Heart and Kidney, for better or for worse

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1 Heart and Kidney, for better or for worse P. van Paassen, MD, PhD Dept. Nephrology and Clinical Immunology Maastricht UMC+ Hartfalen dag Zeist,

2 Disclosure potential conflicts of interest Geen (potentiële) belangenverstrengeling Voor bijeenkomst mogelijk relevante relaties: Sponsoring of onderzoeksgeld Honorarium of andere (financiële) vergoeding geen geen Aandeelhouder geen Bedrijfsnamen Andere relatie, namelijk geen

3 Ronco et al. J Am Coll Cardiol 2008

4 a double edged sword Naranjo et al. Dis Mon 2017

5 GFR measurements renal function endogenous, creatinine exo creatinine clearance [CrCl] MDRD CKD EPI Inulin/DTPA/iothalamate CrCl = U Cr V P Cr U-prot S-albumin/urea/Na/K Ca/P/PTH Tot CO2 Hemoglobin/EPO

6 over and underestimation of renal function * Cystatin C may be a better marker of renal function Webster et al. Lancet 2017

7 normal decline in egfr CKD N egfr t=0 follow up, yr. decline/yr. Levey et al. J Am Soc Nephrol, , 2, [8.7] [7.6] 4, [4.5] 4.3 [4.7] Eriksen et al. Kidney Int, [ ] Levin et al. Am J Kidney Dis, , 4, *rapid decline per year if egfr 5 ml/min/1.73m 2

8 CKD and cardiovascular disease [1] Go et al. N Engl J Med 2004

9 coronary artery calcification among patients with CKD Chen et al. JAMA Cardiol 2017

10 risk of CVD depends on calcification among patients with CKD adjusted for CKD, Hb A1c, P, FGF23, etc. Chen et al. JAMA Cardiol 2017

11 pathophysiology of the cardiorenal syndrome type 2 heart failure induced kidney damage

12 the normal cardiorenal axis low cardiac output [CO] genetics environment compensated kidney modified from Ronco et al. J Am Coll Cardiol 2008

13 Kidney compensation HF: a syndrome of renal sodium and water retention

14 Cardio-renal interactions in volume expansion and congestion in chronic heart failure. Wayne L. Miller Circ Heart Fail. 2016;9:e002922

15 Paradigm of interstitial and intravascular volume expansion in chronic heart failure. Wayne L. Miller Circ Heart Fail. 2016;9:e002922

16 stable glomerular filtration rate [GFR] normal GFR during the first weeks, [1] LAD coronary artery ligation reserve capacity; male [2] [1] Lekawanvijit et al. Am J Physiol Heart Circ Physiol 2012 [2] Levey et al. Ann Int Med 1999

17 renal autoregulation; constant over MAP mmhg vascular smooth muscle cells and tubuloglomerular feedback blood flow capillary pressure arteriolar resistance Pollak et al. Clin J Am Soc Nephrol 2014

18 Structure of the renal corpuscle, looking into the Bowman s capsule at glomerular capillary tuft. 2.10*6 nephrons Martin R. Pollak et al. CJASN 2014;9: by American Society of Nephrology

19 major determinants of [glomerular] ultrafiltration RAS, SNS Kf, ultrafiltration coefficient P, hydraulic pressure NPs IVP low CO π A, oncotic pressure Q A, plasmaflow SNGFR, single nephron GFR Pollak et al. Clin J Am Soc Nephrol 2014

20 macula densa water solutes Peritubular capillaries Countercurrent Osmolar gradient medulla NaCL content determines secretion of adenosine by MD as marker of GFR, leading tot constriction of v afferent=tgf

21 RAS in response to decreased renal perfusion low Na, low Cl renin increased GFR, single nephron AT II SNS intraglomerular pressure RAS efferent arteriole FF=GFR/ERPF

22 expanding intravascular fluid due to sodium retention 65% 10% water solutes Na, % 20% AT II 5% ALDO

23 hyperfiltration; the other side of the medal? glomerular hyperfiltration and cardiovascular events in 8749 participants HR 1.6 [95% CI, ] 5 th percentile 95 th percentile CVE defined as infarction, heart failure, revascularisation, sudden cardiac death Reboldi et al. Kidney Int 2017

24 type 2, chronic cardiorenal syndrome chronic hypoperfusion increased renal vasc. resistance renal congestion anemia, hypoxia RAS[!], SNS[!] Na, water retention Ca, P hypertension sclerosis and fibrosis modified from Ronco et al. J Am Coll Cardiol 2008

25 [acute] subtle renal inflammation after LAD coronary artery ligation; ischemia KIM 1 * also, increased macrophage infiltration and IL 6 mrna * kidney injury molecule 1 Lekawanvijit et al. Am J Physiol Heart Circ Physiol 2012

26 interstitial fibrosis can be found after 4 16 wks picrosirius red 1 wk Lekawanvijit et al. Am J Physiol Heart Circ Physiol 2012

27 AT II causes epithelial mesenchymal differentiation/fibrosis AT II stimulates renal Smads phosphorylation and the TGFβ axis Smad2 HK2 cobblestone spindle-shaped, fibroblast like Carvajal et al. Kidney Int 2008

IFTA is common among patients with end-stage HF male/female 13/1 HF, ischemic HF, non-ischemic HF, amyloidosis 8 5

28 IFTA is common among patients with end-stage HF male/female 13/1 HF, ischemic HF, non-ischemic HF, amyloidosis egfr, ml/min uprot, gm/d <0.5 IFTA <30% 30-60% >60% PAS Golestaneh et al. J Heart Lung Transplant 2014

29 but, it s not only a forward problem inverse association between egfr and CVP >5 mmhg adjusted for age, sex, cardiac index r = , P < Damman et al. J Am Coll Cardiol 2009

30 HF a state of renal sodium and volume retention Osmoregulation (Pna, AVP) Volumeregulation (ANGII/Aldo) However far more complicated in HF: Both hypo-na and hyper-na are serious risk factors.

31 HF and hypo-na: RAAS-activity increases despite volume overload AVP increases SNS increases Clearance free-water impaired

32 HF and hyper-na Elderly, frail Diet, Thirst Loop diuretics

33 treatment of heart failure and it s renal consequences

34 65% 10% water solutes Na, % 20% 5% all diuretics but spironolactone work in the lumen

35 commonly prescribed diuretics ter Maaten et al. Nat Rev Cardiol 2015

36 >30% of HF have [loop ] diuretic resistance the so-called braking phenomenon u[na] AT II, aldosterone furosemide, bumetanide measure u[na], u[k]

37 Braking phenomenon Dose more frequently, or add thiazides

38 how to manage [loop ] diuretic resistance? IV administration bumetanide[!] also binds to globulins HCT[!] K + sparing agents ter Maaten et al. Nat Rev Cardiol 2015

39 Pharmacology (loop-)diuretics Equipotent dosing Switch classes in case no effect probably useless (dosing!)

40 Pharmacology (loop-)diuretics NB spironolacton: actieve metabolieten T ½ ca. 1½ uur (spironolacton), 9 12 uur (7α thiomethylspironolacton), uur (canrenon)

41 (loop-)diuretics Effect bumetanide h Effect furosemide 4-5 h Remaining time is rebound = no net negative effect on Na loss Particularly in case : - Diuretic response low (Urine Na 24 /K) - Medication free interval long - Salt intake

42 (loop-)diuretics Synchronize intake and drug dosing - loop diuretic before meals Slow release less effective?

43 (loop-)diuretics - therapy GFR 15 ml/min: Only 10-20% furosemide in tubule: so increase dose IV to oral: bumetanide identical furosemide 1-10 times (x ceiling dosis mg iv) Dosing based on effect!

44 (loop-)diuretics - therapy Normal response on 40 mg furosemide (of equivalent bumetanide): mmol Natrium & 3-4 L urine in 3-4 h. Max. response 20-25% filtered Natrium In case GFR 15 ml/min, then 25 mmol Natrium per dose. So restrict salt intake Add thiazide

45 Loop-diuretics combi thiazides Mild KI: mg/day Severe KI: mg/day Loading dose? ( T½) Once a day (T½) Severe KI: more and more often (NYHA II-III 3-4x)

46 (loop-)diuretics intravenous

47 Diuretics - more? (thiazides) Predictive: Urine low Na- High K: distal reabsorption Natrium::> so #### Urine low Na-low K: less effect Add amiloride in stead of triamterene (conversion lower in congested liver), even in addition to spironolacton/eplerenone

48 What about kidney function? Deterioration often acute and hemodynamically, not structural Renal autoregulation Treat blood pressure Treat heart failure and accept kidney function (to certain extent)

49 the protective effects of RAS blockade improved survival [CONSENSUS, SOLVD] anti fibrotic effects [1] improved pressure natriuresis [2] [1] [2] van Paassen et al. J Am Soc Nephrol 2001

50 what about dual blockade? lessons from the ONTARGET ONgoing Telmisartan Alone and combined with Ramipril Global Endpoint Trial cardiovascular death ARB and ACEi combined additional 2 3 mmhg BP reduction less proteinuria [S]AEs, increased prevalence acute kidney injury/ doubling SCr hyperkalemia Yusuf et al. N Engl J Med 2008

51 AKI in the setting of RAS blockade dehydration elderly, atherosclerosis, NSAIDs diarrhea, fever check for SCr, K Scherpbier et al. Ned Tijdrschr Geneeskd 2010

52 hyperkalemia among HF patients; particularly when SCr >150 mm Palmer et al. N Engl J Med 2004

53 Role of renal replacement therapy? UF? CAPD? Data still unclear

54 PD in CHF Rationale: End-stage congestive heart failure is a serious invalidating condition with a poor prognosis and increasing incidence. Non-randomized observations showed peritoneal dialysis in these patients to improve clinically from NYHA stadium III-IV to as low as NYHA stadium I-II. A randomized trial is needed to test whether PD improves symptoms in this condition and to find an optimal scheme. Groningen trial still running, WMT Janssen (Martini hospital)

55 Conclusion Cardio-renal failure is a fascinating clinical challenge There is problably no such thing as a normal kidney or a normal heart in this perspective, when checking meticulously organ function and structure. It is a systemic disease. Even closer cooperation between cardiology and nephrology (and immunology) is warranted

56 Conclusion Treatment needs to be guided by deep understanding of underlying (patho)- physiological mechanisms in order to better maintain volume status, organ perfusion, and inhibit ongoing inflammation and fibrosis

The Cardiorenal Syndrome in Heart Failure

The Cardiorenal Syndrome in Heart Failure Van N Selby, MD Assistant Professor of Medicine Advanced Heart Failure Program, UCSF October 9, 2015 Disclosures None 1 Cardiorenal Syndrome (CRS) A pathophysiologic