In Compliance with ACCME Standards for Commercial Support of CME activities…

John K. Maesaka, MD1.

Advisory board—Pfizer, Inc., Otsuka

Pharmaceutical US

2.

Research grant-

Otsuka

Pharmaceutical US

Complexity of differentiating cerebral-renal salt wasting (RSW) from SIADH, emerging importance of determining fractional urate excretion

John K. Maesaka, MD

Hyponatremia is in a state of flux

Confusion in the literatureInability to differentiate RSW from SIADHPresent approach does not seem to be workingPropose a new approach to hyponatremia

Traditional Approach to Hyponatremia

1. Euvolemia2. Hypovolemia3. Hypervolemia (edema)

RSW

Rare - internists and nephrologists. It’s all SIADH!

Textbooks nephrology/medicineReview Articles

RSW

Common by:neurosurgeons critical careneurologists

Why Such a Diagnostic Discrepancy?

Largely an inability to assess volume. Are they euvolemic or hypovolemic?

Therapeutic Dilemma

SIADH-actually hypervolemic, water-loaded

-Water restrictSalt Wasting-hypovolemic

-Salt and water supplementation

Diagnostic Dilemma SIADH vs RSW

Both characterized by:Association with intracranial diseasesHyponatremiaConcentrated urineUrinary [Na] usually> 20 mEq/LNormal renal/adrenal/thyroid functionNonedematousHypouricemia, Increased FEurateOnly difference is volume status

So, let us review pertinent volume studies

Volume Studies-Neurosurgical Patients gold standard radioisotope dilution methods

BV BV UNaRSW SIADH mEq/L

Nelson-HN 10 (83%) 2 41-203Wijdicks-SAH

HN 8 (89%) 1 -NN 8 (67%) 4

SivakumarHN 17/18 (94%) 43-210

RSW much more common than SIADH in neurosurgical patients.

Chronic Hyponatremia Associated with Falls

122 chronic hyponatremics115-132 mEq/L

Falls in 21.3% hyponatremics vs 5.3% controls. i.e. 4X increase in falls

SAME FREQUENCY OF FALLS REGARDLESS OF LEVEL OF HYPONATREMIA- 115-132 mEq/L

Renneboog et al. Am J Med. 2006; 119: 711-718.

Renneboog B et al. Am J Med. 2006;199:71.e1-71 19

Hyponatremia & Gait

Gait instability significantly increased in hyponatremia

Gait stability normalized

Correction of

hyponatremia

Hyponatremia, Fractures & Falls

Falls and fractureshyponatremics -13.6% controls -3.9%

4.16 adjusted OR for fracture after fall

Gankam Kengne FG et al. Q J Med. 2008;101:583-588. Sandhu HS et al. Int Urol Nephrol. 2009;41:733-737.

21

Symptomatic Hyponatremia

Increasing awareness that even mild hyponatremia induces symptomsEditorial Does ‘asymptomatic hyponatremia’ exist?(Schrier R. Nature Rev. 2010)

Movement to treat all hyponatremics, creating an urgency to resolve the diagnostic dilemma

SIADH-Uric Acid and Hyponatremia

Beck, LH. NEJM 301:528-530, 1979

14-

12-

Serum 10-

Urate 8-

mg/dl 6-4-

2-

SIADH Other Hyponatremia

Beck, L.H. NEJM 301:528-530;1979

Beck’s Proposal

Coexistence of hyponatremia and hypouricemia (<4mg/dL) differentiates SIADH from most other causes of hyponatremia

Beck, LH. NEJM 301:528-530, 1979

SIADH FEurate before and after correction of hyponatremia

Patient FEurateN=5-10%

%1. Before 14.1

After 8.52. Before 24.2

After 9.93. Before 38.0

After 6.3

Beck, LH. NEJM 301:528-530, 1979

SUA, FEUA and SNa Before and After Correction of hyponatremia 4 papers published on this subject

SIADH

FEurateSNaSUA

Before AfterCorrection-hyponatremia

Insight Case-RSW

40 y.o.m, Adenocarcinoma-LungPE- postural hypotension

responsive to saline-No edema Serum: Na 116, Cr 0.6, urate 2.6 Urine: Osm 323, Na 41, FEurate 26.5%

Insight Case-RSW

Must be SIADH-no cerebral disease (-) CT scan of brain. He had hyponatremia and hypouricemia (Beck-SIADH)

Convinced he had RSW-postural hypotension-responsive to saline.

Proposal: Increased FEurate will persist after correction of hyponatremia by water restriction

SIADH vs RSW

FEurateSNa

Before AfterCorrection-hyponatremia

Insight Case-RSW

Fluid restriction-More wt loss, lethargic, weak, somnolent, postural dizziness, unsteady gait, slurred speech, postural hypotension.

Serum Na 138, uric acid 2.2, FEurate 14.7%, UNa 181

All signs and symptoms of volume depletion corrected with saline. T3, T4, Cortisol and ACTH stimulation test normal.

Serum Sodium, urate, FEurate, UNa Before and After Correction of Hyponatremia

Patient Serum Na Serum Urate FEurate Urine Na (mEq/L) (mg/dL) % mEq/L

1. Before 121 1.1 34.2 99After 138 1.5 30.0 156

2. Before 120 2.0 26.5 42After 138 2.2 14.7 181

3. Before 130 2.1 22.6 73After 139 2.5 22.6 130

4. Before 126 2.1 - 96After 135 2.8 16.1 37

5. Before 130 2.2 - -

After 139 2.1 29.8 114

Increased FEurate ± Hyponatremia

Described in:Neurosurgical diseases of multiple etiologiesAIDSAlzheimer’s diseaseDisseminated CryptoBronchogenic carcinoma metastatic to brain

Without cerebral diseaseMetastatic pancreatic carcinomaBronchogenic carcinomaHodgkins Disease

Differentiation of SIADH from RSW Works with hypertonic saline to correct hyponatremia

SIADH RSW

FEUA

SNa

Before After Before AfterCorrection of Hyponatremia

Insight Case

74 y.o.f. non-edematous, hip fracture. No Cerebral Disease

Na-129, Creatinine-0.8, uric acid-3.4 UNa 6 mEq/L, Uosm 362

FEurate 29.6%

Maesaka JK et al. (2007) Kidney Int,71,pp.822-826

Insight Case

7.1% decreased blood volume-radioisotope dilution-plasma and RBC volumes↑renin and ↑aldosteroneNormal adrenal and thyroid function

Maesaka JK et al. (2007) Kidney Int,71,pp.822-826

Saline infusion (125 ml/hr)

Maesaka JK et al. (2007) Kidney Int,71,pp.822-826

Plasma ADH levels in RSW

Time ADH-pg/ml

Baseline- 2.5

Dilute urine- Undetectable

Maesaka JK et al. (2007) Kidney Int,71,pp.822-826

Regulation of AVP Secretion

Increased plasma osmolality and decreased blood volume stimulate AVP secretion, but volume stimulus is more potent than osmolality.

AVP=arginine vasopressin.Stricker et al. In: Fundamental Neuroscience. 2nd ed. 2003;1011-1029.

-30 -20 -10 0 10 200

5

10

15

20

25

Plas

ma

Vaso

pres

sin

(pg/

Plas

ma

Vaso

pres

sin

(pg/

mL

mL ))

Percent ChangePercent Change

Plasma osmolality

Basal

Blood pressure/volume

Persistent increase in FEurate after correction hyponatremia-RSW

Maesaka JK et al. (2007) Kidney Int,71,pp.822-826

‘Is it cerebral or renal salt wasting’Change cerebral salt wasting to renal salt wasting

Mini-review-Kidney International-2009

Maesaka JK et al. Mini-review. Kidney Int. 2009 76:934-8

New Insight Case

83 Y.O. F-Colon Ca, HTNSerum Na-124, Cr-0.4, urate-2.8Uosm-336, UNa-43FEurate-9.6%, repeated x 3 <10%

Not consistent with SIADH or RSW!!Uosm 115 mosm/kg on random urine, reset osmostat!!Proved by water-loading test-Uosm 99 mosm/kg

Hyponatremia with Normal FEurate

Reset Osmostat (RO) (Imbriano et al J Nephrol 2012)

14 consecutive patients with hyponatremia and normal FEurate had RO (8 -Uosm < 200 mosm/kg-random urine, 6-normal water-loading test-ADH unmeasurable)8 hypouricemia, urate < 4 mg/dL, all had normal FEurate.FEurate is superior to serum urate!!

RO pathophysiologically different from SIADH

Normal FEuratePredictable, suppressible ADH

Types of the Syndrome of Inappropriate Antidiuresis (SIAD)

Ellison D, Berl T. N Engl J Med 2007;356:2064-2072

Study of Nonedematous Hyponatremia FEurate and Water Volume

About half of admissions to hospital have ROSIADH more common than RSW outside of neurosurgical unitMore RSW without cerebral diseaseAll patients with RO and SIADH have increased total (deuterium) and extracellular (sodium bromide) water volumes

Traditional Approach to Hyponatremia

1. Euvolemia2. Hypovolemia3. Hypervolemia (edema)

Assessing Volume Status in Hyponatremia

Extremely inaccurate SIADH and RO are not euvolemic. Hypervolemic!Some unwilling to treat SIADH and RO with V2 receptor blockers because they will become hypovolemic.Propose new algorithm that eliminates need to assess volume, UNa, renin, aldosterone or BNP

Renin, Aldosterone and BNP not useful—too many factors that affect them!

More FEurate in hyponatremias

Unequivocal cases of:Addison’s Disease—FEurate 2% and 3%

Myxedema—FEurate 29% and 30%

NF probably affects sodium transport in the proximal tubule

70% Na reabsorption

30% Na to distal tubule

0.4% Na in urine

Tubular handling of urate

90-95% urate reabsorption

5-10% presented to DT

No distal tubule urate transport

5-10% filtered urate excreted in urine

0.4% Na in urine

Urate/Lithium transported only in PT

Lithium transported 1:1 with Na in proximal tubule

30% Li/Na to distal tubule-No Li transport in distal tubule

5-10% of filtered urate excreted in urine

Serum urate and FEurateEffect of plasma on Na transport in rats

control, multi-infarct dementia and Alzheimer’s

Effect of plasma infusions on sodium excretion rates in rats

IC=intracranial diseases-Increased FEurate-normonatremiaTime 0 represents end of plasma infusion 4 h after firstexposure to plasma.

Studies in myxedematous rats

DiScalaHypertonic saline increased sodium excretion 3.4 fold

45% vs 12 %36% reduction in GFR17.1% reduction in ECV-inulin space

Papper—Micropuncture study30% and 32% reduction in GFR and renal plasma flow28% reduction in proximal tubule Na reabsorption4.3 and 2.3 fold increase in FE sodium and water excretion in urine.

Myxedematous patients are salt wasters!!

Volume depletion due to salt wastingRAT STUDIESDecreased ECVDecreased GFRMajor decrease in proximal tubule sodium reabsorptionHUMAN DATASupported by increased FEurate of 30% in hyponatremic-myxedematous patient.

Approach to Hyponatremia

Hyponatremia Normonatremia

FEurate < 11% FEurate > 11%Hypertonic saline

Psychogenic Polydipsia NormonatremiaReset OsmostatPrerenal azotemia

ECV depletion Addison’s Disease

Congestive heart failure Cirrhosis Nephrosis

FEurate < 11% FEurate > 11%

SIADH RSWHypothyroidism

New manuscript in press

“Failure of Volume Approach to Hyponatremia: A new Algorithm”

Current Status of RSW

It is not rareEstablished to be more common than SIADH in neurosurgical patients.Encountering more RSW patients without clinical cerebral disease.Investigate cause of RSW Demonstrated presence of circulating natriuretic factor (NF) in RSW

Protocol to study hypothyroidism Identify them-we will do the rest

IRB-approved protocol for studyStudy any hypothyroid patient before treatmentObtain informed consent to do study

Collect blood and urine Na, K, Osmolality, creatinine, urate, phosphorus

Perform total and extracellular water volume—deuterium and sodium bromideSave plasma 5 cc at -80°C

Question is whether we repeat studies after successfully treating these patients if they are salt wasters.

Developing a protocol to demonstrate NF in RSW

Preferable to expose luminal and basolateral surfaces of tubule cell because it may require a receptor for endocytosis. Decided to do clearance studies in ratsCan expose both sides of cell to NF

Demonstrating Natriuretic Factor in RSW

Because uric acid is transported only in the proximal tubule, we postulated that the NF was probably a protein that acted on proximal tubule

Lithium excretion rates in rats treated with plasma from Alzheimer’s disease and multi-infarct dementia and

mini mental state examination score

Other pertinent data in neurosurgical and Alzheimer diseases

GFRs and blood pressures were similar in all groups of rats

Age and gender-matched controlsMulti-infarct dementiaNeurosurgical patientsAlzheimer’s disease

Data inconsistent with effect of ANP/BNPNatriuretic factor is not ANP/BNP

Attempts to isolate NF

Extreme difficulty to identify NF by rat clearance studies.Needed an in-vitro bioassayPlasma given IP induced salt wasting in ratsMust be a small protein that can be filtered at glomerulus, saturate any receptors present and excreted in urine.

Ammonium Sulfate Precipitation of Urine Proteins

Neurosurgical patients with:increased FEurate and normonatremiaNormal FEurate and normonatremia

SIADHIncreased FEurate and hyponatremia

SIADH Neurosurg.

FEUA

SNa

Before After Before AfterCorrection of Hyponatremia

Ammonium Sulfate Precipitation of Urine Proteins

22Na Urine Protein

Inhibition of transcellular sodium transport (positive in red)

Neurosurgical patients with:increased FEurate-normonatremiaNormal FEurate-normonatremia

SIADHIncreased FEurate-hyponatremia