The Good, the Bad, and the Ugly

1. The Good, the Bad, and the Ugly Bruce Wall, MD October 9th, 2006

2. Case Presentation: admit 9/14/6 • “I am feeling tired every morning…” • HPI: 81 yo WM with HBP, remote tobacco, and ASCVD. Complains of mid epigastric ‘discomfort’, with 15lb weight loss @ 6 months. Worse in the morning, better in the afternoon. Denies ‘pain’, change in bowel habits, blood in stool, or substernal symptoms. Appetite is better in the afternoon. No response to Reglan, PPI, or prn use of Tums. Gastroenterologist admitted patient for current symptoms, and noted @ K+ 7.2meq/L.

3. HPI: continued • No recent exposure to ACE/ARB, NSAID’s, Diuretics, (including aldactone, amiloride, or triamterene). • He denies any CURRENT voiding problems - S/P TURP in April 2006, complicated by severe post operative hyponatremia (resolved by discharge). Baseline CKD with BUN 35mg%, Creatinine of 1.7mg%, both pre and post prostate resection. • Repeat K+ level drawn confirmed the hyperkalemia. • Dietary intake of potassium likely quite low. No salt substitute. • No family history of unexplained hyperkalemia. • CT scan on admission, without contrast, was negative for obstruction. • No history of extreme temperature or exertion • No subcutaneous Heparin exposure

4. Past History: • Chronic Kidney Disease: “ CKD ” • Baseline creatinine of 1.7mg% - estimated GFR: (140-age)/creat = 34.7ml/min • MDRD equation: ml/min/1.73sqmeters = 186 x (SCr)power-1.54 x (age)power-0.203 x (0.742) (female) X 1.21 (AfricanAmerican) = 38.6ml/min/1.73sqmeters • Glofil ( Iodine 131 isotope): not done

5. Chronic Kidney Disease • Stage I: > 90 ml/min • Stage II: 60 - 89 ml/min • Stage III: 30 – 59 ml/min • Stage IV: 15 – 29 ml/min • Stage V: < 15 ml/min • ICD9 codes: 585.1, etc… • Therefore this patient has stage III disease

6. Past Medical History: • 1) Coronary artery disease, associated with SSS, required previous stent • 2) Hypertension, essential • 3) BPH – S/P TURP June 2006 • 4) Gastritis – EGD biopsy January 2006 • 5) Villous adenoma – November 2004

7. History: continued • Medications: ‘absolutely clueless’ – Labetalol, Plavix, baby ASA, Lipitor, & Procardia • Review of Systems: 80 pack year history of smoking. Mid epigastric discomfort +/-worsened after large meal. No evidence of pancreatitis. No previous TIA or classic claudication. Nocturia is minimal. No bone pain or hypercalcemia.

8. Physical Exam: • Height 5feet 6inches. Weight @ 130lbs. BP 120/66 P 80 regular R 16 unlabored • EKG contained P waves, and normal T’s • HEENT: mild wasting NECK: no bruits LUNGS: slight prolonged expiration HEART: RRR, no murmur, no tachy/brady ABDOMEN: no bruits, non-tender, soft EXTREMITIES: good pulses, no edema NEURO/PSYCH: non-focal; poor historian

9. Laboratory exam: • WBC 4K Hemoglobin 11.2gms Plts125K • Na+ 145 K+ 7.2 Cl- 105 HCO3 22 BUN 73 Creatinine 2.2 Mg++ 1.6 • Blood cultures NEGATIVEUrinalysis: 1+protein 1+leukocyte esterase 100 WBC’s/HPF 15-20 RBC’s/HPF • ESR 16 DIG level 1.9 LFT’s WNL lipase 25 albumin 3.9 PSA 1.3 • Stat renal sonogram negative for obstruction • No evidence of paraproteinemia / M spike

10. HYPERKALEMIA: input – output = accumulation… • Which is more efficient: ability of GI tract to absorb water, or the ability of kidney to excrete? • With normal renal function, most dietary potassium is excreted in urine within 6-8 hours • Therefore, hyperkalemia is rarely caused by dietary ingestion UNLESS low GFR

11. Therapy for hyperkalemia • Do not forget hyperventilation • IV medications to drive K+ into cells • Diagnosis and correction of acidosis • Kayexalate therapy: PO vs Enema; case reports of gastric rupture… • To Rx or not to Rx, that is the question • Is normal EKG, enough?

12. Causes of increased urinary K+ secretion: • A) Hyperkalemia • B) Increased plasma aldosterone levels • C) Increased delivery of sodium to distal tubule

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14. Hyperkalemia: definitions • TRANSIENT HYPERKALEMIA: likely from net release of K+ from cells (will review 12 different potential causes) • PERSISTENT HYPERKALEMIA: requires impairment of urinary K+ excretion (low aldosterone or low Na+ delivery)

15. Increased K+ release from cells: • (1) PSEUDOHYPERKALEMIA: - trauma during collection process - spherocytosis - leukocytosis > 150K - thrombocytosis > 500K - familial type of pseudohyperkalemia: (likely from temperature dependent leak of K+ that occurs after the collection)

16. Increased K+ release from cells: • (2) METABOLIC ACIDOSIS: related to requirement of cellular electroneutrality0.6meq/L increase for every 0.1unit change in pHless common in organic acidoses, i.e. lactic acidosis and DKA (where K+ shift is actually related to lack of insulin)

17. Increased release K+ from cells: • (3) INSULIN DEFICIENCY & HYPERGLYCEMIARelative decrease in insulin affects transport of K+. This is an important mechanism in DKA patients who may be total body potassium depleted

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19. Increased K+ release from cells: • (4) TISSUE CATABOLISM:Trauma, tumor lysis syndrome, acute hypothermia, and acute renal failure • (5) EXERCISE: Very small effect (without ARF); K+ may rise during exercise and fall, post.

20. Increased K+ release from cells: • (6) Beta adrenergic blockade:Therefore, beta agonists are used to Rx hyperkalemia(see figure)

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22. Increased K+ release from cells: • (7) DIGITALIS TOXICITY:inhibition of Na+-K+-ATPase pump • (8) HYPERKALEMIC form of PERIODIC PARALYSISpoint mutation in gene for alpha subunit of skeletal muscle sodium channel • (9) SUCCINYLCHOLINE

23. Increased K+ release from cells: • (10) Calcineurin inhibitors: Neoral® brand of cyclosporin and Prograf® brand of tacrolimus Activate ATP dependent K+ channels (plus chronic renal disease) • (11) K+ based PCN: rarely in neonates • (12) Stored RBC’s: rarely in CKD pts

24. REDUCED URINARY K+ Excretion: Persistent Hyperkalemia • HYPOALDOSTERONISM:multiple causes: deficiency and resistance • CKD: K+ excretion generally maintained in advanced CKD as long as both aldosterone secretion and distal flow are maintained

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26. Reduced urinary K+ excretion: • Chronic Kidney Disease – most consider “multiple insults” - oliguria - dietary abuse - crush injury - medications - decreased circulating volume - acute rejection @ transplantation - Lupus nephritis - hyperkalemic form of type I RTA

27. What caused our patient’s symptoms? Hyperkalemia? • GI symptoms remains a mystery… • Family members arrived with meds from home: Bactrim DS BID for the 7 days • Trimethoprim 160mg / Sulfamethoxazole 800mg: Indicated UTI, acute otitis, acute on chronic bronchitis, shigellosis, PCP, and traveler’s diarrhea • Contraindications: allergy, folate deficiency, CKD, hepatic insufficiency, thiazides, MTX

28. Case reports • Hyperkalemia in hospitalized patients treated with trimethoprim-sulfamethoxazole Alappan, et al, Ann Inter Med 1996 Feb 1 • 105 pts; serum K+ increased by 1.21mmol • Worse in diabetics; worse if creat > 1.3mg%

29. Case reports • Trimethoprim-sulfamethoxazole: Hyperkalemia is an important complication regardless of dose • Perazella et al; Clin Nephrol 1996 SeptIncreased incidence of hyperkalemia in AIDS pts treated for PCP. Trimethoprim acts like amiloride to reduce urinary K+ excretion

30. Case reports: • Trimethoprim-induced hyperkalemia: An analysis of reported cases • Marinella: Gerontology 1999 Jul-Aug 45Literature search: 9 cases; mean age 76; mean duration 10days; baseline creat 1; baseline K+ 4.55Mean peak K+ 7.0mmol/Lno deaths

31. Dr. Allison Liddell • Comments on Bactrim

32. One last thought on urinary K+ • Urinary K+ excretion is of limited utility in persistent hyperkalemia • Estimation of the transtubular potassium concentration gradient (TTKG) will help separate hypoaldosteronism from CKD or volume depletion • TTKG = [urine K / (urine osm/serum osm)] / divided by the serum K+ • Value < 7 suggestive of hypoaldosteronism, as long as urine osm > serum osm, and U Na+ > 25