Screening, Diagnosis, and Assessment of Disease in CKD PatientsKDIGO with HCV

Tawesak Tanwandee, MD. Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok DISCLOSURES

• Grant/research support

• Merck, Roche, Arbutus, Janssen, Exact Science

• No disclosure relevantKDIGO to this talk TOPICS

• HCV problem in CKD

• Impact of advanced CKD on liver markers (ALT, AST)

• Non-invasive measures KDIGO (biochemical and elastography) vs biopsies

• Relevant KDIGO guideline recommendation statements Prevalence of HCV in dialysis and kidney transplantation Anti HCV positive after renal transplantation

Authors Reference Country Patients, n Anti-HCV year positive, n

Pereira B., et al. (study 1) 1997 USA 103 21 (22.8%) Country Anti-HCV Anti-HCV- Reference Pereira B., et al. (study 2) 1997 USA 103 23 (22.3%) Prevalence Positive (%) Patients (n) Legendre C., et al. 1998 France 499 112 (22.4%) Batty D., et al. 2001 USA 28 692 1624 (5.7%) Belgium 11.8 51/433 Jadoul et al. Breitenfeldt. M., et al. 2002 Germany 927 160 (17.2%) Netherlands 3.4 76/2286 Schneeberger Forman J., et al. 2004 USA 354 26 (7.3%) et al. Mahmond I.,et al. 2004 Egypt 133 80 (60.1%) Italy 22.5 2274/10097 Lombardi et al. Bruchfeld A., et al. 2004 Sweden 571 51 (8.9%) Aroldl A., et al. 2005 Italy 541 244 (45.1%) USA 22.3 88/394 Fabrizi et al. KDIGO Mitwalli A., et al. 2006 Saudi Arabia 448 286 (63.8%) France 16.3 216/1323 Salama et al. Einollahi B., et al. 2007 Iran 3028 NA Ingsathit A., et al 2007 Thailand 346 22 (3.6%) 0.85% % in the general population Luan F., et al. 2008 USA 79 337 3708 (4.7%) Gentil M., et al. 2009 Spain 3861 232 (6.7%)

Ridruejo E., et al 2010 Argentina 542 180 (33.2%) Poordad F et al. Semin Liver Dis 2004 Morales J., et al. 2010 Spain 4304 587 (13.6 %)

Scott D., et al. 2010 Australia, NZ 7572 140 (1.8%)

Singh N., et al. 2012 USA 2169 154 (7.1%) Fabrizi F et al. J Viral Hepat 2014 HCV infection is more frequent in patients with CKD but the prevalence is decreasing Number of incident virus (HCV) infections from outbreaks in the United States dialysis facilities reported to the Centers for Disease Control and Prevention, 2008-2017

35

30

25 20 KDIGO 15

10

5

0 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

Year Nguyen DB. et al. Seminar in Dialysis 2019 Prevalence of anti-HCV positive in advanced CKD not requiring dialysis

Authors Prevalence rate Year Country Fabrizi et al 44/221(20%) 1994 Italy Lopez-Alcorocho et al 6/35(17%) 2001 Spain Bergman et al 57/396(14.4%) 2005 USA De Los Rios et al 1/99(1%) 2006 Peru Sit et al 12/171(7%) KDIGO 2007 Turkey Lemos et al 41/1041(3.9%) 2008 Brazil Hammad et al 20/66(30.3%) 2009 Egypt Li Cavoli et al 24/320(7.5%) 2011 Italy Shafi et al 49/180(27.2%) 2017 Pakistan

Fabrizi et. al. Seminars in Dialysis 2019

Prevalence (%) of having anti-HCV antibodies amongst patients receiving PD (white bars) or HD (black bars) across different Asia-Pacific countries

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Johnson DW. et al. Nephrol Dial Transplant 2009 Annual incidence of anti-HCV antibody amongst patients receiving PD (white bars) or HD (black bars) across different Asia-Pacific countries

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Johnson DW. et al. Nephrol Dial Transplant 2009 Global estimates of HCV infection in HIV-infected individuals by global burden of disease region

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Platt L. et al. Lancet Infect Dis 2016 More fibrosis progression in coinfected patients

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Naggie S, Sulkowski MS. Gastroenterology 2012 Prevalence of in HIV-infected patients

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Castellares C. Journal of , 2008 Detection and evaluation of HCV in CKD

Anti-HCV Positive Negative

HCV Ag? NAT Monthly ALT

Positive Negative HBsAg Anti-HBs KDIGO Anti-HCV q 6 Current infection Resolved or low viremic months

Liver test and evaluation Monthly ALT for treatment

NAT q 6 months

Modified from KDIGO guideline 2018 Comparison between HCVcAg and PCR HCV-RNA test in dialysis patients

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Cavoli GL. Hepatitis Research and Treatment 2012 Impact of advanced CKD on liver markersKDIGO (ALT, AST)

AST levels were significantly lower in both Group A (18.48 ± 4.14) and Group B (10.08 ± 3.49) as compared to controls in Group C (30.5 ± 10.75), (P < 0.001).

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Ray L. Int J Appl Basic Med Res 2015 Impact of CKD on liver markers AST and ALT levels in Age-Matched Study and healthy groups

Concentrations of AST/ALT in both chronic dialysis and chronic kidney disease patients most commonly fall within the lower end of the range of normal values

Exact cause is unknown -Related to pyridoxine deficiency KDIGO (pyridoxal phosphate is a necessary coenzyme for ALT and AST) -Presence of an inhibitory substance in the uremic milieu which improves after dialysis 25-40% of HCV in CKD with normal AST/ALT have advanced liver fibrosis (Marcellin P. J Hepatol 1999)

Fabrizi F et al. Am J of kidney diseases, 2001 : 1009-1015 Liver Fibrosis Assessment Non-invasive tests vs

• Liver biopsy is goal standard, especially to assess liver status before KT • Safe but considered invasive • Risk of bleeding (platelet dysfunction, recurrent anticoagulant) • Sampling error, intra-, inter-observer variability of histological reading KDIGO • Non-invasive tests have become available and validated in CKD • Liver biopsy only reserved for those with discordance result Liver biopsy

Liver biopsy is the current gold standard for the evaluation of hepatic fibrosis but has several limitations:

ü followed by complications requiring hospitalization in 1-3% patients • 20-30% pain • 0.3% morbidity (hemorrhages) • 0.03% mortality

è poor acceptance from both patients and prescribing physicians KDIGO

ü lacks reproducibility and accuracy • liver sample represents only 1/50,000 of the total liver • 10-20% of inter and intra observer variability to assess fibrosis

è 24% false negatives for the detection of cirrhosis Biomarker Groups Example of Individual Components Example of Panel Biomarkers

Direct

Collagen and HA,MMP 1 ELF, Fibrospect extracellular matrix MMP 8, PIII NP HA score, Hepascore components Laminin Leroy score Hepatic stellate cell and TIMP 1, TGF b ELF fibrogenic Angiotensin II, YKL 40 Fibrospect cell mediators Indirect

Portal hypertension Platelet count Fibrometer, Fibroindex Spleen size FIB-4, Pohl index Testa index, Wai score Synthetic parameters Albumin KDIGO PGAA index Platelet count Fibrometer Liver enzymes AST, ALT APRI, BAAT score and AST/ALT ratio Fibrometer, Fibroindex GGT, Bilirubin Fibrotest, Forns Hepascore, HA score NAFLD simple index Pohl index, Wai score Miscellaneous Cholesterol NAFLD simple index Insulin resistance BAAT score Forns ROC curves of APRI* in predicting HD patients with CHC presenting significant hepatic fibrosis ( >F2)

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*AST-to-platelet ratio index(AST/ULN)/Platelet x 100 Liu CH. Kidney Int 2010 APRI is more accurate than FIB-4

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APRI (AUROC=0.97) FIB-4 (AUROC=0.74)

FIB-4, Age (year) x AST/platelet x √ALT Wadhva RK. J Transl Int Med 2018 Fibrotest

Logistic regression equation of 6 parameters

• Alpha-2-macroglobulin • • apolipoproteinKDIGO A1 • GGT • total bilirubin • ALT Various tests and thresholds to evaluate liver fibrosis

Test Cut-off Interpretation APRIa <0.4 No fibrosis to mild fibrosis (F0-F2) >0.95 Advanced fibrosis (F3-F4) FIB-4a <1.45 No fibrosis to mild fibrosis (F0-F2) >3.25 Advanced fibrosis (F3-F4) Fibrotest/Fibrosure 0-0.58 No fibrosis to mild fibrosis (F0-F2) 0.59-1 KDIGO Advanced fibrosis (F3-F4)

HVPG 6-10 mmHg Compensated cirrhosis >12 mmHg Decompensated cirrhosis with significant PHT

aAPRI, AST-to-platelet ratio index (AST/ULN)/Platelet x 100) aFIB-4, Age (year) x AST/platelet x √ALT

Adapted from Cottone C. Seminars in Dialysis 2019 APRI vs Transient Elastography (TE)

ROC curves of Fibroscan® and APRI ≥F2, TE (0.96, 95% CI: 0.94 to 0.98) and APRI (0.84, 95% CI: 0.79 to 0.88; P < 0.001 ≥F3, TE (0.98, 95% CI: 0.97 to 1.00) and APRI (0.93, 95% CI: 0.90 to 0.97; P = 0.04) F4, AUCKDIGO of TE (0.99, 95% CI: 0.98 to 1.00) and APRI (0.92, 95% CI: 0.89 to 0.96; P = 0.13

Liu CH. Clin J Am Soc Nephrol 2011. Transient elastography and histologic correlation

KDIGO TE score (kPa METAVIR Stage Histological finding <7 F0-1 No fibrosis, periportal fibrosis without septa 7.1-9.5 F2 Portal fibrosis with septa 9.6-12.4 F3 Bridging fibrosis >12.5 F4 Cirrhosis

Adapted from Cottone C. Seminars in Dialysis 2019 Transient elastography

• Most reliable non-invasive test • Limitation • Level increases • After meal (return to baseline 120 min. after meal)$ • Elevated central venous pressure (CHF, hypervolemia) • Significant reductionKDIGO if done after net ultrafiltration >2.5 L post HD* • Difficult to perform in PD (fluid left in abdominal space may prevent propagation of shear wave)

$ Palazzo H et. Al. Inter J Hepatol 2015 * Taneja S. et. al. Dig Dis Sci 2017; Khunpakdee N et. al. Blood Purif 2015

Magnetic Resonance Elastography (MRE)

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• MRE has high accuracy for diagnosis of significant or advanced fibrosis and cirrhosis, independent of BMI and etiology of CLD

Singh S et al. Clin Gastroenterol Hepatol. 2015 Elastography Techniques Limitations

Technique Confounders Quality criteria Failure Units Range inflammation Obesity Other Well defined IQR/ TE ** **XL Steatosis? 3-27% kPa 2-75 M<30% SimilarKDIGO to pSWE/ARFI +? +? Not well defined 2% m/sec 0.5-4.4 TE? Similar to 2D SWE +? +? Not well defined 13% kPa 2-150 TE? MRE + - Iron Not well defined 0-2% kPa 2-12 Applicability of non-invasive tests

= reliability+ failure rate Fibrotest TE

90% KDIGO 80%

N=342,346 N=13,669 Poynard T, et al BMC Gastroenterol 2011 Castera L, et al Hepatol 2010 Evaluation of patients with CKD and HCV

Viremic HCV in CKD

Non-invasive evaluation of liver fibrosis

Non-conclusive/discordant KDIGO Advanced fibrosis (F3-F4)

Liver biopsy Assessment of PHT Endoscopy, non-invasive radiological or HVPG

Modified from KDIGO guideline 2018 Other testing of patients with HCV infection

• All patients with CKD at the time of HCV diagnosis • Urinalysis, eGFR • If no evidence of kidney disease, repeat screening for kidney disease if NAT still positive • All CKD with history KDIGO of HCV (NAT+ or -) • Follow-up for progression of kidney disease • Vaccination against HAV and HBV • Screening for HIV • Evaluation of portal hypertension in advanced fibrosis

Modified from KDIGO guideline 2018 Asia represents countries with wide range of economic incomes and healthcare spending

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World Bank economic classification Low income of Asian countries Prasad N. Kidney Dis 2015 Features of dialysis registries in Asia

Registry name Patient-level (common abbreviation), Accessibility data Treatments Out-comes year of establishment availability Hong Kong Renal Registry + + +++ +++ (HKRR), 1995 Korean Renal Registry, 1985 ++ ++ +++ +++ Malaysian National Renal Registry ++ +++ +++ +++ (NRR), 1993 Shanghai Dialysis Registry, 1996 KDIGO + + ++ +++

Singapore Renal Registry, 2001 +++ ++ +++ +++

Taiwan Renal Registry Data + + +++ + System (TWRDS), 1987 Thailand Renal Replacement ++ + +++ + Therapy Registry (TRT), 1997

Prasad N. Kidney Dis 2015 Unique challenges in Asia

• No standard practices in CKD in many countries, even different centers in the same country • Diversity of clinical practice • Application of universal precaution • Application of HCVKDIGO tests and evaluation for fibrosis • Many countries cannot afford NAT, HCV Ag as alternative? • Fibrosis assessment? • Access to HCV treatment, especially where there is no SOF-free generic drug for CKD with eGFR < 30

Conclusion

• HCV infection in various stages of CKD is still common • New infection is now less frequent but still occurs • Standard practice for HCV prevention varies • Co-infection with HBV, HIV can have more progressive disease • Assessment of liver fibrosis is important, not only to guide treatment but also decision for KT KDIGO • Diferrent economic background in Asian countries can affect current standard practice • How should we optimize KDIGO guideline especially in countries with low income