Therapeutic Challenges in CKD & ESRD: Managing Acid-base & electrolytes. No financial disclosure

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1 Therapeutic Challenges in CKD & ESRD: Managing Acid-base & electrolytes Qi Qian, MD, FASN Mayo Clinic, College of Medicine No financial disclosure 2016 MFMER

2 ü - ü - 1. Acidosis 2. Hyperkalemia 3. Volume and BP (hyper/hypotension) 4. Hyponatremia 2016 MFMER

3 Cases: CKD and ESRD #1 A 62-y/o F, stage 3 CKD due to DN, HTN and dyslipidemia, presented with 3 days of diarrhea. She has been on a stable dosage of lisinopril, HCTZ, Lopressor, and insulin. PE: BP 136/62, HR 100, lungs: clear, cardiac: RRR, abdomen soft, no edema, neurologically nonfocal. Labs: Na 136, K 3.6, Cl 103, HCO 3-18, BUN 42, Cr 1.6. Urinalysis: protein/cr ratio of 3.0. Microscopy: bland. #2 An 81-y/o man with ESRD on HD x18 mos. He has COPD, CAD, DN, HTN and obesity (BMI 44). He presented with respiratory distress, placed on bipap, and admitted to the micu. PE: BP 150/96, pulse 82, RR 30/min, FIO2 60%, O 2 88%. Lungs: decreased breathing sounds bilaterally. Regular hear rate. Soft abdomen extremity edema. Labs prior to dialysis: Na 130, K 5.8, Cl 94, HCO 3-18, BUN 38, Cr 6.8. Chest x-ray: + Pulmonary vascular congestion, cardiomegaly and right lower lobe infiltration. Meds: Amlodipine 10 mg, Lipitor 20 mg, steroid inhaler MFMER

4 Acidosis in CKD is common --- one of the earliest complications of CKD Occurrence rate: CKD stage 2: 7% CKD stage 3: 13% CKD stage 4: 37% CRIC (Chronic Renal Insufficiency Cohort) Study Prevalence of and risk factors for reduced serum bicarbonate in chronic kidney disease. Nephrology. 2014;19(10): Kidney Int 1986, 30(5): Kidney Int 1998, 54(2): J ClinInvest 1996, 97(6): J ClinInvest 1996, 97(4): J ClinInvest 1995, 95(1): NDT 2009, 24, MFMER

5 Acidosis induces ammonia genesis and complement activation Rat remnant kidney model Chronic NaHCO 3 supplementation vs. NaCl NaHCO3 NaCl supplementation NaHCO 3 group: Ø Lowered renal vein ammonia concentrations Ø Reduced tubular deposition of complement components (C3, C5b-9) LM IF(C3) Ø Less tubulointerstitial damage (structural and functional) Ammonia, as a nitrogen nucleophile, reacts biochemically with C3 to trigger the activation of the alternative complement pathway. C5b-9 J Clin Invest 1985, 76(2): MFMER MFMER slide-5

6 2011 MFMER slide MFMER

7 Acidosis: Multiple negative consequences Zha & Qian Nutrients 2017, 9(3), MFMER slide MFMER

8 Chronic Renal Insufficiency Cohort (CRIC) study n=3,939, CKD stages 2 4, Median f/u = 3.9 years Every 1 meq/l higher [HCO 3- ] was associated with a 3% (95% CI, 1-6%) lower risk of developing ESRD or egfr decline Am J Kidney Dis 2013, 62(4): MFMER

9 In epidemiologic studies, low serum bicarbonate has been associated with high mortality MFMER slide MFMER

10 N=134, CKD stages 4, 5 HCO meq/l Intervention: NaHCO 3 vs. usual care. Follow up: 2 years NaHCO 3 group had a slower scr clearance decline and lower risk for ESRD after. NaHCO 3 improved nutritional status MFMER slide MFMER J Am Soc Nephrol. 2009;20(9):2075

11 N=59 CKD Sodium citrate (n=30) Serum HCO mmol/l Follow up: 2 years Citrate group: urine endothelin-1 excretion and N-acetyl-b-Dglucosaminidase (a marker of kidney tubulointerstitial injury) were significantly lower. The rate of egfr decline was significantly slower. Sodium citrate was kidney-protective adjunct to blood pressure reduction and ACE inhibition. Kidney Int. 2010;77(7): MFMER slide MFMER

12 Question: Where are the acids coming from? (acid origin) 1. Dietary proteins 2. Dietary salt 3. Kidney Excretion 4. All of the above 2016 MFMER

13 Dietary proteins: amino acids, further broken down to acids and bases. Proteins in contemporary diet generate predominantly acidic products: Hydrogen chloride (HCl) and sulfuric acid. Proteins contain phosphoric acids = an endogenous acid production (NEAP) of ~1 meq/kg/day, ~80 meq/day in an average adult. These acids are nonvolatile and rely on the kidneys for their excretion. Dietary salt (NaCl): In CKD/ESRD, dietary salt contribute to acidosis MFMER

14 1.5 mmol NaCl Intravenous salt (saline, 0.9% NaCl) and oral salt intake have very difference impact! 2011 MFMER slide MFMER

15 1. Salt loading: IV versus Oral infusion (0.9% NaCl) on - systemic acid-base status - volume status 2. Oral salt loading: Enterorenal regulations: - Uroguanylin - Pendrin Implication in CKD/ESRD 2011 MFMER slide MFMER

16 Oral salt intake: Intestine 2011 MFMER slide MFMER

17 UGN transcriptional regulation of the hpds gene encoding pendrin, a major anion exchanger in the CCD. UGN induced decrease pendrin expression (mrna and protein) 2011 MFMER slide MFMER

18 CKD/ESRD Key: NEAP, heavily influenced by diet, and may vary greatly 2011 MFMER slide MFMER

19 N=79 Stage 1 CKD N=120 stage 2 CKD Duration: 30 days 2016 MFMER

20 N=108 Total CO2: meq/l 2016 MFMER

21 egfr: ml/min/1.73 m2). TCO2: 22 mm, Daily NaHCO3: 1.0 meq/kg/day (n=35) or fruits and vegetables dosed to reduce dietary acid by half (n=36) MFMER

22 Current practice s.hco3 upper limit: meq/l (mmol/l) -- Need more study 2011 MFMER slide MFMER

23 Key Points Acidosis in CKD common and increase mortality Protein catabolism, muscle wasting, Bone demineralization, Insulin resistance, impaired thyroid hormone and growth hormone secretion, Exacerbatingf β2 microglobulin accumulation 2011 MFMER slide MFMER

24 Acid-base alterations in ESRD during HD 2016 MFMER

25 Our patient: An 81-y/o man with ESRD on HD x18 mos. He has COPD, CAD, DN, HTN and obesity (BMI 44). He presented with respiratory distress, placed on bipap, and admitted to the micu. PE: BP 150/96, pulse 82, RR 30/min, FIO2 60%, O 2 88%. Lungs: decreased breathing sounds bilaterally. Regular hear rate. Soft abdomen extremity edema. Pre-HD Labs: Na 130, K 5.8, Cl 94, HCO 3-18, BUN 38, Cr 6.8. Chest x-ray: + Pulmonary vascular congestion, cardiomegaly and right lower lobe infiltration. Meds: Amlodipine 10 mg, Lipitor 20 mg, steroid inhaler MFMER

26 Reduction of metabolic acidosis in ESRD patients Ø improves insulin sensitivity, Ø reduces muscle protein catabolism, Ø increases parathyroid gland sensitivity to serum calcium and improves bone turnover. Metabolic alkalosis in HD patients: Ø related to the high dialysate bicarbonate Ø malignant cardiac arrhythmia, contributing to acute cardiac death. Ø Hypotension/hemodynamic instability during dialysis. Ø Intra-dialytic and post-dialytic hypercapnia, Ø hypokalemia and hypocalcemia. Dialysate bicarbonate tracks mortality in this patient population, higher dialysate bicarbonate, higher mortality. J Am Soc of Neph 8: , Kidney Int 37: , 1989). Am J Nephrol 14: , J Am Soc Nephrol 20: , MFMER

27 Study Design: DOPPS, an international prospective cohort study N=17,031 patients, thrice-weekly in-center hemodialysis 11 countries ( ) Predictor: Dialysate HCO 3- concentration. Outcomes: All-cause and cause-specific mortality and first hospitalization, using Cox regression to estimate the effects of dialysate bicarbonate concentration, adjusting for potential confounders MFMER slide MFMER

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29 There was a positive association between dialysate HCO 3 - and the incidence of intradialytic hypotension (OR per 4 meq/l higher [HCO 3- ] 1.12 [95% CI, ) only 3% of patients fit the criteria for intradialytic hypotension, limiting statistical power. Dialysate [HCO 3- ] also was associated with interdialytic weight gain (0.09 kg [95% CI, ] increase per 4-mEq/L higher [HCO 3- ]) MFMER

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31 Key results: Conclusions: High [HCO 3- ], especially prolonged exposure, may contribute to adverse outcomes, likely through the development of postdialysis metabolic alkalosis. Additional studies are warranted to identify the optimal dialysate bicarbonate concentration. Hi [HCO 3- ]: Ø Larger interdialytic weight gain Ø More Hypotension during dialysis Ø Higher rate of infection infectious mortality Ø Higher overall mortality K shift likely contribute Metabolic alkalosis --- can exert multiple cellular and tissue effects K-DOQI guidelines: A mid-week serum bicarbonate level of > 22 mmol/l for HD patients. * less than half of HD patients fulfill this minimal serum bicarbonate goal MFMER slide MFMER

32 High dialysate bicarb does not impact pre-hd bicarb N=53 stable HD patients Ø 25 meq/l in 10, Ø 30 meq/l in 30, Ø 35 meq/l in 13 Blood gas from arterial line before and after dialysis in the mid-week Pre-HD arterial HCO 3- : mildly acidotic in all 3 groups, but not different Post-HD arterial HCO3 were alkalotic, more in the group of 35 meq/l Dialysate bicarbonate: 25 to 35 meq/l Make no difference in Pre-HD acidosis. but causes more post-hd alkalemia in higher bicarbonate dialysate. Electrolyte & Blood Pressure 5:95-101, MFMER slide MFMER

33 A 2017 study -- Panesar et al. Measured inter/intra-dialytic changes in serum HCO 3- and degrees of alkalosis N=39 HD, 4 groups Group 1 (N = 9): meq/l Group 2 (N = 5): meq/l Group 3 (N = 10): meq/l Group 4 (N = 15): meq/l Serial (pre-hd & post-hd) s.hco 3 - Pre-HD s.hco 3- (44 h and 68 h after HD) in all four groups were not statistically different. Post-HD s.hco 3- (Immediate and 2 h) sig. increased (alkalosis) in all 4 groups: proportional to dialysate HCO 3 - Therapeutic Apheresis and Dialysis 2017; 21(2) 2016 MFMER

34 High HCO3 dialysate causes large and rapid fluctuations in s. HCO 3 - during the intra/inter-dialytic period, which returns to baseline within 44 to 68 h after dialysis. This refutes the necessity to correct pre-dialysis acidosis with high HCO 3- dialysate since rapid equilibration is likely to occur and unnecessarily exposes patients to large shifts in their acid-base balance MFMER

35 Back to our patient, An 81-y/o man with ESRD on HD x18 mos. He has COPD, CAD, DN, HTN and obesity (BMI 44). He presented with respiratory distress, placed on bipap, and admitted to the micu. PE: BP 150/96, pulse 82, RR 30/min, FIO2 60%, O 2 88%. Lungs: decreased breathing sounds bilaterally. Cardiac: RRR. Abdomen: Soft. Extremities: Positive 1-2+ dependent edema. Labs prior to dialysis: Na 130, K 5.8, Cl 94, HCO 3-18, BUN 38, Cr 6.8. Chest x-ray: + Pulmonary vascular congestion, cardiomegaly and right lower lobe infiltration. Meds: Amlodipine 10 mg, Lipitor 20 mg, steroid inhaler. Question: What would be the best dialysate of choice? 1. 2K, 32 HCO K, 30 HCO K, 28 HCO K, 28 HCO MFMER

36 2016 MFMER

37 egrf>60 ml/min/bsa HR of Mortalityn=55,266, egfr<60 Pre-HD serum K Kidney Int 2011;79: MFMER

38 K handling in CKD Hyperkalemia generally occurs when: high-k diet (oliguria may present) hypoaldosteronism Type IV RTA impaired cellular uptake tissue breakdown (rhabdomyolysis) Medications: ACE inhibitor or ARB (most common) 2016 MFMER

39 Serum [K] in HD patients: Hypo and hyper-kalemia are common in HD patients: --- pre-dialysis hyper- and post dialysis hypokalemia: ( 2 K dialysate). Post-dialysis hypokalemia has been associated with lifethreatening cardiac arrhythmias and sudden cardiac deaths The leading cause of death in the dialysis population: Sudden cardiac deaths 2011 MFMER slide MFMER

40 Dialysis patients with implantable cardioverter defibrillator-2 (ICD-2 trial), N=40 (65% HD, 35% PD), ICD remotely monitor patient rhythm, recorded the exact time of onset of all atrial fibrillation (AF) episodes. 386 AF episodes in 11 HD and 3 PD patients in 28 mos MFMER slide MFMER

41 Case-control study HD patients (n = 43,000), dialysate K of <2 meq/l doubled the risk of sudden cardiac arrest irrespective of pre-dialysis K level Low K bath cardiac arrest Kidney Int 2011;79: MFMER slide MFMER

42 Dialysis Outcomes and Practice Patterns Study (DOPPS) analysis of HD patients 12 different countries (n = 37,765) low K dialysate (1 or K) was independently associated with higher risk of sudden cardiac death and all-cause mortality compared to K ( 3 K meq/l) dialysate 2011 MFMER slide MFMER Clin J Am Soc Nephrol 2012;7:

43 Design: Prospective cohort study. Setting: 55,183 patients from 20 countries in the DOPPS phases 1 to 5 ( ). Predictor: Dialysate potassium concentration at study entry. Outcomes: Cox regression was used to estimate the association between dialysate K and both all-cause mortality and an arrhythmia composite outcome (arrhythmia-related hospitalization or sudden death), adjusting for potential confounders. Am J Kidney Dis. 69(2): MFMER

44 Results: Median follow-up of 16.5 months, 24% of patients died and 7% had an arrhythmia composite outcome. No meaningful difference in clinical outcomes was observed for patients treated with a dialysate K of 3 versus 2 meq/l (adjusted HRs were 0.96 [95% CI, ] for mortality and 0.98 [95% CI, ] for arrhythmia composite). Results were similar across predialysis serum potassium levels. Higher s.k was associated with adverse outcomes. However, dialysate K had only minimal impact on serum K predialysis (0.09 [95% CI, ] meq/l serum potassium per 1 meq/l greater dialysate K). Conclusions: --- These results suggest that approaches other than altering dialysate K (eg, education on dietary potassium sources and prescription of potassium-binding medications) may merit further attention to reduce risks associated with high serum potassium levels. Am J Kidney Dis. 69(2): MFMER

45 For our patient: An 81-y/o man with ESRD on HD x18 mos. He has COPD, CAD, DN, HTN and obesity (BMI 44). He presented with respiratory distress, placed on bipap, and admitted to the micu. PE: BP 150/96, pulse 82, RR 30/min, FIO2 60%, O 2 88%. Lungs: decreased breathing sounds bilaterally. Cardiac: RRR. Abdomen: Soft. Extremities: Positive 1-2+ dependent edema. Labs prior to dialysis: Na 130, K 5.8, Cl 94, HCO 3-18, BUN 38, Cr 6.8. Chest x-ray: + Pulmonary vascular congestion, cardiomegaly and right lower lobe infiltration. Meds: Amlodipine 10 mg, Lipitor 20 mg, steroid inhaler. Question: What would be the best dialysate of choice 1. 2K, 32 HCO K, 30 HCO K, 28 HCO K, 28 HCO MFMER

46 Recommendations Avoid/minimizing pre-dialysis hyperkalemia and post-dialysis hypokalemia. Use 3 K dialysate for patients with pre-dialysis serum K of <5 mmol/l Longer dialysis More frequent Avoid large interdialytic weight gain Pay attention to dialysate calcium and Mg Control of inter-dialytic hyperkalemia with diet and medication (Potential: patiromer and/or K profiling may be explored) Dhondup, Qian. Blood Purif. 2017;43(1-3): MFMER slide MFMER

47 Thank you! 2016 MFMER