Renal Dysfunction in Cirrhosis

Sandeep KhuranaProfessor of Medicine

Medical Director, Liver TransplantationGeisinger Clinic

Importance of Renal Function in Cirrhosis

• Cr and BUN are predictors of death in cirrhosis.

• Serum Cr (SCr) is one of key variables of model of end-stage liver disease (MELD) score—a good predictor of 3-month mortality.

• Pre-transplant SCr is predictor of post-OLT survival .

19%

68% 32%

66%

25% 9%

HEPATOLOGY 48:2064, 2008

HEPATOLOGY 48:2064, 2008

• HRS-1: an abrupt deterioration in renal function that occurs mostly in an inpatient setting and often develops after a precipitating event such as SBP.

• HRS-2: steady or slowly progressive course that occurs (mostly) in an outpatient setting in patients with refractory ascites.

• 1-year and 5-year probabilities of developing HRS in patients with ascites—20% and 40%, respectively.

• Survival of patients with HRS-1 < HRS-2 (median survival 1.0 versus 6.7 months).

• Highest Risk: in patients with marked Na and water retentionand activation of vasoconstrictive systems.

Journal of Hepatology 2015, 968

Proposed New Criteria for HRS

• Prerenal azotemia - UNa≤20 mEq/L- FENa≤1%- urine osmolality (500 mOsm/kg)

• ATN - high UNa (40 mEq/L)- high FENa (2%)- urine osmolality < 350 mOsm/kg

• In patients with HRS- those on a high dose of diuretics, UNa>10 mEq/L.

• In cirrhosis, patients with ATN can have FENa 1%.

Other Characteristics in HRS• Median Child-Pugh score of 11.2• Low MAP • Low serum Na*If these findings are absent, the diagnosis of HRS is unlikely

Goals of Medical Treatment

• Reduce vasodilation.• Increase effective intra-vascular

volume and pressure.• Reduce renal vasoconstriction.

Prevention• Prevent/treat volume depletion or vasodilatation.• Measures include

– careful use of diuretics with close weight and laboratory follow-up.– preventing weight loss of more than 1 kg/day.– avoidance of diarrhea with the use of lactulose by adjusting its

dose to obtain two to three semi-formed bowel movements/day.– use of albumin after large-volume paracentesis (LVP).– administration of albumin in the setting of SBP.– antibiotic prophylaxis for SBP.

Albumin for Non-SBP Bacterial Infections

Journal of Hepatology 57; 759, 2012

Journal of Hepatology 57; 759, 2012

Role of Cardiac Output• 24 patients with alcoholic cirrhosis and ascites without HRS 1.• Nine—refractory ascites and 15—non-refractory ascites. Exclusion

criteria: gastrointestinal bleeding within the wk before the study, SBP, insulin-dependent diabetes, acute or chronic intrinsic renal or cardiovascular diseases, arterial HTN, abnormal ECG, acute medical conditions such as infections or acute heart or lung diseases and pre-existing cardiac or pulmonary diseases.

• Alcohol abstinence for 6 weeks. • All had normal baseline ECG, oxymetry and myocardial perfusion imaging

without signs of ischemia.• Diuretics and beta-blockers were discontinued 3 days before the

investigations. None were receiving any other drugs that could interfere with cardiovascular system or nephrotoxic drugs.

• Na restricted diet of 60 mmol/day for 72 h before the investigations. All were instructed orally and given written information on sodium restriction by a dietician.

• All patients were hospitalized during the last 24 h prior to the study.GUT 59:105, 2010

GUT 59:105, 2010

Cox Multivariate RegressionFactor HR for Death

(95% CI)Child-Pugh C 1.76 (1.09-2.8)HCC 1.94 (1.25-3.02)Beta-blockers 2.61 (1.63-4.19)Renal Impairment 3.27 (1.73-6.17)Hyponatremia 7.07 (3.77-13.25)

Hepatology 52:1017, 2010

β-Blockers or No β-Blockers?

Diagnostic Limitations of SCr• Does not distinguish among various causes of renal injury.

• Lags behind renal injury and is a delayed marker of decreased renal function.

• Can be normal or only minimally elevated despite significant renal disease because of renal reserve.

• Is influenced by non-renal factors such as body weight, age, sex, total body volume, drugs, muscle metabolism, and protein intake.

• Is a poor reflection of kidney function because of reduced muscle mass, particularly in patients with severe liver disease. The patients may have a normal SCr in the setting of a very low GFR.

BIOMARKERS OF RENAL INJURY

Neutrophil Gelatinase-Associated Lipocalin

Journal of Hepatology 57;267, 2012

Patients (n) No Ascites Ascites Ascites + Renal Impairment

All (187) 103 (78-135) 139 (90-192)* 249 (170-352)***Non-Infected (129) 94 (78-115) 130 (89-175)* 212 (166-326)***

Factor Functional ARF(N=64) ATN (N=30)SCr 3.56 ± 1.22 4.47 ± 2.22UNa (mEQ/L) 21.1 ± 20.4 63.9 ± 26.1***UCr (mg%) 132 ± 59 72 ± 34***Uosm (mosm/kg) 422 ± 106 344 ± 43***Urine output 899 ± 770 468 ± 531*FeNa% 0.36 ± 0.25 3.33 ± 2.77***Ur IL-18 (pg/mg Cr) 332 (151-511.5) 2195 (892.5-3280)***S IL-18 (pg/mg Cr) 871 (492-1442) 1193 (725.5-2420)*Hospital Mortality 45/64 (70.3%) 27/30 (90.0%)*

Journal of Gastroenterology and Hepatology, 2012

Urinary IL-18

Journal of Gastroenterology and Hepatology, 2012

VASOCONSTRICTORS

HEPATOLOGY 51: 576,2010

Favors Treatment

FavorsTreatment

Role of Albumin• Potentiates vasoconstrictors.• Diagnostic use: 1g/kg/day for at least 2 days.• Therapeutic use: 25-50 g/day.

Albumin Dialysis

GUT 59:381, 2010

ROLE OF TIPS

J Vasc Interv Radiol 21:1370, 2010

J Vasc Interv Radiol 21:1370, 2010

Treatment Endpoints

• Treatment can be discontinued – if there is no reduction in SCr after the first 3 days.– if SCr does not decrease by at least 50% within 14 days at

the highest dose.

• In patients with early response, treatment should be continued– until reversal of HRS (decrease in SCr below 1.5 mg/dL).– or for a maximum of 14 days.

• Therapy should be restarted if HRS recurs.• Once SCr normalizes, should TIPS be considered?

PREVENTION

European Journal of Gastroenterology & Hepatology 23;210, 2011

SIMULTANEOUS LIVER-KIDNEY TRANSPLANTATION

• Orthotopic Liver transplantation (OLT) is the only definitive therapy for HRS- associated with improvement in survival.

• Rationale to reverse HRS: Improving renal function pretransplantation is associated with improved post-transplantation outcomes.

-Patients with HRS who undergo OLT have more complications and a higher in-hospital mortality.

-Outcome of OLT in patients with HRS treated with vasopressin analogs before transplantation is similar to that of patients undergoing transplantation without HRS.

Liver Transplantation 18:1237, 2012

• Concerns:-Some patients who undergo SLKT may have reversible renal failure.-Liver transplant may be premature in those with end-stage renal disease.

• Consensus Conference (2007) recommended that SLKT should be approved for • Cirrhotic patients with symptomatic portal hypertension and end-stage renal

disease.• Liver failure and CKD with glomerular filtration rate (GFR) 30 mL/min or less,

acute kidney injury or HRS with SCr level 2.0 mg/dL or higher and dialysis 8 weeks or more.

• Liver failure and CKD and biopsy demonstrating greater than 30% glomerulosclerosis or 30% fibrosis.

• Between 2/2002 and 12/2008, 4275 cirrhotic patients with renal failure underwent OLT.

• LTA was performed in 2774 and SLKT in 1501 patients.

• HRS (n=369), known cause other than HRS (n= 839), and unknown cause (n= 293).

• Renal failure was defined as SCr ≥ 2.5 mg/dL at the time of OLT or dialysis at least twice/wk before OLT.

Transplantation 94; 411, 2012

Transplantation 94; 411, 2012

Transplantation 94; 411, 2012

OPTN GUIDELINES FOR SLKT

Clin J Am Soc Nephrol 12: 848–852, 2017

Summary and Conclusions• Renal dysfunction reduces survival in both pre- and post-

OLT patients.• Early action is required

– Treatment of infections, hypovolemia.• Watchful of patients with ascites and hyponatremia.• Cautious use of β-blockers.• Early TIPS?• Biomarkers-not promising.• SLKT-awaiting future trends.• LDLT is equivalent to DDLT for HRS.