (10%) and risk of death or rehospitalization (8%) for each 3 mEq/L decreased in sodium below 140 mEq/L

Gheorghiade M et al. Eur Heart J 2007;28:980-988.

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OPTIMIZE-HF: Hyponatremia and increased LOS, hospital mortality, post-discharge mortality and death/rehospitalization


•  ESCAPE: Evaluation Study of Congestive heart Failure and Pulmonary Artery Catheterization Effectiveness

•  Randomized, controlled study of PA catheters in NYHA class IV heart failure pts

•  433 patients, 103 pts with Na ≤134 mEq/L, 71 with persistent hyponatremia

•  Higher risk of all-cause 6-month mortality, heart failure hospitalization, and death or rehospitalization in hyponatremic pts

Georghiade M et al. Arch Intern Med 2007;167:1998-2005.


•  Prospective cohort study of 98,411 hospitalized adults in two Boston teaching hospitals between 2000-2003

•  Multivariable logistic regression •  1° endpoints: in-hospital, 1-year, and 5-year mortality •  Results (compared with normonatremic patients)

–  14.5% had hyponatremia on initial measurement –  Increased in-hospital death, OR 1.47 –  Increased 1-year mortality, HR 1.38 –  Increased 5-year mortality, HR 1.25 –  Increased risk of death (OR 1.37) for mild hyponatremia

130-134 mEq/L

Waikar SS et al. Am J Med 2009;122:679-686.

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•  6769 adult candidates for primary liver transplant •  Predictors of mortality

–  MELD score: Model for End-Stage Liver Disease •  Serum bilirubin, creatinine, and INR

–  Serum sodium

•  Proposed Adjustment of MELD scores for serum Na Kim WR et al. NEJM 2008;359:1018-1026.


Hyponatremia and Mortality in ESLD

Kim WR et al. NEJM 2008;359:1018-1026.


Vaptans: Vasopressin-Receptor Antagonists


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Schrier RW et al. NEJM 2006;355(20):2099-2112


SALT: Study of Ascending Levels of Tolvaptan in Hyponatremia

•  Multicenter, randomized, controlled, double-blind •  248 patients with hyponatremia, either euvolemic or

hypervolemic •  Tolvaptan vs. placebo

–  V2 receptor antagonist –  30 mg PO daily, increased to 60 mg daily based on

serum Na

•  1° endpoint: AUC serum [Na] at days 4 and 30 •  Results: Tolvaptan increased serum Na •  Side effects: thirst, dry mouth, increased urination

Schrier RW et al. NEJM 2006;355(20):2099-2112


•  Randomized, controlled •  84 hospitalized patients with Na 115-130 mEq/L •  Euvolemic or hypervolemic •  Conivaptan, V1A/V2 receptor antagonist

–  20 mg loading dose IV, followed by –  96 hr infusion of 40 or 80 mg per day

•  1° endpoint: AUC serum [Na] •  Conclusion: Significant improvement in serum [Na] Zeltser D et al. Am J Nephrol 2007;27:447-457.

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•  Multicenter, double-blind, randomized, controlled •  110 patients, cirrhotics, ascites, Na < 130 mmol/L •  Satavaptan 5, 12.5, or 25 mg PO daily vs. placebo •  Reduced weight and abdominal girth •  Increased serum sodium

Gines P et al. Hepatology 2008;48:2014-213.


•  Multicenter, double-blind, randomized, controlled •  83 patients, Na < 130 mmol/L •  Hypervolemic or euvolemic •  Conivaptan 40 or 80 mg IV daily x 5 vs. placebo •  V1A/V2 receptor antagonist •  Increased likelihood of improvement in serum

sodium by ≥6 mmol/L or normalized sodium in patients who received conivaptan

•  Favorable safety profile Annane D et al. Am J Med Sci 2009;337:28-36.


•  Multicenter phase 2 trial of 319 patients LVEF <40% hospitalized with persistent HF on standard rx

•  Tolvaptan 30, 60, or 90 mg PO daily vs. placebo •  1° endpoint: change in body weight at 24 hrs,

worsening heart failure (death, hospitalization, or unscheduled visits for heart failure).

•  Findings: decrease in body weight, but no difference in worsening heart failure. Post-hoc analysis, 60-day mortality lower in tolvaptan pts with kidney disease or severe HF

Gheorghiade M et al. JAMA 2004;291:1963-1971.

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•  Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan

•  Multicenter, randomized, controlled, double-blind •  4133 pts hospitalized with heart failure in 359 sites

in North/South America and Europe •  Tolvaptan 30 mg PO daily vs. placebo ≥ 60 days •  Median follow up 9.9 months •  1° endpoints

–  All cause mortality –  CV death or hospitalization for heart failure

Konstam MA et al. JAMA 2007;297:1319-1331.


EVEREST: Tolvaptan and mortality (L) and CV mortality/HF hospitalization (R)



EVEREST: Tolvaptan in Heart Failure

•  No difference in 2° endpoints –  Cardiovascular mortality –  Cardiovascular death or hospitalization –  Worsening heart failure

•  Tolvaptan improved –  Day 1 patient-assessed dyspnea –  Day 1 body weight and day 7 edema –  Serum sodium in hyponatremic pts

•  Side effects included thirst and dry mouth, otherwise tolvaptan was well tolerated


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•  Retrospective review of 62 hospitalized adult hyponatremic pts who received hypertonic saline in acute care, teaching hospital

•  Median infusion HTS rate 0.38 mL/kg/hr •  Median serum Na correction rate 0.47 mEq/L/hr •  11.3% serum Na increased > 12 mEq/L/24 hrs •  9.7% serum Na increased > 18 mEq/L/48 hrs •  Inadvertent overcorrection due to water diuresis in

40%

Mohmand HK et al. Clin J Am Soc Nephrol 2007;2:1110-1117.


•  Chronic hyponatremia in rats •  Rapid correction of serum Na (~20 mEq/L in 24 hrs)

–  Saline –  Saline + dexamethasone –  Saline followed by reinduction of hyponatremia

Kengne FG et al. Kidney Intl 2009;76:614-621.


Reinduction of Hyponatremia after overly rapid correction of serum Na in rats

•  Dexamethasone and hyponatremia reinduction groups had reduced neuro symptoms at day 5

•  Reinduction group had reduced mortality at day 10 Kengne FG et al. Kidney Intl 2009;76:614-621.

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Sterns RH, Hix JK. Kidney Intl 2009;76:587-589.


•  Retrospective analysis of 20 hyponatremic pts who had received ddAVP

•  6 pts given ddAVP after serum Na increased > 12 mEq/L in 24 hrs

–  5 of 6 pts were prevented from exceed Na increase > 18 mEq/L in 48 hrs

•  14 pts given ddAVP to prevent overly rapid correction of serum Na

–  Serum Na did not increase more than 12 mEq/L in 24 hours or 18 mEq/L in 48 hrs

Perianayagam A et al. Clin J Am Soc Nephrol 2008;3:331-336.


Cerebral Salt Wasting

•  CSW first described in 1950. –  Peters JP et al. Trans Assoc Am Physicians 1950;63:57-64

•  SIADH first described in 1957. –  Schwartz WB et al. Am J Med 1957;23:529-42. –  Carter NW, Rector FC Jr, Seldin DW. NEJM 1961;264:67-72.

•  More common than SIADH in neurosurgical pts? •  Recent reviews and editorials of CSW in literature

–  Maesaka JK et al. Kidney Intl 2009;76:934-938. –  Rivkees SA. Curr Opin Pediatr 2008;20:448-452. –  Cerda-Esteve M et al. Eur J Intern Med 2008;19:249-254.

–  Vespa P. Surg Neurol 2008;69:230-232. –  Sterns RH, Silver SM. J Am Soc Nephrol 2008;19:194-196.

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•  Extracellular volume depletion due to renal sodium transport abnormality

•  Negative sodium balance •  Hypovolemic hyponatremia with reduced plasma and

total blood volumes •  Usually presents within 10 days of neurological event,

e.g. neurosurgery, stroke, or SAH. Has also been described with CNS infection or metastatic disease.

•  Usually resolves within 3-4 weeks. Palmer BF. Trends Endo Metabol 2003;14:182-187.


Palmer BF. Trends Endo Metabol 2003;14:182-187.

Diagnostic Algorithm: CSW vs. SIADH


SIADH vs. Cerebral Salt Wasting SIADH CSW

Clinical Features Cerebral lesion, neurosurgery

Volume status Euvolemia Hypovolemia

Pathophysiology Inappropriate ADH in euvolemic pt

Renal salt wasting

Diagnostics nL Hct, nL albumin, ↓BUN:Cr

↑Hct, ↑albumin, ↑BUN:Cr

Treatment Free water restriction

Na, Iso/hypertonic saline,

fludrocortisone Shared features Hyponatremia, hypouricemia

urine Na > 20 mmol/L, FEurate > 10% normal thyroid and adrenal function

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CSW Mechanism?

Palmer BF. Trends Endo Metabol 2003;14:182-187.


Rahman M et al. Neurosurgery 2009;65:925-936.


Hyponatremia in Neurosurgical Patients: Clinical Guidelines Development

•  Multidisciplinary panel –  2 Neurosurgeons, 2 nephrologists, 1 endocrinologist –  1 pharmacist, 4 nurses, 4 nurse practitioners

•  Literature review

Rahman M et al. Neurosurgery 2009;65:925-936.

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Hyponatremia in Neurosurgical Patients: Clinical Guidelines •  Serum Na < 131 should be investigated and treated

(class 2) •  Evaluation should include physical findings, basic labs,

and invasive monitoring when available (class 3) •  Testing levels of ADH and natriuretic peptides is not

indicated (class 3) •  Serum Na correction rate ≤ 10 mEq/L per day (class 3) •  Treatment should include replacement of serum sodium

and IV fluids (class 3) •  Hyponatremic subarachnoid hemorrhage pts

–  Hydrocortisone may be used to prevent natriuresis (1) –  Fludrocortisone may be considered in pts at risk for

vasospasm (1) –  Pts at risk for vasospasm should not be treated with fluid

restriction (2) Rahman M et al. Neurosurgery 2009;65:925-936.


•  Two infants with hyponatremia, clinically SIADH, but undetectable ADH levels

•  Missense mutations of V2R gene at codon 137 (arginine cysteine or leucine)

•  Gain of function mutations of V2R constitutive activation NSIAD

Feldman BJ et al. NEJM 2005;352:1884-1890.

Nucleotide Sequence of the Wild-Type and Two Mutant AVPR2 Genes in the Affected Region (Panel A) and Diagram of V2R (Panel B)

Feldman, B. et al. N Engl J Med 2005;352:1884-1890

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Hypernatremia, Diabetes Insipidus


•  Systematic review identified 19 studies with 1137 patients

•  Diabetes insipidus –  Diagnostic test: standard water deprivation test –  Prevalence:

•  26% acutely •  6.9% in long-term survivors

Schneider HJ et al. JAMA 2007;298:1429-1438.


•  Congenital NDI can live into adulthood, followed closely to avoid bladder dysfxn, kidney disease, and other complications

•  Treatment: increased water intake, low sodium diet, thiazides, and indomethacin

•  Acquired NDI: lithium, protein malnutrition, hypercalcemia, hypokalemia, post-obstruction diuresis

•  Normal aging can cause partial NDI Sands JM, Bichet DG. Ann Intern Med 2006;144:186-194.

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•  90% of NDI due to V2R mutations •  211 V2R mutations that cause NDI in 326 families •  21 V2R variants that do NOT cause NDI in 71

kindreds •  Mutations: missense, frameshift, inframe deletion,

deletion, insertion, nonsense, duplication, splicing and combined mutations.

•  Missense mutations in 55.83% of NDI families. Spanakis E et al. J Cell Physiol 2008;217:605-617.


Summary

•  Hyponatremia –  Predictor of poor outcomes in general population,

liver transplant, heart failure –  Vaptans for hypervolemic and euvolemic

hyponatremia may improve serum sodium and volume overload, but no proven benefit in HF

–  Potential use of ddAVP to reverse overly rapid correction of hyponatremia

–  Increasing interest in cerebral salt wasting

•  V2R mutations –  Gain of function: Nephrogenic Syndrome of

Inappropriate Antidiuresis (NSIAD) –  Loss of function: Nephrogenic DI

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Disorders of Sodium, Water, and ADH - UCSF · PDF fileDisorders of Sodium, Water, and ADH ... – Guidelines for hyponatremia in neurosurgical patients ... Diagnostic Algorithm: CSW