1. Case Conference 報告者： R3 蕭景中 報告者： R3 蕭景中 指導老師：方基存醫師 指導老師：方基存醫師 報告日期： 2012/03/28 報告日期： 2012/03/28

2. Patient's Profiles Age: 48 Gender: male Ethnic: Taiwanese Marital status: married Occupation: 房地產 before Travel history: no travel history in recent 3 months

3. Chief Complaints High blood pressure with headache for 2-3days

4. Present Illness The 48year-old male sufferred from high blood pressure with SBP about 200mmHg for 2-3 days Bitemporal headache,decreased appetitie and bilateral lower leg edema was also noted Drank 味增魚湯 every day during Chineses year for one month

5. Present Illness No nasuea,vomiting,shortness of breath,blurred vision,decreased urine output No fever, cough, dysuria,abdominal pain,tarry stool Admitted 2011/10/14-2011/10/20 due to acute pyelonephritis Visit ER once 2012/01/14 due to right ankle swelling r/o gout, discharge after symptomatic relief

6. Present Illness Visit ER 02/02,hypertension (245/114mmHg)and renal function deterioration (3.34(01/11)  11.97(02/02)) noted Under the impression of acute on chronic renal failure,he was admitted

7. Past history Hepatocellular carcinoma,T1N0M0,s/p partial hepatectomy and TACE,s/p cadaver liver transplantation 2009/05,under MMF and tacrolimus Liver cirrhosis,child C,HCV related,s/p interferon-alpha and ribavirin 2009/07- 2010/02 Chronic kidney disease,stage IV

8. Past history Moderate aortic stenosis and aortic regurgication,EF:57%,no surgical indication Diabetic mellitus under OHA Recurrent urinary tract infection(6-7 times in current two years) Spleen rupture due to traffic accident s/p splenectomy 26years ago Gout

9. Personal history Allergy: no known allergy to drugs or food Alcohol :social but quitted now Smoking:1PPD*21years,quitted now Betelnut :social but quitted now

10. Family history 78 46 48 DM HCC,HCV,DM Old CVA,bedridden

11. Medication history Immunosupressant: 2009/05:tacrolimus 1-2mg Q12h MMF:1mg Q12h HCV: 2009/07-2010/02: interferon-alpha and ribavirin

12. Physical examination (02/02 at Taipei ER) T:36/ ℃ P:70/min R:18/min BP:245/114mmHg 身高 :176CM (20120204) 體重 :84.3KG (20120204) BMI:27.2 GENERAL APPEARANCE: Fair looking CONSCIOUSNESS: Clear, E 4 V 5 M 6 HEENT: Sclera: not icteric Conjunctiva:not pale NECK: Supple No jugular vein engorgement No lymphadenopathy

13. CHEST: Smooth breath pattern Bilateral symmetric expansion Breathing sound: bilateral clear HEART: Regular heart beat without audible murmur No audible S3; No audible S4

14. ABDOMEN: Soft and distended No tenderness, No rebounding pain Normoactive bowel sound Operation scar 7cm over midline,12cm over RUQ and LUQ BACK:no bilateral knocking pain EXTREMITIES: Freely movable grade II leg edema SKIN: No rash, no petechiae, no purpura uvula swelling, no erythema or tenderness

15. 血液 2012/02/02 WBC 6300 Hemoglobin12.9 Hematocrit37.8 MCV 90 MCH 30.6 MCHC 34.1 RDW 14.3 Platelets218k Segment60 Lymphocyte25.9 Monocyte3.9 Eosinophil9.0 admission

16. 生化 2011/06/242011/12/292012/02/02 BUN46.959125 Creatinine3.283.1811.97 NaNa133144 K5.33.3 Calcium9.09.27.4 Inorganic P4.13.79.4 AST33 ALT14 12 Albumin4.24 Total Protein7.4 BNP T-Cholesterol235 Glucose(AC)122 pHpH7.35 pCO232 HCO317.4 Uric acid13.8 admission

17. 鏡檢2011/11232012/01/112012/02//02 ColoryellowYellowYellow TurbidityclearClearClear Sp.gravity1.0121.0151.013 pH5.05.56.0 LeukocyteNegativeNegativeNegative NitriteNegativeNegativeNegative Protein3+(300) 4+ (1000) GlucoseTrace(100)Trace(100)Trace(100) KetoneNegativeNegativeNegative Urobilinogen0.10.10.1 BilirubinNegativeNegativeNegative Blood1+2+ Granular Cast --- RBC41852 WBC443 Epithelial cell 220 admission

18. 1.acute on chronic renal failure, RIFLE:F, Suspected acute urate nephropathy or malignant hypertension related, r/o RPGN 2.Post transplantation diabetic mellitus 3. Hepatocellular carcinoma,T1N0M0,s/p partial hepatectomy and TACE,s/p cadaver liver transplantation 2009/05,under MMF and tacrolimus 4.Moderate aortic stenosis and aortic regurgication,EF:57%,no surgical indication 5.gout Initial impression

19. 2009/0 2 2009/052009/062009/0 7 2010/022010/0 6 2010/10 BUN/Cr48/2.9163/3.3939/1.542/2.6543/2.6351/2.4648/2.39 AST/AL T 87/8498/5261/64180/12 4 31/31127/10 1 49/33 Bil T/D2.31.2/071.2/0.71.2/0.5 9 0.6/0.22.0/1.20.3/0.2 Albumin2.52.93.0 3.274.023.09 HCV RNA 0.0006 1 百萬 IU/ml 38.7 百 萬 IU/ml Not detect Not dectect Urine protein 75mg/dl (1+) 150mg/ dl(2+) 300mg/ dl(3+) 100mg( 2+)

20. 2011/022011/062011/082011/102011/122012/0 1 BUN/Cr39/2.1746/3.2839/1.542/2.6543/2.6351/2.46 AST/AL T 27/1621/1761/64180/12 4 31/31127/10 1 Bil T/D0.8/0.40.61.2/0.71.2/0.5 9 0.6/0.22.0/1.2 Albumin3.92.93.0 3.274.02 HCV RNA Urine protein 1000mg (4+) ileus 300mg/ dl(3+) 300mg/ dl(3+): UTI 1000m g/dl(4+) UTI

21. Kidney Sonography 2012/02/03 Left Kidney Length: 11.9 cm Right Kidney Length: 11.8 cm There is focal calyceal dilatation in the upper pole of the right kidney. There are two echo-free lesions (1.3 x 1.3 cm in the pelvis and 1.3 x 1.1 cm in the lower pole) with posterior wall enhancement over the left kidney. No renal mass, or stone is noted. IMP:1. Parenchymal renal disease. 2. Left renal cysts.

22. 02/0402/0502/0602/0702/0802/0902/1002/11 BUN Cr 125.8 11.94 114.3 12.22 106.1 12.18 Hydration:IVF 40cc/hr+allopurinol 0.5pc qd Cardiac echo GS HD OPH 24hour urine TP

23. 02/1202/1302/1402/15 02/1602/1702/1802/19 HD BUN Cr 64.1 10.59 Serum 50.9 8.98 60.8 8.84

24. 02/2002/2102/22 02/23 02/2402/2502/2602/27 BUN Cr 60.8 8.84 41.2 7.73 46.2 9.49 HD Kidney biopsy

25. 02/2802/2903/01 03/02 03/0303/0403/0503/06 BUN Cr 33.9 7.2 65.5 9.52 TCC HD

26. 03/0703/0803/09 BUN Cr 03/1003/1103/12 18.7 3.78 HD 03/13 03/14 HD Cardiac echo

27. 03/1503/1603/17 BUN Cr HD

28. 1.Acute on chronic renal failure reaching End stage renal disease, diabetic nephropathy related Aggravating factor: hypertension, NSAID, Immunosuppressant, heart failure, gout Under maintanence hemodilaysis Q246 2.Post transplantation diabetic mellitus 3. Hepatocellular carcinoma,T1N0M0,s/p partial hepatectomy and TACE,s/p cadaver liver transplantation 2009/05,under MMF and tacrolimus 4.Congestive heart failiure, Fc III,favored valular heart related,EF:46% Final impression

29. Outline Early and chronic renal dysfunction after liver transplantation 1.Early renal dysfunction after liver transplantation 2.Early kidney dysfunction predict chronic kidney disease 3.Chronic renal failure after liver transplantation Post transplantation diabetic mellitus 1.Definition,impact and risk factor 2.HCV and PTDM 3.Immunosupressant and PTDM

30. Methods: 246 LDLT recipients,to review postoperative renal dysfunction Results: Intraoperative blood loss and preoperative serum creatinine were significant independent risk factors for the development of early renal dysfunction Patients who required RRT had a lower survival rate

33. Methods:181 liver transplantation in which recipient was alived during followed up(2.7years),Renal dysfunction defined as Cr>2 Results: PRT-DM and early postoperative acute renal dysfunction predict chronic kidney disease

35. Methods: 69,321 persons who received nonrenal transplants in the United States between 1990 and 2000.To estimate the cumulative incidence of chronic renal failure and association of death

36. Results: The five-year risk of chronic renal failure varied according to the type of organ transplanted — from 6.9% among recipients of heart–lung transplants to 21.3% among recipients of intestine transplants.

39. Results: increased risk of chronic renal failure was associated with age, female sex, pretransplantation GFR and hepatitis C infection, hypertension,diabetes mellitus, postoperative acute renal failure

42. Results: The occurrence of chronic renal failure significantly increased the risk of death Treatment of ESRD with kidney transplantation was associated with a five year risk of death that was significantly lower than that associated with dialysis (relative risk, 0.56; P=0.02).

45. Post transplantation DM Metabolic complication after solid organ transplantation Increased cardiovascular mortality and morbidity in transplantation recipients Multiple risk factors related to develop of PTDM

46. Incidence of PTDM Often underestimated due to lack of standard definition Confounded by patient with diabetics before transplantation Variable incidence due to different steroid regimen and immunosuppressants

47. Definition

48. Impact of PTDM(graft) Diabetes mellitus after renal transplantation. Transplantation 65:380 –384, 1998 Outcome of patients with new-onset diabetes mellitus after liver transplantation compared with those without diabetes mellitus Liver Transpl 8:708 –713, 2002  increasing the risk of graft-related complications such as graft rejection, graft loss,and infection

49. Outcome of Patients With New-Onset Diabetes Mellitus After Liver Transplantation Compared With Those Without Diabetes Mellitus

50. Cumulative CV events

51. Impact of PTDM(survival) Risk factors and consequences of post-transplant diabetes mellitus Clin Transplant 2010: 24:

53. Pretransplantation factors Post-transplant hyperglycaemia: a study of risk factors Nephrol Dial Transplant (2003) 18: 164–171

54. Post-transplant hyperglycaemia: a study of risk factors Nephrol Dial Transplant (2003) 18: 164–171

55. Pre-transplant 1-h OGTT value > 50th percentile and rapid increase in BMI pre-transplant had the highest risk.

56. Post-transplant hyperglycaemia: a study of risk factors Nephrol Dial Transplant (2003) 18: 164–171

57. Conclusion: Pre-transplant factors including greater age, abnormal glucose tolerance parameters, and rapid gain in dry weight on HD, along with higher prednisolone and CsA doses early post-transplant were the important factors associated with the development of PTDM.

58. Predictors of new onset diabetes after renal transplantation Clin Transplant 2007: 19: 136–143

59. Predictors of new onset diabetes after renal transplantation Clin Transplant 2007: 19: 136–143

60. Conclusion:Risk factors for the development of NODAT were older age, Body weight, higher mean pre-transplant random plasma glucose,higher plasma glucose within the first seven day post-transplant and use of tacrolimus

61. Risk factors and consequences of post-transplant diabetes mellitus Clin Transplant 2010: 24: E170–E177

62. Risk factors and consequences of post-transplant diabetes mellitus Clin Transplant 2010: 24: E170–E177

63. Conclusion: Age, tacrolimus, and HCV are independent risk factors for PTDM

64. Introduction: Re-infection with HCV after liver transplantation for HCV is immediate and virtually universal following reperfusion of the allograft, and is associated with accelerated fibrosis progression leading to cirrhosis in 10–30% of cases within 5 years and > 40% within 10 years

65. Introduction: HCV infection is further complicated in nontransplant and transplant settings by association with the extrahepatic effects of insulin resistance and DM. Not only is chronic HCV infection linked with the onset of insulin resistance, but insulin resistance may also contribute to the morbidity and mortality associated with chronic HCV infection

66. Is HCV a metabolic diseases?? Those with HCV were more than three times as likely to have type 2 diabetes as those without HCV Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med 2000; 133: 592–599 Significantly increased risk for DM in patients with HCV compared with either noninfected control individuals or patients with HBV Hepatitis C infection and risk of diabetes: A systematic review and meta analysis. J Hepatol 2008;49: 831–844

67. Is HCV a metabolic diseases?? Chronic HCV infection was associated with insulin resistance and insulin resistance a risk factor for rate of fibrosis progression Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression Gastroenterology 2003; 125: 1695–1704

68. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med 2000; 133: 592–599

69. HCV vs noninfected individuals Hepatitis C infection and risk of diabetes: A systematic review and Meta analysis. J Hepatol 2008;49: 831–844

70. HCV vs HBV Hepatitis C infection and risk of diabetes: A systematic review and Meta analysis. J Hepatol 2008;49: 831–844

71. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression Gastroenterology 2003; 125: 1695–1704

72. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression Gastroenterology 2003; 125: 1695–1704

76. HCV and PTDM

79. HCV(+) liver transplant recipients found that those with insulin resistance were twice as likely to develop fibrosis stage ≥ 3 at 5 years posttransplant as those with normal insulin sensitivity (43% vs. 21%; p = 0.016) Insulin resistance, serum adipokines and risk of fibrosis progression in patients transplanted for hepatitis C. Am J Transplant 2009;9:1406 1413.

80. 82 liver transplant recipients with HCV recurrence, metabolic syndrome was present in half of patients at 1 year posttransplant and was associated with fibrosis progression beyond 1 year (multivariate OR 6.3; p = 0.017) The significance of metabolic syndrome in the setting of recurrent hepatitis C after liver transplantation. Liver Transpl 2008; 14: 1287 1293..

81. 778 HCV-positive liver transplant recipients up for a median of 6 years, recipients with PTDM(including those with DM before transplant) had increased HCV-related mortality (4.5% vs. 1.8%; p = 0.036) and HCV related graft loss (4.7% vs. 1.8%; p = 0.026) compared with recipients with no or transient PTDM Negative impact of new-onset diabetes mellitus on patient and graft Survival after liver transplantation: Long-term follow up. Transplantation 2006; 82: 1625–1628.

83. Cyclosporin and tacrolimus Cyclosporin: CyA restructures cyclophilin to form inhibitory complexes that blocks the phosphatase activity of calcineurin resulting in the inhibition of translocation of NFATc from the cytoplasm to the nucleus and the suppression of T-cell activation and cytokine gene transcription

84. Cyclosporin and tacrolimus Tacrolimus:FK506 exerts its immunosuppressive effect by forming immunophilin complexes with FK-binding protein (FKBP)12, which can interrupt this pathway by inhibiting calcineurin’s phosphatase activity, thereby blocking T- cell-mediated immune responses

85. New onset diabetes mellitus was reported in 13.4% of patients after solid organ transplantation, with a higher incidence in patients receiving tacrolimus than cyclosporine (16.6% vs.9.8%).This trend was observed across renal, liver, heart and lung transplant groups

92. Back to our patient Causes of renal failure in the patient were multifactors and post transplantation diabetic mellitus play an important role The management of HCV infection is very important in the patient and affect the patient and graft survival

93. Thank you for you attention

94. 2012/02/07 total protein(U):405.5mg/dl Urine amount:1550ml Cr(U):46.88mg/dl  24hour CCr:4.12 24hour urine protein:6.2g/day Back

95. 血清 02/13 ANAnegative C3 100 C427.1 PEP/IFENo paraprotein back 血清 02/13 RPRNon-reactive HBs Ag negative HCV Ab positive IgG1360 IgA309 IgM 76 IgE1330 HbA1C6.6 Uric acid10 Cryoglobulin+ serum12/29 TG259 cholestrol158 FK506<1.2

96. OPH consultation No evidence of DM retinopathy

97. Cardiac echo 1. Dilated LA, Dilated LV;Thick LV Walls. c/w Hypertension-related LV Hypertrophy + Cirrhotic Cardiomyopathy +AS,AR-related,EF:34.5% 2. Marked LV Contractility Failure, esp. LV posterior segment hypokinesiaw as noted.nature? 3. Mild MR, Mild to Moderate Calcified AS, Mild to Moderate AR. 4. No thrombus, no vegetation, no pericardial effusion, no mitral stenosis. PS: Decreased LV EF was noted as compared with previous exam. nature?(LV EF = 52 % by cath at 20101-03-11).

101. Renal biopsy DX: KIDNEY, NEEDLE BIOPSY----DIABETIC NODULAR SCLEROSIS ----NEAR END-STAGE RENAL DISEASE MICRO D: H AND E SECTIONS HAVE 20 GLOMERULI.14 ARE OBSOLETE,3 HAVE SEVERE SCLEROSIS WITH FOCAL K-W NODULES, 3 HAVE MODERATE NODULAR SCLEROSIS. THE INTERSTITIUM HAS SEVERE FIBROSIS AND MODERATE CHRONIC INFLAMMATION. TUBULES HAVE SEVERE ATROPHY. ARTERIES HAVE MODERATE TO SEVERE SCLEROSIS. IMMUNOFLUORESCENCE SECTIONS HAVE 13 GLOMERULI, 8 ARE OBSOLETE. THERE ARE IRREGULAR 1-2+IGM AND C3. BACK

102. Cardiac echo 03/14 1. Hypokinesis of inferior and posterior segments with impaired LV performance. 2. Dilated aortic root, LA, LV and IVS thickening 3. Moderate AS, mild to moderate AR, mild MR. EF:46% BACK