Important aspects of acid-base disorders

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1 Important aspects of acid-base disorders I. David Weiner, M.D. Co-holder, C. Craig and Audrae Tisher Chair in Nephrology Division of Nephrology, Hypertension and Transplantation University of Florida College of Medicine Gainesville, FL USA NF/SGVHS, Gainesville, FL USA

2 Some interesting thoughts, courtesy of HL Mencken Life is a struggle,

3 Some interesting thoughts, courtesy of HL Mencken Life is a struggle, Not against sin,

4 Some interesting thoughts, courtesy of HL Mencken Life is a struggle, Not against sin, Not against the money power,

5 Some interesting thoughts, courtesy of HL Mencken Life is a struggle, Not against sin, Not against the money power, Not against malicious animal magnetism,

6 Some interesting thoughts, courtesy of HL Mencken Life is a struggle, Not against sin, Not against the money power, Not against malicious animal magnetism, But against hydrogen ions.

7 Why care about chronic metabolic acidosis? Prepared by I. David Weiner, M.D.

5% 3% 4% 5% 11% 0% 60-89 50-59 40-49 30-39 20-29 <20

8 Metabolic acidosis is common, particularly in patients with CKD Prevalence 40% 40% 35% 30% 25% 20% 21% 15% 10% 5% 3% 4% 5% 11% 0% <20 egfr (ml/min/1.73m²) Moranne, J Am Soc Nephrol 20: , 2009

9 What are the risks of treating chronic metabolic acidosis in people with CKD? NaHCO₃ and/or Na-citrate Na+ load Worsening of BP control? Worsening of CHF? Worsening of proteinuria? Worsening progression of CKD? K-citrate Worsening of hyperkalemia? Risk of Al+³ overload Major barrier to intestinal Al+³ uptake is charge Citrate complexes with Al+³ in the gastrointestinal tract Increases Al+³ absorption ~100x

10 Should we treat metabolic acidosis in CKD patients? Patients studied Stage IV CKD Plasma HCO 3 - > 16 and < 20 Stable medical condition Excluded Malignancy Morbid obesity Poorly controlled hypertension (> 150/90 despite 4 meds) Overt CHF Treatment Oral NaHCO 3, dosed to serum HCO 3-23 Prepared by I. David Weiner, M.D. J Am Soc Nephrol 20: , 2009.

11 Sodium bicarbonate improved metabolic acidosis Prepared by I. David Weiner, M.D. J Am Soc Nephrol 20: , 2009.

12 Sodium bicarbonate did not worsen BP Prepared by I. David Weiner, M.D. J Am Soc Nephrol 20: , 2009.

13 Sodium bicarbonate did not worsen proteinuria Prepared by I. David Weiner, M.D. J Am Soc Nephrol 20: , 2009.

14 Sodium bicarbonate slowed progression of CKD Prepared by I. David Weiner, M.D. J Am Soc Nephrol 20: , 2009.

15 Sodium bicarbonate decreased development of ESRD Prepared by I. David Weiner, M.D. J Am Soc Nephrol 20: , 2009.

16 Sodium bicarbonate improved plasma albumin Prepared by I. David Weiner, M.D. J Am Soc Nephrol 20: , 2009.

17 Big muscles are better than small ones Prepared by I. David Weiner, M.D.

18 Sodium bicarbonate increased skeletal muscle mass Prepared by I. David Weiner, M.D. J Am Soc Nephrol 20: , 2009.

19 Excretion (mmol d ¹) Why should NaHCO₃ improve muscle mass? What is the effect of chronic metabolic acidosis on skeletal muscles? What is the body s response to chronic metabolic acidosis? Increased ammonia excretion Kidneys generate ammonia from glutamine (1 glutamine 2 NH₄+) Renal acid excretion in response to chronic metabolic acidosis Basal Ammonia Titratable acid Acidosis, Day Acidosis, Day Acidosis, Day 5 (data from: Elkinton JR, et al, Am J Medicine 36:554-75, 1960)

5 mmol L ¹ Total extracellular fluid volume, ~15 L 7.

20 Excretion (mmol d ¹) Why should NaHCO₃ improve muscle mass? What is the body s response to chronic metabolic acidosis? Increased ammonia excretion Kidneys generate ammonia from glutamine (1 glutamine 2 NH₄+) What is the available amount of glutamine? 0.5 mmol L ¹ Total extracellular fluid volume, ~15 L 7.5 mmol Renal acid excretion in response to chronic metabolic acidosis Basal Ammonia Titratable acid Acidosis, Day Acidosis, Day Acidosis, Day 5 (data from: Elkinton JR, et al, Am J Medicine 36:554-75, 1960)

21 Why does NaCl, but not NaHCO₃, increase BP Collecting Duct Lumen ENaC Na Pendrin Cl HCO₃

22 CKD and metabolic acidosis Common Easily treatable Safe and beneficial to treat Double-check results if HCO₃ < 20 mmol/l Start NaHCO₃, 1300 mg bid Titrate, as needed, to HCO₃ of 24 mmol/l Prepared by I. David Weiner, M.D.

23 Why do some, but not all, patients with CKD develop metabolic acidosis? Inaccuracies in egfr determination Factors other than GFR regulate renal acid excretion Angiotensin II Aldosterone Diet-based differences in endogenous acid production

24 Rate of endogenous acid production predicts serum HCO₃ JJ Scialla, et al, Clin J Am Soc Nephrol 6: , 2011.`

25 Rate of endogenous acid production predicts serum HCO₃ JJ Scialla, et al, Clin J Am Soc Nephrol 6: , 2011.`

26 Rate of endogenous acid production predicts changes in GFR JJ Scialla, et al., Kidney International (2012) 82,

27 Why do some with CKD develop metabolic acidosis? Inaccuracies in egfr determination Factors other than GFR regulate renal acid excretion Angiotensin II Aldosterone Diet-based differences in endogenous acid production Animal-based proteins H+ production K+-containing food HCO₃ production

28 Endogenous acid production predicts changes in GFR JJ Scialla, et al., Kidney International (2012) 82,

29 Endogenous acid production predicts changes in GFR JJ Scialla, et al., Kidney International (2012) 82,

30 Endogenous acid production predicts changes in GFR JJ Scialla, et al., Kidney International (2012) 82,

31 What about the K+ load and the risk of hyperkalemia? S Korgaonkar, et al. Clin J Am Soc Nephrol 5: , 2010

32 CKD-associated metabolic acidosis Common Easily treatable Safe and beneficial to treat Double-check results if HCO₃ < 20 mmol/l Start NaHCO₃, 1300 mg bid Titrate, as needed, to HCO₃ of 24 mmol/l May have dietary component Diet higher in fruits and vegetables that are metabolized to alkali precursors may help to slow progressive CKD

33 Next question Can metabolic acidosis be present even when the serum HCO₃ is normal? Huh? Definition for discussion: Metabolic acidosis is present if renal acid excretion does NOT match total acid production and alternative mechanisms are utilized to maintain serum HCO₃

34 Renal acid excretion may not equal acid production in patients with CKD Goodman AD, et al, JCI 40: , 1965.

35 Is acid production balanced by acid excretion with normal kidneys? J Lemann, et al, JCI 44:507-17, 1965.

36 Metabolic acidosis induces renal calcium losses J Lemann, et al, JCI 45: , 1966.

37 Effects of chronic metabolic acidosis on bones Alkali content in bones is 5x content in all body fluids Acidosis Stimulates bone resorption Represses bone formation Calcium released during bone resorption is excreted by kidneys DA Bushinsky, et al, AJP Renal 245:F204-9, 1983.

38 Aging leads to chronic, mild metabolic acidosis Low bone mineral density is present in 50% of postmenopausal women Could age-related acidbase changes contribute to low bone density?

39 Can oral alkali therapy improve bone metabolism in post-menopausal women? 18 post-menopausal women Control diet (per 60 kg) for 6 days Ca +2, 16 mmol Protein, 1.6 gm/kg Na +, 119 mmol K +, 59 mmol Treatment KHCO 3, 1-2 mmol/kg 18 days Sebastian A, et al, NEJM 330: , 1994.

Alkali administration decreases urinary Ca+² excretion Urinary Ca +2 (mg (60 kg) -1 d -1 ) 350

40 Alkali administration decreases urinary Ca+² excretion Urinary Ca +2 (mg (60 kg) -1 d -1 ) Control Treatment Recovery Sebastian A, et al, NEJM 330: , 1994.

41 Is there a long-term benefit to alkali therapy? 181 non-vegetarian, post-menopausal women All had low lumbar spine BMD T score, <-1 and >-4 Randomized Treatment, K-citrate (Urocit-K), 10 mmol x3 per day Control, KCl, 10 mmol x3 per day S Jehle, et al, JASN 17: , 2006.

42 Alkali administration decreases urinary calcium excretion S Jehle, et al, JASN 17: , 2006.

43 Alkali administration improves bone density Similar effects on femoral neck and hip S Jehle, et al, JASN 17: , 2006.

44 Alkali administration improves bone density S Jehle, et al, JASN 17: , 2006.

45 K Citrate therapy also decreases blood pressure S Jehle, et al, JASN 17: , 2006.

Summary Metabolic acidosis is common in CKD Treatment with NaHCO₃ improves multiple aspects Dietary K+ intake in CKD patients predicts Serum

46 Summary Metabolic acidosis is common in CKD Treatment with NaHCO₃ improves multiple aspects Dietary K+ intake in CKD patients predicts Serum HCO₃ Stability of CKD In post-menopausal women with low bone mineral density Treatment with K-citrate Improves bone density Lowers blood pressure

New aspects of acid-base disorders

New aspects of acid-base disorders I. David Weiner, M.D. C. Craig and Audrae Tisher Chair in Nephrology Division of Nephrology, Hypertension and Transplantation University of Florida College of Medicine