David B. Mount, MD

Renal Division, BWH

Renal Division,

VA Boston Healthcare System

Sodium Cases

Disclosures

• None

Case #1

ID: A 28 yo woman admitted

with nausea and vomiting

HPI: The patient had been in her usual state of health until the day of admission. That afternoon, she exercised heavily at the gym on a treadmill, much greater than her usual exertion. She took 4 Advils after exercising, for “muscle pains”. She then drank 3 bottles of water, one liter each, out of concern that she was dehydrated.

HPI (Cont’d)She subsequently went to a Red Sox game with family members, where she drank another 3 bottles of water, along with a bottle of Powerade.

At the ball game she noticed a headache, then she felt “shaky”, with difficulty walking and paresthesias in her legs. She was brought to the BWH ER by her father, arriving at 10:33 PM. On arrival to the triage area she vomited.

• On ROS, she denied illness prior to the day of admission. Specifically, no prior diarrhea, headache, or fever. She denied ingesting alcohol at the ball game, and denied drug use.

• The ER notes documented that she stated “I’m drowning” and that she stated she had “made a terrible mistake”. Neurology consult note stated that she had a friend who recently died of water intoxication.

PMH: None. In particular, no psychiatric history

Medication: Oral contraceptive, 4 tablets of Advil on the day of admission NKDA

FH: type II DM, father has high cholesterol

Physical Exam (ER):23:30: Diaphoretic, tachypneic, nauseated, anxious.23:40: “more comfortable”

HR 104, RR 38, bp 146/70, O2 sat 100% on room air Weight 80 kgsHEENT: unremarkable Chest: clear Abdomen: soft, non tenderNeuro: Alert and oriented X3. Normal speech.

CN II-XII intact. Cerebellar: tremor on finger-to-nose, L>R. Motor: “normal plantar flexion, normal dorsiflexion”,

hand grip 5/5 bilateral.

Labs (ER)

23:55, Day of admission

Serum OSM 252

Na 121 Cl 89 BUN 10 BS 165K 3.4 HCO316 Creat 0.75 AG 16HCT 38 WBC 10 Plts 325Urine 3+ ketones

ECG: NSR, no ST/T wave changes

Subsequent Course:0:37 Given 1 mg of Zofran IV1:00 “Continued to shake and have nausea”. KVO N/S

discontinued after receipt of bloodwork. Foley inserted, returning 180 cc of urine.

2:00 CXR performed, report called to floor, patient awaiting bed on Medicine.

Primary diagnosis: HyponatremiaSecondary diagnosis: Water intoxication

3:00 RN called to bedside by patient’s father. Patient incoherent, twitching. This myclonic activity escalated to clonic activity of arms/legs, lasting ~1 minute. Given 2 mg of IV ativan while this GTC was resolving.

4:32 AM CT head, non-contrast: “No acute intracranial abnormality is seen; no edema.”

Subsequent Neurology/Renal read: Mild sulcal effacement c/w mild cerebral edema.

5:30 AM Renal service called, hypertonic saline advised, beginning at 70 ml/hr.

7:30 AM Nephrology attending finishes his consult note…..

Note made of anisocoria: R pupil > L, no RAPD. 2/6 apical PSM, chest clear.

Labs, Days 1-3

DAY TIME Na K Cl HCO3 AG OsmS OsmU NaU

1 23:30 121 3.4 89 16 16 252

2 1:55 702 124

4:00 129 3.6 91 9 29

6:00 124 3.7 93 19 12 256 581 97

8:00 125 3.4 98 18 9

10:00 133 3.4 104 19 10

12:00 135 3.7 106 20 9

13:00 71 19

3 5:00 136 4.2 108 21 7 268

Clinical Impression

• Acute, symptomatic hyponatremia, in the setting of over-exertion and polydipsia.

• Hyperglycemic ketoacidosis, in the absence of admitted alcohol intake or known insulinopenia/insulin resistance.

• Subsequent lactic acidosis after generalized tonic-clonic seizure.

Causes of Acute Hyponatremia• Iatrogenic

– Postoperative – premenopausal women

– Hypotonic fluids with cause of vasopressin

– Glycine irrigant – TURP, uterine surgery

– Colonoscopy preparation

– Recent institution of thiazides

• Polydipsia

• Ecstasy ingestion → thirst and SIADH

• Exercise induced

• Multifactorial, e.g. thiazide therapy and polydipsia

Causative Factors In This Case

• Polydipsia → marked in free H2O intake

• Acute exercise, much greater than her usual activity → vasopressin

• NSAID intake → renal potentiation of vasopressin effects

• Post-exercise pain → vasopressin

• Female sex → neurological consequences

Exercise-Associated Hyponatremia

• Typically associated with prolonged exertion, e.g. marathons

• Risk/Etiological Factors:– Non-osmotic increase in vasopressin

– Excessive weight gain/water intake

– NSAID use (some but not all studies)

– Duration of exercise and/or relative race time

– Extremes of body weight

Urinary PGE2 Varies with Hydration Status

Sun et al, AJP-Renal, 2005

PGE1 inhibits Vasopressin-Stimulated H2O Absorption in the CCD

Grantham and Orloff, JCI, 1968

PerfusedCCD

(cortical collecting

duct)

Vasopressin- and Prostaglandin-Dependent Events in Principal Cells

Clinical Symptoms in 15 Patients With Acute Symptomatic HypoNa

Lauriat and Berl, JASN, 1997, from Arieff, Adv Intern Med, 32:328, 1987

Clinical Signs in 15 Patients With Acute Symptomatic HypoNa

Lauriat and Berl, JASN, 1997, from Arieff, Adv Intern Med, 32:328, 1987

Two Mechanisms of Hypoxia in Acute Hyponatremia

1) Hypercapneic2) Pulmonary edema

Ayus & Arieff, Chest, 1995

We Hopefully Agree……

• Management should include:– hypertonic saline– ABG, CXR, and CNS imaging– supplemental O2 if hypoxic– loop diuretic (Rx of pulmonary edema and

countercurrent mechanism)

• Target Na+ is not well-established, but symptoms typically respond to an increase in serum Na+ of 4-6 mM

David Ellison and Tom Berl, NEJM, 356, 2064-2072, 2007

The Adrogue/Madias Formula Underestimates ∆Na+ After Hypertonic Saline

Mohmand et al, CJASN, 2007

Are Your Concerned About the 14 mEqu/L Increase in Na+

Over the First 12 Hours?

Rate of Correction and Neurological Outcome: No Sequelae in Acute Hyponatremia

Sterns et al, JASN, 1994

Not So Fast!!• Opinion-based controversy in the management

of acute symptomatic hyponatremia – see Ellison and Berl, NEJM, 356, 2064-2072, 2007

• “Despite the need to rapidly correct acute symptomatic hyponatremia, the total increase in serum [Na+] should not exceed 12 mmol/L in the first 24 hours, the same limit recommended in treatment of asymptomatic patients.” (Verbalis, Endocrin/Met Clinics, 32, 2003)

• A modest increase reduces acute symptoms.

Case #2

ID: 31 year old woman, G2P2, 6 weeks postpartum, presents to the Emergency Room (ER) with nausea.

HPI: The patient has a h/o HTN, initiallynoted at the time of her first delivery 3½years ago. She has subsequently beentreated with atenolol, changed tolabetalol during her 2nd pregnancy. Noissues with HTN/proteinuria thispregnancy, the patient delivered a terminfant by Caesarian section 6 weeksPTA, with an uneventful postpartumcourse.

HPI (cont’d)The patient recently developed intermittent severe headaches and leg cramps, with home blood pressure of 140/100; seen in her primary physician's office 4 days prior to admission, hydrochlorothiazide was added to her regimen. Within 2 days of starting the hydrochlorothiazide, the patient developed nausea, vomiting, and orthostastic dizziness.

Medications: labetalol 200 mg bid , hydrochlorothiazide 12.5 mg daily, oral iron, a multivitamin, prn acetaminophen.

SH: The patient is married. She previously worked in retail. There is no history of cigarette, alcohol, or drug abuse.

FH: HTN.

Exam: The patient is in no acute distress. She is afebrile. Her blood pressure is 172/104, pulse 63. JVP is seen at 6 cm, with no peripheral edema. Lungs are clear. S1/S2 normal. Abdominal exam is unremarkable. Neurological examination is non-focal. Head and neck exam is unremarkable.

Labs: Na+ is 113, K+ 4.1, Cl- 80, CO2 23, BUN 10 mg/dL, creatinine 0.4 mg/dL.

TSH 1.58 iU/ml (.3-5.5), cortisol 26.2 μg/dL.

Urine Na+ 130, Uosm 649 mOsm/kg; serum osmolality is ordered but not performed.

A chest x-ray is unremarkable, CT scan of the head shows “no acute intracranial pathology”.

The patient’s euvolemic hyponatremia is felt to be due to the alteration in osmotic sensitivity of AVP release associated with pregnancy (? unlikely this far post-partum) and thiazide-associated hyponatremia.

She is treated with 3% saline and furosemide. Her serum Na+ increases to 117 mM within one day, 120 mM the second day, and 130 mM at the time of hospital discharge 4 days after admission. Serum Na+ is repeated ten weeks later and found to be 132 mM.

Thiazide-Associated Hyponatremia

• Complex pathophysiology– Volume depletion with AVP

– Polydipsia - particularly with hypokalemia

– Direct effects of thiazide on distal H2O absorption – antagonized by prostaglandins, ? role for relative in COX2 activity

• Heterogeneous presentation– SIADH-like picture, i.e. euvolemic, with generous

urine Na+, serum urate <4 mg/dL

– Volume depletion, with low urine urine Na+, serum urate >4 mg/dL.

Back to Our Patient….

The patient is seen in FU 26 weeks later. On ROS, c/o left-sided rhinorrhea.

She is now on metoprolol 100 mg PO daily and loratidine 10 mg daily.

She is euvolemic on physical exam, with a blood pressure of 114/82.

Na+ 128 mM; urine Na+ 210 mM UOsm1093 mOsm/kg.

You Take A Closer Look at Her Head CT….

Thickening in the left nasal cavity, ? left nasal polyp

Olfactory Neuroblastoma and SIADH

• Biopsy revealed an olfactory neuroblastoma, with resolution of her hyponatremia after resection.

• >10 reported cases, with two additional cases in association with the related tumor sinonasal neuroendocrine carcinoma.

• A common theme is the substantial delay, even 6-8 years, between the onset of hyponatremia and diagnosis of olfactory neuroblastoma as the cause.

Olfactory Neuroblastoma and SIADH

Immunohisto of a case of SIADHWith olfactory neuroblastoma

Neurophysin staining

AVP staining

Osterman et al, Arch Intern Med 1986;146:1731-5

Case #2 – Key Points

• Not all tumor-associated SIADH is small cell lung cancer (75%).

• Rapidity and pathogenesis of thiazide-associated hyponatremia.

• The importance of multifactorial hyponatremia.

• The importance of careful imaging in SIADH– Chest CT – can miss SCLC with CXR

– Head CT – also look at sinuses…

Case #3

ID: A 67 yo woman presented to the ER with a 2 week history of worsening fatigue/generalized weakness, poor appetite, and episodes of lightheadedness upon standing.

HPI: Patient has a history of gastrointestinal stromal tumor (GIST) diagnosed in 4/10, s/p Imatinib treatment from 05/05/10 to 06/15/10 complicated by hepatitis/cholestasis. She was hospitalized 3 weeks prior to this presentation for worsening chronic low back pain. Noted to have hyponatremia; due to the suspicion for SIADH, patient was prescribed fluid restriction of 1.5 L/day. She returns with weakness and orthostasis. ROS negative for N&V, diarrhea, fevers, chest pain, dyspnea, headaches, confusion, abdominal pain or any urinary symptoms.

PMH: Gastrointestinal stromal tumor (GIST) diagnosed in 4/10 s/p Imatinib treatment from 05/05/10 to 06/15/10, Imatinib -induced hepatitis/cholestasis, GERD, DM (type 2), HTN, chronic low back pain-arthritis, colonic polyps, burn injury to abdomen and left hand as a child.

Medications: Famotidine 20 MG PO QHS, KCl 20 MEQ PO QD, Lantus 14 units at HS, Multivitamin, Phos-nak 250 MG PO BID, Ursodiol 300 MG PO TID, Oxycodone 10-15 mg PO Q 4 hr prn

Family history: Non-contributory

Social history: Lives alone and able to perform ADLs independently. Retired home health aide. Remote h/o smoking, 15-20 pk-yr,. EtOH 2x weekly. No recreational drug use.

Exam: Temp 98 BP 74/50 (improved to 120/77 after 1.5 L NS in ER) HR 80 JVP 5 cm, no edema.

S1/S2 normal w/o murmur, chest clear. Abdomen soft, non-tender. H&N normal. Neuro non-focal. Skin notable for old RUQ and left hand burn scars.

Na 120, K 3.8, Cl 87, HCO3 20, BUN 7, Cr 0.67, glucose 79, Ca 9.3 Mg 2.0, Phos 2.0

T protein 4.7, Albumin 2.2, PT 13.3, PTT 34, T bili 19.5, D bili 13.6, ALT 151, AST 133, Alk phos1026

Serum osm 291, U osm 612, U Na 146, U Cl 173, U K 48.3, U Cr 22.1, U protein 8.7 (after 1.5 L of normal saline)

WBC 5.5, Hg 10, Plt 442, CRP 18.7

Urine drug screen negative ; serum negative for ethanol, methanol, isopropanol

Questions

1. What additional tests are needed?

2. What is the most likely explanation for her hyponatremia?

3. What should be the treatment plan for her hyponatremia?

Pseudohyponatremia

Normal serum

• Water 93%

• Fat and proteins 7%

• S. sodium 142 mEq/L

• Sodium concentration in physiologically important serum water 154 mEq/L

(142 ÷ 0.93= 154)

Abnormal serum

• Water 80%

• Fat/proteins 20%

• Sodium concentration in physiologically important serum water 154 mEq/L

(154 X 0.80= 123)

• S. sodium 123 mEq/L

Serum Sodium Measurement

• Flame photometry-– Diluted serum samples

– Ultra fine spray of dilution is blown across a flame

– Measures intensity of light emitted at the wavelength characteristic of sodium, intensity being proportional to number of sodium atoms in the sample

– Calibration with a standard aqueous solution of known sodium concentration allows determination of the sodium concentration in the unknown sample (number of atoms/volume of sample).

Ion Selective Electrode Potentiometry

• Measures electrical potential across a sodium-selective membrane immersed in unknown serum sample

• Electrical potential is a function of the sodium activity in the sample

• Measurement by ISE applied to undiluted serum - direct-reading potentiometry

• Measurement by ISE applied to diluted serum - indirect-reading potentiometry

Sodium Measurement

American Journal of Medicine 1989

Our Patient

Imatinib

Cholestasis

Pseudohyponatremia

Hepatotoxicity of Imatinib

• CML– Severe elevation of liver enzymes or

bilirubin- 5%

– Treatment discontinuation-1.0%

• GIST– Severe elevation of liver enzymes or

bilirubin- up to 7% of GIST patients

Lipid Panel

• Serum cholesterol 1883 H mg/dL 140-200

• Serum TG 945 H mg/dL 30-149

• HDL Cholesterol 30 L mg/dL 40-59

• LDL Cholesterol, Direct 1760 H mg/dL 0-129

• VLDL, Calculated 93 H mg/dL 0-30

*Due to icterus, cholesterol and TG values may be falsely decreased

Lipoprotein Electrophoresis

“There is a band of unknown significance located between the LDL band and the expected location of the VLDL band. This interferent is mostly lipoprotein X…”

Lipoprotein X

• Seen in– Intra or extrahepatic cholestasis– Lecithin:cholesterol acyltransferase

deficiency → glomerulosclerosis– Newborn infants with immature liver

function• Composed of phospholipids and

unesterified cholesterol

Lipoprotein-X in LCAT Deficiency

1 – normal serum 2 – LCAT-deficient patient 3 – purified Lp-X

Kidney International (2001) 60, 520–532

Acquired Lipoprotein X

• Incubation of bile lipoproteins with serum or albumin in vitro leads to the appearance of lipoprotein-X–like particles

• Aside from interfering with laboratory tests and, in extreme cases, causing the hyperviscosity syndrome, high levels of lipoprotein X do not usually lead to any pathologic consequences

Case #3 – Key Points

• ALWAYS CHECK SERUM OSMOLALITY IN HYPONATREMIA!!

• Therapeutic consequences of misdiagnosing pseudohyponatremia – inappropriate fluid restriction.

• Lipoprotein X and pseudohyponatremia.

HPI: 48 yo male, transferred from OSH for the management of worsening hyponatremia and a seizure.

• He had been discharged one week prior, after a 3-day admission for post-colostomy C diff colitis .

• He was transferred from another hospital after 3 witnessed focal seizures, with involuntary movement of his right arm responsive to benzodiazepines.

Case #4

HPI (cont’d)Serum [Na+] was 120 mM on presentation, increasing to 126 after an unspecified volume of normal saline. Serum [Na+] was 119 on transfer, dropping to 116 six hours later after an additional 500 ml of saline; this provoked a Renal consultation.

On ROS, he is dysarthric, which his mother states is typical for when he is hyponatremic. Also states he’s “mentally slowed down”. Denies H/A or nausea.

PMH:1) Large L MCA-territory stroke in 2007 due to L

carotid artery dissection. Chronic neurogenic bladder and bowel, leading to suprapubic catheter and diverting colostomy one month PTA.

2) Chronic thrombocytosis due to JAK2-associated MP, maintained on hydroxyurea.

3) Chronic hyponatremia, serum [Na+] <132 since entering the VA system in 2008. Attributed to SIADH, but with episodes of worsening hyponatremia that have been reputedly responsive to saline.

Meds: acetaminophen prn, lorazepam prnASA 325 mg PO dailydicyclomine cap 10 mg PO bid prn hydroxyurea 1000 mg PO qTTSat levetiracetam 500 mg PO bidmetoprolol 25 mg PO bidmetronidazole 500 mg PO tid

Family history: + for stroke (mother, age 75)Social history: Ex smoker, quit after stroke in 2007. No alcohol, no illicit drugs. Chronic rehab resident.

Exam: supine HR 86 and bp118/72, standing 106 and 111/70.

Cachectic. Alert, oriented, but dysarthric.

• JVP 3 cm, no edema. All pulses palpable, no bruits. HS normal, no murmur. Chest clear.

• Facial droop with some activation upon smiling. Right UE with some atrophy and contraction; R hand 0/5, proximal arm 2-3/5.

• Abdomen benign, with colostomy and suprapubic catheter.

InvestigationsLabs: WBC 5.5 Hb 11.6 Plts 491

Na 116 K 4.9 Cl 90 HCO3 19

BUN 8 Creat 0.6

Glu 198 Alb 3.1 Ca 8.4 Phos 4.0

Mg 2.0 Urate <3 mg/dL

Serum Osm 257

UOsm 389

Urine Na 69, Urine K 37, Urine Cl 84

BNP 31 pg/mL (5-100)

Cortisol 18.81 μg/mL TSH 1.8

plasma renin 0.66 ng/mL/H (0.25-5.82)

serum aldosterone 1 ng/mL

FeUrate 12.44% (using SUA of 3, was <3)

FePhosphate 11.5%

Other imaging:Normal CXRNormal CT chest

Clinical Course• Patient initially treated with hypertonic saline,

30 ml/hr for 12 hours, with in serum [Na+] to 123 and improvement in speech and mental status.

• Given ? volume depletion and orthostasis, off β-blockade, with persistently urine [Na+], patient was treated with IV normal saline for 3 days with steady in serum [Na+].

• However, continued in serum [Na+] to 131 as saline tapered off, despite urine [Na+].

Diagnosis???• Renal/Cerebral salt wasting?

– ? of relative hypovolemia, with persistently high urine Na

– would classically expect higher FeUrate/PO4

– more typically associated with acuteneurological events

– serum [Na+] continued as saline and urine [Na+] , which argues against RSW/CSW

• SIADH? OK, but then, what’s the cause?– no known culprit meds, chest CT normal

– ? related to large stroke

BNP 31 pg/mL (5-100)

Cortisol 18.81 μg/mL TSH 1.8plasma renin 0.66 ng/mL/H (0.25-5.82)serum aldosterone 1 ng/mL

Arginine vasopressin:1.5 pg/ml (1-13), serum Na 122 1.9 pg/ml, serum Na 127

Where’s the Vasopressin??

Patterns of AVP Release in SIADH

A) Unregulated, erraticB) Baseline increase, normal osmotic responseC) “Reset osmostat”D) Suppressed AVP

Robertson, Am J Med. 2006;119(7 Suppl 1):S36-42

Two Boys with Hyponatremia

Feldman et al, N Engl J Med. 2005 May 5;352(18):1884-90

Nephrogenic SIADH (NSIAD) is due to Mutations in the V2 Vasopressin Receptor

(V2R)

Feldman et al, N Engl J Med. 2005 May 5;352(18):1884-90

R137 C137 R137L

Gain of Function in the V2R in Nephrogenic SIADH

NSIAD Mutations Target a Critical Residue in the V2 Receptor, Also Involved in

Hereditary Nephrogenic DI

The mutations allaffect an Arginine (R)within the “DRY/H” motif of rhodopsin-likeG protein-coupledreceptors.

Mutation of this conservedR in the α1b adrenergicreceptor also causesconstitutive activation.

The Clinical Phenotype of NSIAD

• The V2R is on the X chromosome; female carriers are variably affected, due to competing effects of somatic X inactivation and the heterozygous activating mutation.

• Highly variable phenotype in affected males.

• Typically discovered in infancy, but reported in adults, including >70 year-olds with SIADH.

• AVP levels range from undetectable to very low and inappropriate to sOsm, with reported urine Osm of 250-950.

Sands and Bichet, Ann Intern Med. 2006 Feb 7;144(3):186-94

III.1 – female heteroIII.2 – female heteroIII.4 – female heteroIV.4 – male hemizygous

urine aquaporin-2

Male patient. No suppression of aquaporin-2, with minimal free water clearance after water loading (not shown here)

Ranchin et al, J Clin Endo Metab, 95, E37, 2010

Case #4 – Key Points• Consider measuring [AVP] in hyponatremic patients

with “idiopathic” SIADH.

• An unknown fraction of the 10% of patients with SIADH and suppressed [AVP] are likely to have nephrogenic SIAD (NSIAD) due to activating V2R mutations.

• Commercial genetic testing is available, typically as testing for genetic nephrogenic DI (sequencing all the coding exons of V2R).

• Treatment options in NSIAD other than water restriction are not clear, but oral urea has been successful.

Case #5

ID: 63yo Caucasian male with

hypernatremia, longterm Psychiatry

inpatient.

• HPI: The patient was transferred for recurrent aspiration pneumonia, requiring intubation and ICU care.

• Reported history of polydipsia and long-term lithium use for approx four years.

• He developed hypernatraemia and AKI while in the ICU, with peak serum Na of 156 and peak creatinine of 2.6. Urine Osm was measured once, found to be 157 mOsm/kg, with coincident serum Osm of 318 mOsm/kg.

PMH: Schizophrenia, COPD, Oesophageal dysmotility, Recurrent aspirations, Dementia, Tardive Dyskinesia

Meds: Omeprazole 20mg daily, Cholecalciferol 1000u daily, Albuterol nebs qid, Ipratropium inhaler qid, Olanzapine 5mg bid, Lorazepam prn agitation

Family history: Unknown

Social history: Ex smoker, no alcohol, no illicit drugs. Institutionalized psych patient

Exam: BP 139/64 HR 89 T 99 Weight 97.5Kg

Drowsy, non-verbal.

JVP 5 cm, no edema. All pulses palpable, no bruits.

H+N: no nodes, no ulcerations, oropharynx normal

CVS: normal S1 and S2, nil added, no murmurs

Chest: normal vesicular breath sounds throughout

Abdo: Soft, nontender, no masses, BS present and normal

InvestigationsLabs: WBC 9.5 Hb 11.1 Plts 174

Na 150 K 3.9 Cl 114 HCO3 26 BUN 8 Creat 1.7

Glu 95 Alb 3.1 Ca 8.1 Phos 2.6 Mg 2.0 Serum Osm 303

Urine Na 34, UK 5.2, UCl 27, UOsm 137; Urine output 3.4L prev 24 hours

Ultrasound – no hydronephrosis, ‘normal’ sized kidneys, normal echogenicity

Clinical Impression

• Hypernatremia due to ongoing water diuresis polyuria with urine Osm of 137 mOsm/kg when serum Osm was 303 mOsm/kg.

• Water diuresis due to lithium-associated nephrogenic DI (NDI).

• AKI on CKD due to volume depletion.

Lithium-Associated NDI

• NDI and polyuria in 20-40% of patients treated with lithium, correlates with duration of therapy.

• Polyuria may also be due to polydipsia and/or central DI, hence confirmation of NDI is essential.

• Lithium causes chronic tubulointerstitial scarring and CKD after prolonged therapy; patients may also have a persistent NDI long after stopping lithium.

Pathogenesis of Lithium-Associated NDI

• Decreased density of V2 vasopressin receptors.

• Uncoupling of stimulatory G protein from V2 receptor – displacement of Mg2+ by Li+.

• Inhibition of renal glycogen synthase kinase-3 (GSK3), ? CNS target of lithium.– Up-regulation of medullary COX2 negative

effect of local prostaglandins on concentrating mechanisms.

– Uncoupling of adenylate cyclase from V2 receptor.

Salt and Water Transport by the Inner Medullary Collecting Duct

Downregulation of Aquaporin-2 by Hypokalemia and Lithium

Neilsen et al, JCI, 1996

GSK-3 Deletion in Mouse CCD Blunts V2-Stimulated cAMP Generation

A) Urine cAMP after water deprivation in wild-type (WT) and GSK-3 knockout (KO) miceB) Cyclic AMP generation in papillae from WT and KO mice

Rao et al, JASN, 2010 , 21, 428-437

Lithium Enters Principal Cells Via the Amiloride-Sensitive Epithelial Na Channel (ENaC)

ENaC Deletion in Mouse CCD Abrogates Lithium-Associated NDI

Christensen et al, JASN, 2011 22:253-61

ENaC KO- mice withdeletion of α-ENaC inCCD

Amiloride in Lithium-Associated NDI

Bedford et al, CJASN, 2008 3:1324-31

Acute Management

• Repletion of both free water deficit and ongoing free water loss from NDI.

• Free water deficit = [(Na+ − 140)/140] ×TBW. = 4.2 liters at a weight of 97.5 kg and serum [Na+] of 150 mM.

• This free water deficit was replaced slowly over 48-72 hrs, to avoid decreasing the serum [Na+] by >10 mM /24 hours.

Acute Management (Cont’d)• NEED TO CONSIDER ONGOING FREE

WATER LOSS AS WELL – calculate electrolyte-free water excretion

• CeH2O = V (1 – UNa + UK / PNa)

= 2.5 liters/day

• Need to replace daily electrolyte-free water excretion, along with repleting the deficit.

• Therefore, initial IV free water repletion should be ~ 4.5 liters/24 hours, with frequent labs to avoid increase > 10 mM/day

Chronic Management• Polydipsia / increased free water intake;

suitable for the majority of patients.

• Thiazide therapy– Volume depletion proximal H2O absorption

– ? Direct effects on distal H2O absorption

• NSAIDs / COX2 inhibitors +/- DDAVP– Abrogates negative effects of prostaglandins

– GFR can be an issue

• Amiloride– Inhibits Li+ absorption via ENaC.

– Efficacy after chronic Lithium Rx.

Chronic Management of This Patient

• Concerns regarding his aspiration risk, ? magnified by free water intake.

• CKD ruled out use of NSAID/COX2 inhibitors and thiazide.

• ? Partial NDI use of DDAVP Rx to urine Osm and reduce polyuria.

• Therefore, we pursued a water deprivation test.

Water Deprivation Test

Time 0 +6 +8 +12 +18 hours

Na 145 148 150 152 152 mM

K 5.4 5.3 3.9 3.9 3.9 mM

Cl 111 110 118 120 117 mM

Creat 1.41 1.4 1.3 1.4 1.4 mg/dL

SOsm 309 311 310 mOsm/kg

UOsm 132 140 201 237 257 mOsm/kg

UNa 61 mM

AVP 8.4 6.3 pg/mL

+9 hours - DDAVP

Water Deprivation Test (cont’d)• Urine Osm failed to >50% or >150 mOsm/kg

after both water deprivation and the administration of DDAVP complete NDI.

• Key issues/points for water deprivation testing:– Avoid overnight deprivation severe

hypernatremia.

– Follow serum Na+ hourly – more accurate and rapid than serum Osm.

– Incorporate AVP measurement – use protease inhibitor in pregnancy-associated DI (with vasopressinase).