Hepatorenal syndrome

1. Hepatorenal syndrome Terminal Functional Renal Failure

2. First described in 1961 • Liver disease with ascites • Oliguric failure • Absence of histopathologic changes • Terminal Functional Renal Failure

3. Frerichs (1861) • The renal secretion usually dimishes in quantity; the urine becomes scanty, and red or brown-coloured, and often deposits a sediment of a red or bluish-red hue; in rare cases it is pale and ammoniacal. When the cirrhosis is accompanied by jaundice, the urine is more or less deeply tinged with bile-pigment. In not a few cases, it is albuminous, owing to the disease of the liver being complicated with degeneration of the kidneys. I have observed this eight times in 36 cases.

4. Frerichs (1861) • Sometimes the secretion of urine in cirrhosis is reduced to a very small quantity, especially when, after the performance of paracentesis, the ascitic fluid continues to flow off freely; in one case, six ounces only were passed in 24 hours. (See cases subsequently detailed.) We might have expected to have found the destruction of the hepatic parenchyma, accompanied by alterations in the quality as well as in quantity of urine, but I have not succeeded in detecting any peculiar products in the secretion. Leucine has been repeatedly sought for, but I have nevere succeeded in discovering it.

5. Flint (AJMS 45: 306-339, 1963) • The existence of a relation of causation between the two affections, and, if such a relation exists, the question whether the affection of the kidneys proceeds from dsease of the liver, or vice versa, are to be determined by ascertaining in a sufficiently large collection of cases which of the affections occurs prior to the other. The facts noted with respect to the autopsies in the fatal cases now under consideration, are insufficient to shed light on theses points. The same questions, however, will occur in connection with the histories of the non-fatal cases, inasmuch as the presence of albumen in the urine may be considered as a pretty uniform criterion of the existence of disease of the kidneys.

6. Flint • It is worthy of remark that in none of the cases in which disease of the kidneys coexisted, were these organs contracted, a fact which renders the absence of albumen in the urine more reliable as evidence, in cases of hydro-peritoneum, that the kidneys are not diseased, since it is chiefly in cases of contracted kidneys that we meet with the exceptional instances in which albuminuria is wanting.

7. Overview • Definitions • Diagnosis & Prognosis • Pathophysiology • Precipitating factors • Treatments • HRS and liver transplantation

8. Definition • Terminal functional renal failure • Associated with cirrhosis with ascites • Impairment is reversed only with a functional liver.

9. Official Definitions • First diagnostic criteria – 1978. Consensus conference in Sassari, Italy • Major Criteria • Renal insufficiency without an identifiable cause • Severe liver disease • Urine tubular function intact • No sustained improvement with volume expansion

10. Official Definitions • Minor Criteria • Oliguric • Little proteinuria • May be precipitated by infection or volume loss • May be follow-up by ATN

11. International Ascites Club • Founded in Florence, Italy in 1990 • Seven member board, elected to 4 year terms • Meet bi-annually • 214 members • Purpose: To define the terminology surrounding ascites and its complications. • Now the International Club of Ascites

12. International Ascites Club • Hepatorenal syndrome was addressed in 1996 • Major Criteria • Renal insufficiency • Severe liver disease (with portal hypertension) • No sustained improvement with volume expansion • Absence of shock, active infection or nephrotoxins • No other identifiable cause of renal dysfunction • Proteinuria <500 mg/dL • All must be present to make the diagnosis

13. International Ascites Club • Minor Criteria • Urine volume <500 mL/d • Tubular function intact • Urine sodium <10 mEq/L • Urine osmol > serum osmol • Urine RBC <50 per high power field • Serum sodium <130 mEq/L • Not required, but support the diagnosis

14. Subtypes of HRS • Type 1 HRS – rapidly progressive • Doubling of serum creatinine in < 2 weeks • Creatinine > 2.5 • GFR < 20 • Often associated with an acute precipitating event • Type 2 HRS – slowly progressive • Creatinine >1.5 • Typically spontaneous

15. Epidemiology • Once diagnosed with cirrhosis • 18% one year risk • 39% five year risk • Type 1 represents 75% of cases of HRS

16. Prognosis • Type 1 • Untreated mortality • 80% at 2 weeks • 90% at 3 months • MELD score independent • Type 2 • Untreated mortality • 50% at 6 months • MELD score dependent • MELD <20 – 50% survival at 8 months • MELD >20 – 50% survival at 1 month

17. Overview of Pathophysiology Activation of renal SNS Impaired Renal Perfusion Baroreceptor Activation Peripheral Vasodilation Cytokines and vasoactive mediators

18. Pathophysiology - Vasodilation • Literature invariably describes the peripheral vascular changes leading to the hemodynamic changes as: • “Vasodilation” • This is more accurately described as decreased vascular resistance

19. Systemic vascular resistance • R = 8L / r4 (L = length of tube,  = fluid viscosity, r is the radius of the tube) • Flow (Q) = pressure difference across the vascular bed (P) / resistance across the bed (R) • Cardiac output = stroke volume  heart rate

20. Systemic vascular resistance • P = SVR  cardiac output • P = (MAP – CVP) • (MAP – CVP) = SVR  cardiac output • MAP  (average vessel radius  cardiac output)

21. SVR - What are the active variables • Radius of the blood vessels • “Vasodilation” • Cardiac function • Stroke volume (pre-load + contractility) • Heart rate • Because the vasculature is not a single tube, SVR is not simply a function of the average radius

22. Variables of resistance • Parallel circuitry introduces another variable • Our equation for resistance is for a single tube • R = 8L / r4 (L = length of tube,  = fluid viscosity, r is the radius of the tube) • We must consider how multiple resistors acting in parallel affect the net systemic resistance

23. Resistors in series • Resistors in series • Simply sum the resistances of each of the individual resistors.

24. Parallel Resistors

25. Parallel Resistors • Every time you add an additional route for flow, you reduce the net resistance.

26. The Human Resistance • We are made up of parallel circuits within parallel circuits, within parallel circuits

27. EXAMPLE • Every branch off the aorta forms a parallel circuit that reconnects to the vena cava • Each branch then sub-divides to feed individual organs • E.g., the celiac goes to stomach, pancreas, liver, duodenum. • Branches to an organ then subdivide into segmental arteries.

28. BRAIN BOWELS LIVER KIDNEYS MUSCLES SKIN

29. Equation for resistance 1 1 1 1 1 1 1 _____ _______ ________ ______ _______ ________ ______ = + + + + + Rtotal Rbrain Rbowels Rliver Rkidneys Rmuscles Rskin

30. Splanchnic resistance • Assume each capillary bed in the splanchnic circulation carries the same transcapillary resistance (R1 = R2 = … = Rn) 1 1 1 1  =  +  + . . . +  Rtotal R1 R2 Rn n  ( ) 1 1  =  Rtotal R1 Rtotal = R1 n

31. Change in splanchnic resistance • Hepatorenal syndrome is, in part, characterized by low splanchnic resistance • The literature describes this as vasodilation • May equally reflect increased capillary bed recruitment or addition of alternative low-resistant circuits

32. What are the active variables • Radius of the blood vessels • The intrinsic resistance of each capillary bed • Number of capillary beds recruited • Cardiac function • Stroke volume (pre-load and contractility) • Heart rate

34. What is changing the SVR • Decreased globally or regionally? • Given the parallel circuitry of the vasculature it is possible to have • Regional vasodilation • Compensatory regional vasoconstriction • Net decrease in overall SVR

35. What is changing the SVR • Specifically • Severe splanchnic vasodilation • Extrasplanchnic vasoconstriction • Net drop in SVR with compensatory • Increase in cardiac output • Hypotension once heart unable to compensate

36. Iwao et al. • Compared Child-Pugh grades and controls • SMA blood flow • SMA pulsatile index • FA blood flow • FA pulsatile index

37. Results • Cirrhosis (Grade A) compared to controls had: • Equivalent MAP • Increased cardiac output • Decrease total systemic vascular resistance • Increased SMA blood flow • Decreased SMA pulsatility (reflects vascular tone) • Slightly increased FA blood flow • Slightly decreased FA pulsatility

38. Controls Grade 1 Grade 2 Grade 3 -  -   - -  -  -   -   - -   - Cardiac output SVR Pulse Blood flow Pulsatility Blood flow Pulsatility

39. SVR and cirrhosis • Early and compensated cirrhosis without ascites • Global decrease in SVR (approximately 13%) • Extrasplanchnic • Splanchnic • Increased cardiac output is compensatory • Blood pressure stable • Renal perfusion normal

40. Global causes of decreased SVR • Structural • AVM, telangiectasias • Act as additional and low-resistance pathways for blood • Neurohormonal • Increased activity of nitric oxide synthase • Decreased vascular tone

41. Cardiac Dysfunction? • Torregrosa • Tried to show systolic and diastolic dysfunction in cirrhosis • Did not account for baseline hyperdynamic state • Did not report all their data • Made claims of difference despite lack of statistical significance • Maximal exercise showed identical heart rate, ejection fraction, and cardiac output between all groups

42. Cardiac dysfunction? • If there is any, it’s probably not significant intrinsic cardiac disease.

43. Nitric Oxide • Implicated as a mediator of vasodilation in advanced cirrhosis • Splanchnic • Extrasplanchnic • Nitric oxide and NOS are up-regulated in decompensated cirrhosis

44. Nitric Oxide Synthase (NOS) • Three isoforms • Neuronal (nNOS) = NOS1 • Inducible (iNOS) = NOS2 • Endothelia (eNOS) = NOS3 • Convert arginine to nitric oxide • Regulation??? • Everything and their dogs have been implicated in NOS regulation • Phosphorylation, intracellular Ca, NF-B, etc.

45. NOS Regulation • NOS activation and inhibition controls vascular tone • Increased activity mediates vasodilation • Decreased activity mediates vasoconstriction • Although mechanistically the literature is a mess, the autonomic nervous system ultimately controls activity.

46. NOS Activity Vasocontricting Signals Local controlling signals NOS Activity Vasodilating Signal

47. Nitric Oxide • Nitric oxide is increased in cirrhosis • Further increased following development of ascites • Nitirc oxide synthase is up-regulated in cirrhosis • Further increased following development of ascites • In cirrhosis, NO causes vascular hypo-responsivity to vasconstrictors • Reversed with treatment using NOS inhibitors

48. Splanchnic circulation NOS Activity Cirrhosis Sympathetic Activation Increased Nitric Oxide Splanchnic Vasodilation

49. “That is the sound of inevitability, Mr. Anderson” Agent Smith, The Matrix Revolutions

50. Splanchnic vasodilatation with decreased SVR Decreased effective circulatory volume Sympathetic Activation RAAS Activation Sodium and volume retention With worsening hypotension, SVR, and effective volume Compensatory maximal vasoconstriction in vascular beds responsive to sympathetic activation