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報告者：報告者： R3 R3 蕭景中蕭景中指導老師：方基存醫師指導老師：方基存醫師報告日期：報告日期： 2012/03/282012/03/28

Patient's Profiles

Age: 48Gender: maleEthnic: TaiwaneseMarital status: marriedOccupation: 房地產 beforeTravel history: no travel history in recent

3 months

Chief Complaints

High blood pressure with headache for 2-3days

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

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

Present Illness

Visit ER 02/02,hypertension (245/114mmHg)and renal function deterioration

(3.34(01/11)11.97(02/02)) notedUnder the impression of acute on chronic renal

failure,he was admitted

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

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

Personal history

Allergy: no known allergy to drugs or foodAlcohol :social but quitted nowSmoking:1PPD*21years,quitted nowBetelnut :social but quitted now

Family history

78 78

4648

DM

HCC,HCV,DM

Old CVA,bedridden

Medication history

Immunosupressant:

2009/05:tacrolimus 1-2mg Q12h

MMF:1mg Q12hHCV:

2009/07-2010/02: interferon-alpha and ribavirin

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:27.2GENERAL APPEARANCE: Fair lookingCONSCIOUSNESS: Clear, E 4 V 5 M 6HEENT: Sclera: not icteric Conjunctiva:not paleNECK: Supple No jugular vein engorgement No lymphadenopathy

CHEST:

Smooth breath pattern

Bilateral symmetric expansion

Breathing sound: bilateral clear HEART:

Regular heart beat without audible murmur

No audible S3; No audible S4

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

血液 2012/02/02

WBC 6300

Hemoglobin 12.9

Hematocrit 37.8

MCV 90

MCH 30.6MCHC 34.1RDW 14.3

Platelets 218k

Segment 60

Lymphocyte 25.9

Monocyte 3.9

Eosinophil 9.0

admission

生化 2011/06/24 2011/12/29 2012/02/02 BUN 46.9 59 125 Creatinine 3.28 3.18 11.97 Na 133 144K 5.3 3.3Calcium 9.0 9.2 7.4Inorganic P 4.1 3.7 9.4AST 33ALT 14 12 Albumin 4.24Total Protein 7.4BNPT-Cholesterol 235Glucose(AC) 122pH 7.35pCO2 32HCO3 17.4Uric acid 13.8

admission

鏡檢鏡檢 2011/11232011/1123 2012/01/112012/01/11 2012/02//022012/02//02

ColorColor yellowyellow YellowYellow YellowYellow

TurbidityTurbidity clearclear ClearClear ClearClear

Sp.gravitySp.gravity 1.0121.012 1.0151.015 1.0131.013

pHpH 5.05.0 5.55.5 6.06.0

LeukocyteLeukocyte NegativeNegative NegativeNegative NegativeNegative

NitriteNitrite NegativeNegative NegativeNegative NegativeNegative

ProteinProtein 3+(300)3+(300) 4+ (1000)4+ (1000) 4+ (1000)4+ (1000)

GlucoseGlucose Trace(100)Trace(100) Trace(100)Trace(100) Trace(100)Trace(100)

KetoneKetone NegativeNegative NegativeNegative NegativeNegative

UrobilinogenUrobilinogen 0.10.1 0.10.1 0.10.1

BilirubinBilirubin NegativeNegative NegativeNegative NegativeNegative

BloodBlood 1+1+ 2+ 2+

Granular CastGranular Cast -- -- --

RBCRBC 44 1818 52

WBCWBC 44 44 3

Epithelial cellEpithelial cell 22 22 00

admission

1.acute on chronic renal failure, RIFLE:F,Suspected acute urate nephropathy or malignanthypertension related, r/o RPGN2.Post transplantation diabetic mellitus3. Hepatocellular carcinoma,T1N0M0,s/p partialhepatectomy and TACE,s/p cadaver livertransplantation 2009/05,under MMF andtacrolimus 4.Moderate aortic stenosis and aortic

regurgication,EF:57%,no surgical indication5.gout

Initial impression

2009/02 2009/05 2009/06 2009/07 2010/02 2010/06 2010/10

BUN/Cr 48/2.91 63/3.39 39/1.5 42/2.65 43/2.63 51/2.46 48/2.39

AST/ALT

87/84 98/52 61/64 180/124 31/31 127/101 49/33

Bil T/D 2.3 1.2/07 1.2/0.7 1.2/0.59 0.6/0.2 2.0/1.2 0.3/0.2

Albumin 2.5 2.9 3.0 3.0 3.27 4.02 3.09

HCV RNA

0.00061百萬IU/ml

0.00061百萬IU/ml

38.7 百萬 IU/ml

Not detect

Not dectect

Urine protein

75mg/dl(1+)

75mg/dl(1+)

75mg/dl(1+)

150mg/dl(2+)

300mg/dl(3+)

100mg(2+)

2011/02 2011/06 2011/08 2011/10 2011/12 2012/01

BUN/Cr 39/2.17 46/3.28 39/1.5 42/2.65 43/2.63 51/2.46

AST/ALT

27/16 21/17 61/64 180/124 31/31 127/101

Bil T/D 0.8/0.4 0.6 1.2/0.7 1.2/0.59 0.6/0.2 2.0/1.2

Albumin 3.9 2.9 3.0 3.0 3.27 4.02

HCV RNA

Urine protein

1000mg(4+)ileus

300mg/dl(3+)

300mg/dl(3+):UTI

1000mg/dl(4+)UTI

Kidney Sonography 2012/02/03

Left Kidney Length: 11.9 cmRight Kidney Length: 11.8 cmThere 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.

02/04 02/05 02/06 02/07 02/08 02/09 02/10 02/11

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

02/12 02/13 02/14 02/15 02/16 02/17 02/18 02/19

HD HD HD

BUN

Cr

64.1

10.59

Serum

50.9

8.98

60.8

8.84

02/20 02/21 02/22 02/23 02/24 02/25 02/26 02/27

BUN

Cr

60.8

8.84

41.2

7.73

46.2

9.49

HD HD HD HD

Kidney biopsy

02/28 02/29 03/01 03/02 03/03 03/04 03/05 03/06

BUN

Cr

33.9

7.2

65.5

9.52

TCC

HD HD HD

03/07 03/08 03/09

BUN

Cr

03/10 03/11 03/12

18.7

3.78

HD

03/13 03/14

HD HD

Cardiac echo

03/15 03/16 03/17

BUN

Cr

HD HD

1.Acute on chronic renal failure reaching Endstage renal disease, diabetic nephropathy relatedAggravating factor: hypertension, NSAID,Immunosuppressant, heart failure, goutUnder maintanence hemodilaysis Q2462.Post transplantation diabetic mellitus3. Hepatocellular carcinoma,T1N0M0,s/p partialhepatectomy and TACE,s/p cadaver livertransplantation 2009/05,under MMF andtacrolimus 4.Congestive heart failiure, Fc III,favored valularheart related,EF:46%

Final impression

Outline• Early and chronic renal dysfunction after

liver transplantation1. Early renal dysfunction after liver transplantation

2. Early kidney dysfunction predict chronic kidney disease

3. Chronic renal failure after liver transplantation

• Post transplantation diabetic mellitus1. Definition,impact and risk factor

2. HCV and PTDM

3. Immunosupressant and PTDM

• 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

• Methods:181 liver transplantation in whichrecipient was alived during followedup(2.7years),Renal dysfunction defined asCr>2• Results: PRT-DM and early postoperative acute renal dysfunction predict chronic kidneydisease

• 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

• 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.

• 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

• Results: The occurrence of chronic renalfailure significantly increased the risk of deathTreatment of ESRD with kidneytransplantation was associated with a fiveyear risk of death that was significantly lowerthan that associated with dialysis (relativerisk, 0.56; P=0.02).

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

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

Definition

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

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

Cumulative CV events

Impact of PTDM(survival)

Risk factors and consequences of post-transplant diabetes mellitus Clin Transplant 2010: 24:

Pretransplantation factors

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

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

• 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.

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

• 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

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

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

• 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

• 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

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 HBVHepatitis C infection and risk of diabetes: A systematic review and meta

analysis. J Hepatol 2008;49: 831–844

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

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

HCV vs noninfected individuals

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

HCV vs HBV

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

Insulin resistance is associated with chronic hepatitis C virus infection andfibrosis progression Gastroenterology 2003; 125: 1695–1704

HCV and PTDM

• 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.

• 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..

• 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 PTDMNegative impact of new-onset diabetes mellitus on patient and graft

Survival after liver transplantation: Long-term follow up.

Transplantation 2006; 82: 1625–1628.

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

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

• 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

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

Thank you for you attention

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

血清 02/13

ANA negative

C3 100

C4 27.1

PEP/IFE No paraprotein

back

血清 02/13

RPR Non-reactive

HBs Ag negative

HCV Ab positive

IgG 1360

IgA 309

IgM 76

IgE 1330

HbA1C 6.6

Uric acid 10

Cryoglobulin +

serum 12/29

TG 259

cholestrol 158

FK506 <1.2

OPH consultation

• No evidence of DM retinopathy

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).

Renal biopsy

DX: KIDNEY, NEEDLE BIOPSY----DIABETIC NODULAR SCLEROSIS ----NEAR END-STAGE RENAL

DISEASEMICRO 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

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

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