1. Renal pathology in other solid organ and bone marrow transplants Anke Schwarz, Deptm. of Nephrology Verena Bröcker, Inst. for Pathology

2. NHL 1997 BMT 1997 Lung Tx 2001 ESRD 2011 37 yrs old

3. Changes in reciprocal s-creatinine (~GFR) in cardiac-transplant recipients Myers et al, NEJM 1984

4. Evolution of GFR in heart-transplanted patients (n=151) Lindelöw et al, JASN 2000

5. Seriel creatinine clearances in patients after lung or lung-heart transplantation (n=115) Kunst et al, J Heart Lung Transplant 2004 Filled boxes=later ESRD

6. Survival at dialysis after lung transplantation compared with expected survival (n=40) Mason et al, J Heart Lung Transplant 2007

7. Renal biopsies after non-renal transplantation 105 renal biopsies in 101 patients 2000 – 2009 (Hannover) 14 after bone marrow transplantation 41 after liver transplantation 30 after lung transplantation 20 after heart transplantation

8. Renal biopsies after non-renal transplantation 105 renal biopsies in 101 patients 2000 – 2009 (Hannover) 14 after bone marrow transplantation 41 after liver transplantation 30 after lung transplantation 20 after heart transplantation 34 renal biopsies in 34 patients 1987 – 2000 (Basel) 20 after bone marrow transplantation 14 after heart transplantation

9. Renal biopsies after non-renal transplantation Indication for renal biopsy in Hannover: non-recovery after ARF at transplant. 9% creatinine increase 83% rapid creatinine increase 22% proteinuria 22% nephrotic syndrome 13% evaluation of renal prognosis before re-transplantation of an extrarenal organ 9%

10. Renal biopsies after non-renal transplantation End stage renal disease in Hannover: BM: 1 out of 1375 patients (0.07%) Liver: 32 out of 2016 patients (1.6%) Lung:35 out of 725 patients (4.8%) Heart:41 out of 505 patients (8.1%)

11. 101 patients with renal biopsies after non-renal transplantation BM (14)Liver (39)Lung (28)Heart (20) Age (yrs)40±1244±1549±1156±14 Gender (♂) 64%74%82%85% BMI25±422±323±427±5 Hypertens.57%62%86%90% Diabetes7%36%39%35%

12. 101 patients with renal biopsies after non-renal transplantation BM (14)Liver (39)Lung (28)Heart (20) Age (yrs)40±1244±1549±1156±14 Gender (♂) 64%74%82%85% BMI25±422±323±427±5 Hypertens.57%62%86%90% Diabetes7%36%39%35%

13. 105 renal biopsies after non-renal transplantation BM (14)Liver (41) Lung (30)Heart (20) Time post- tx (mos) 45±42 62±65 36±40 86±73 GFR (C&G, mL/min)) 48±28 38±22 30±11 29±16

14. 34 renal biopsies after heart transplantation Heart n=14 Basel 1987-2000 Heart n=20 Hannover 2000-2009 Time post-Tx (mos) 20±1586±73 S-Creatinine µmol/L 281±17380±252 Prevalence CNI-toxicity 55%50% P=0.01 NS

15. Main histopathological lesions in kidney biopsies (n=101) * * Interlobular/ arcuata-arteries

16. Acute tubular injury in organ groups n.s.

17. Glomerulosclerosis and fibrosis in organ groups (GS) (IF/TA)

18. Chronic vascular lesions in organ groups p=0.006 (AH)(AS)

19. Bone marrow: SLE, MGN, fibrillary GN Liver: IgA, MPGN Heart: IgA, Shunt-Nephritis Glomerulonephritis and TMA in organ groups

20. Interstitial fibrosis/ tubular atrophy and kidney outcome >/= 3 years follow up

21. Multivariate regression Age at biopsy (mo)Time after tx (mo) regress. coeff. ß pregress. coeff. ß p GS (%)n.s.0.2590.000 IFTA (%)n.s.0.0550.033 AH (0-3)1.63 x 10 -3 0.0146.72 x 10 -3 0.000 Arteriosclerosis (0-3) 1.98 x 10 -3 0.0005.33 x 10 -3 0.001 Impact of age and time after tx on chronic changes

22. AgeTime after tx GS (1%-point increase) 4 months IFTA (1%-point increase) 18 months AH (1 grade increase) 51 years12 years AS (1 grade increase) 42 years16 years Impact of age and time after tx on chronic changes

23. (n=101) Main histopathological diagnosis

24. (n=101) Main histopathological diagnosis “Other” Bone marrow: Nephrocalcinosis, Minimal Change, Cast-Nephropathy Heart: Nephrocalcinosis/ interstitial Nephritis Liver: Diabetic NP, Iron-overload, Minimal Change Lung: Polyoma-Virus NP, Nephrocalcinosis “NOS” No reason for impaired renal function IFTA>20% and GS and nephrosclerosis without obvious reason

25. Kidney biopsies of heart transplanted patients Hannover and Basel

27. Thrombotic microangiopathy Hannover 2000 – 2009 n=10/101 (10%) TMA after BM-Tx:n=1 TMA after liver-Tx:n=5 TMA after lung-Tx: n=4 TMA after heart-Tx:n=0 Basel 1987 – 2000 n=8/34 (24%) TMA after BM-Tx:n=5 TMA after heart-Tx:n=3

28. TMA TMA in 428 renal transplant patients 1.2% TMA in 4203 native kidneys 1.1% TMA in 101 native kidneys after non-renal transplantation in Hannover 2000-2009 10% TMA in 14 native kidneys after non-renal transplantation in Basel 1987-2000 24%

29. TMA after non-renal transplantation Shulman et al 1981 BM 3 autopsy cases Bonser et al 1984 liver case report Dische et al 1988 liver case report Nizze et al 1988 BM, heart 167 autopsies, 15% Griffiths et al 1996 heart, lung 22 histologies, 14% Pillebout et al 2005 liver 15 histologies, 50% Lefaucheur et al 2008 liver 26 histologies, 47%

30. Thrombotic microangiopathy Complement mutation-associated de novo Thrombotic Microangiopathy following kidney transplantation M. Le Quintrec et al AJT 2008 TMA with HUS after RTX n=24 Mutations in genes encoding complement abnormalities 29%

31. Thrombotic microangiopathy Immunosuppression with TMA in Hannover: cyclosporine-basedn=5 tacrolimus-basedn=2 cyclosporine and everolimusn=3

32. glomerular lesion 5 arteriolar lesion 3 ( glomerular & arteriolar lesion 3)

33. Thrombotic microangiopathy Symptoms of TMA in Hannover n=10: hemolytic uremic syndrome 5 severe hypertensive episode 6 lung edema 1 retinal bleeding 1 creatinine increase 8 (proteinuria 4g/day 1)

34. 6 month kidney survival after biopsy TMA p=0.01

35. Renal biopsies after non-renal transplantation most often signs of acute renal failure, pre-existing hypertension and CNI-toxicity high number of patients with glomerulonephritis high number of patients with TMA Conclusion 1

36. Renal biopsies after non-renal transplantation mostly signs of acute renal failure, pre-existing hypertension and CNI-toxicity high number of patients with glomerulonephritis high number of patients with TMA Conclusion 1

37. Renal biopsies after non-renal transplantation mostly signs of acute renal failure, pre-existing hypertension and CNI-toxicity high number of patients with glomerulonephritis high number of patients with TMA Conclusion 1

38. Renal biopsies after non-renal transplantation find early specific lesions in the advanced stage the extent of IFTA determines renal outcome extrarenal transplantation may accelerate the process of „aging“ by multifactorial causes Conclusion 2

39. Renal biopsies after non-renal transplantation find early specific lesions in the advanced stage the extent of IFTA determines renal outcome extrarenal transplantation may accelerate the process of „aging“ by multifactorial causes Conclusion 2

40. Renal biopsies after non-renal transplantation find early specific lesions in the advanced stage the extent of IFTA determines renal outcome extrarenal transplantation may accelerate the process of „aging“ by multifactorial causes Conclusion 2

41. Therapeutic consequences Reduce CNI as much as possible Finish CNI - mTOR inhibitor combination Agressive blood pressure control Plasmapheresis in TMA with HUS Renal replacement planning

42. Renal transplantation by LIVING DONATION 1997-20109 patients10±6 yearsLiver-Tx 2006-20116 patients8±4 yearsLung-Tx 20091 patient15 yearsHeart-Tx

43. Thank you for your attention Department of Nephrology Hermann Haller Anke Schwarz Institute for Pathology Hans Kreipe Jan U. Becker Verena Bröcker Hemato-Oncology Gastro-Enterology Pulmonology Thoracic Surgery Christian Koenecke Jens Gottlieb Christian Strassburg Christoph Bara Frank Lehner AJT 2010

44. Thank you for your attention Department of Nephrology Hermann Haller Anke Schwarz Institute for Pathology Hans Kreipe Jan U. Becker Verena Bröcker Hemato-Oncology Gastro-Enterology Pulmonology Thoracic Surgery Christian Koenecke Jens Gottlieb Christian Strassburg Christoph Bara Frank Lehner Institute for Pathology Michael Mihatsch, Basel AJT 2010

45. Thank you for your attention Department of Nephrology Hermann Haller Anke Schwarz Institute for Pathology Hans Kreipe Jan U. Becker Verena Bröcker Hemato-Oncology Gastro-Enterology Pulmonology Thoracic Surgery Christian Koenecke Jens Gottlieb Christian Strassburg Christoph Bara Frank Lehner Institute for Pathology Michael Mihatsch, Basel AJT 2010