Kidneytransplant pathologyrelatedto immunosuppressiveagents Helmut Hopfer Pathologie
Women, 53 years old. 16 months after kidney transplantation for diabetic nephropathy. Metabolicsyndromeandcoronaryheartdisease. HistoryofgastriculcerationwithGI bleeding. Known schizophrenia and anxiety disorder. Drug morning midday evening Prograf 1.5mg - 1mg Myfortic 180mg - 180mg Prednisolon 5mg - - Amlodipin 10mg - - Dilatrend 12.5mg - - Aspirin cardio 100mg - - Crestor 10mg - - Leponex 25mg - - Pantozol - - 40mg Vitamin D Wild 5 drops - - Lantus, Humalog Aranesp Source: compendium.ch according to schematic 60mg/month
Message 1 othermedications Transplanted patients usually take multiple drugs other than the basic immunosuppression. These may cause or contribute to graft pathology.
Agenda prednisolone not listed azathioprine ciclosporine tacrolimus mycophenolat mofetil sirolimus everolimus abatacept kidney adverse events not listed function, TMA function, TMA function proteinuria, function, (TMA) proteinuria, function, (TMA) not listed calcineurin inhibitors mtor inhibitors Source: compendium.ch
mtor-i: modeofaction FKBP12 SIR mtorc1 cell cycle IL-2, IL-15 decreased lymphocyte proliferation disturbed repair response to tubular injury decreased VEGF synthesis by podocytes Severe acute tubular injury with PAS-negative casts (myeloma-like). Thrombotic microangiopathy. Focal segmental glomerulosclerosis. Increased tubular protein storage.
mtor-i toxicity: pathology J Am Soc Nephrol 14:1037-1045, 2003 Transplantation 83:645-650, 2006 Nephrol Dial Transplant 20:203-209, 2005 Am J Transplant 5:2441-2447, 2005 Clin J Am Soc Nephrol 2:326-333, 2007
Sirolimus-associatedtubulardysfunction mg/mmol creatinine mg/mmol creatinine 60 40 20 0 10 8 6 4 2 0 proteinuria 0 tubular: RBP ** 7 *** 30 *** glomerular: IgG 0 7 30 ** days after transplantation *** 90 *** 90 Sir CsA sirolimus-mmf-predvs. ciclosporin-mmf-pred protocolbiopsies2-7 monthsafter transplantation without signs of rejection SIR CsA microcalcifications 10.3% 9.3% tubular vacuolization 20.5% 14.8% protein storage 61.5% 29.6% Tamm-Horsfall casts 20.5% 22.2% Franz et al., Am J KidneyDis 55:335-343, 2010
Message 2 mtor-i Aggravated acute tubular injury with casts, TMA, or unexplained proteinuria.
Calcineurininhibitors(CNI) Less rejection. Better overall and transplant survival. Acuteandchronicrenal insufficiency. End-stage renal disease. N Engl J Med 311:699-705, 1984 N Engl J Med 326:1654-1660, 1992
CNI: modeofaction CyA cyclophilin antigen-mhc control AA TAC calcineurin FKBP12 transcription CsA7 days EA decreased lymphocyte proliferation isometric vacuolization of tubular epithelium vasoconstrictionofafferent arterioles AA CsA14 days AA Transplantation 44:135-141, 1987
calcineurin-inhibitor chronic toxicity acute toxicity thrombotic microangiopathy reduced GFR glom. ischemia chronic TMA glom. sclerosis FSGS capsular fibrosis atubular glom. vascular dysfunction vasoconstriction afferent arteriole reduced renal blood flow arteriolar hyalinosis isometric vacuolisation interstitial fibrosis tubular atrophy microcalcification tubular dysfunction tub.-int. ischemia inflammation adapted from Clin J Am Soc Nephrol 4:481-508, 2009
Acute CNI toxicity: pathology courtesy: M.J. Mihatsch DD: osmotic nephrosis (plasma expander, IVIG, sepsis, ischemia) DD: TMA related to other factors (rejection, ahus, other drugs)
CNI toxicity: arteriolarhyalinosis IgM pictures courtesy of M.J. Mihatsch
Scoring vascularlesions: ah vs. aah ah0 No PAS-positive hyaline thickening ah1 Mild-to-moderate PAS-positive hyaline thickening in at least one arteriole ah2 Moderate-to-severePAS-positive hyaline thickening in more than one arteriole ah3 SeverePAS-positive hyaline thickeningin many arterioles aah0 No typical lesions of CNI arteriolopathy aah1 Replacement of degenerated smooth muscle cells by hyaline deposits present in only one arteriole, no circumferential involvement. aah2 Replacement of degenerated smooth muscle cells by hyaline deposits present in more than one arteriole, but no circumferential involvement. aah3 Replacement of degenerated smooth muscle cells by hyaline deposits with circumferential involvement, independent of the number of arterioles involved. Kidney Int 55:713-723, 1999; Am J Transplant 6:1444-1450, 2006; Am J Transplant 8:753-760, 2008 Transplant Proc 17, Suppl. 1:101-116, 1985 pictures courtesy of M.J. Mihatsch
Cross sectionalassessmentofcni toxicity n=120 n=101 era 1: azathioprine, steroids era 2: ciclosporine era 3: CNI, mtor-i, MMF; protocol biopsies era 4: tacrolimus, MMF; risk stratification; protocol biopsies Wehmeier et al.: 2222 kidney transplantations at the University Hospital Basel. Swiss Med Wkly 146:w14317, 1016
FrequencyoftubularCNI-toxicity Tubular CNI-toxicity early and dose dependent. More frequent with ciclosporine.
FrequencyofvascularCNI-toxicity Low fequency(<20%) withinthefirstyearpost transplantation. Increasing frequency and severity after the first year post transplantation. No difference between ciclosporine and tacrolimus. Length of treatment more important than dose.
PrevalenceofvascularCNI-toxicity Prevalence in 6 months protocol biopsies with tacrolimus based immunosuppression: <10% ah N Engl J Med 349:2326-2333, 2003
Message 3 -CNI Acute tubular toxicity(isometric vacuolization) and thrombotic microangiopathy occur early and have become rare biopsy findings with tacrolimus. Arteriolar hyalinosis results from subclinical thrombotic microangiopathywitha prevalenceof<10% in earlybiopsies. Itisfoundfrequentlyin (diagnostic) biopsieslateafter transplantation and its severity increases with time with either ciclosporine or tacrolimus. Banffaahscore reflectsthetypicalchangesbetterthantheah score.
SpecificityofCNI-lesions? The question was: «(1) Are there morphological patterns which occur more frequentlyin CsA-treatedpatients? (2) Are there morphological changes specific to CsA therapy? The answer to the first question was yes; tothesecond, no.» Transplant Proc 17, Suppl.1:101-116, 1985 Prof. Dr. M. J. Mihatsch
More frequent, but not specific?! % patients % patients 100 80 60 40 20 0 100 80 60 40 20 0 Aza Aza Azavs. CsA: ah 100 100 80 ** 80 NS 60 60 40 40 20 20 0 0 CsA 3 months CsA 3 months Aza CsA 2 years Azavs. CsA: aah 100 80 80 60 ** 60 NS 40 40 20 20 0 0 Aza CsA 2 years Am J Transplant 11:2635-1646, 2011 100 Aza CsA 10 years Aza ** *** CsA 10 years % patients ah 100 80 60 40 20 0 Tac NS Sir 1 year Tacvs. Sir 100 80 60 40 20 Tac NS Sir Am J Transplant 11:2635-1646, 2011 0 5 years aah ah1 ah2-3 pictures courtesy of M.J. Mihatsch
Not goodforgraft function! Creatinine clearance with/without ah lesions Graft loss beyond 10 years ah+ ah- CsA Control 120 months Am J Pathol 180:1852-1862, 2012 Am J Transplant 11:2635-1646, 2011
Message 4 -specificity None of the lesions associated with CNI toxicity are specific. Context matters. Prevalence depends on the particular immunosuppression protocol used. Arteriolar hyalinosis is not good for transplant survival. Reporting arteriolar hyalinosis is meaningful!
modifiers donor factors other drugs transplantation related rejection arteriolar hyalinosis «CNI-type» hypertension aging diabetes hyperlipidemia