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Table of Contents
CASE REPORT
Year : 2019  |  Volume : 13  |  Issue : 4  |  Page : 307-310

Hyperacute rejection in a blood group incompatible renal transplant recipient – enigma of unfathomable thrombotic microangiopathy!


1 Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Nephropathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Transplant Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission24-Sep-2019
Date of Acceptance26-Nov-2019
Date of Web Publication31-Dec-2019

Correspondence Address:
Dr. Raja Ramachandran
Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_51_19

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  Abstract 


Transplantation-associated thrombotic microangiopathy (TMA) is one of the most disastrous complications of renal transplantation. It may be either de novo (more common with a poor prognosis) or recurrent (with genetic background due to underlying mutations). Varied presentation mandates a high index of clinical suspicion, and the diagnosis usually requires allograft biopsy demonstrating TMA with or without underlying etiology. It has never been reported to mimic hyperacute rejection. In this context, we describe an end-stage renal disease patient with underlying IgA nephropathy, who underwent blood group incompatible renal transplant following successful desensitization and after that had systemic TMA in the 1st-h posttransplant itself, with allograft biopsy revealing florid TMA with no evidence of rejection, tacrolimus toxicity, or infection. Etiology remained elusive despite exhaustive workup and all possible attempts to salvage the allograft went in vain, with subsequent graft nephrectomy at 3 months. The patient after that has undergone a blood group compatible deceased-donor renal transplant and fortunately has normal graft function at 2 years follow-up, enthralling us to hypothesize possible interaction between the endothelial cells of renal allograft and anti-donor hemagglutinin antibodies; a mechanism already avowed for graft loss in blood group incompatible liver transplantation. We, therefore, suggest that patients willing for blood group incompatible renal transplantation need to be counseled beforehand about this, although a rare but devastating entity.

Keywords: Blood group incompatible renal transplantation, hyperacute rejection, transplantation-associated thrombotic microangiopathy


How to cite this article:
Sood V, Kashif AW, Nada R, Sharma A, Ramachandran R. Hyperacute rejection in a blood group incompatible renal transplant recipient – enigma of unfathomable thrombotic microangiopathy!. Indian J Transplant 2019;13:307-10

How to cite this URL:
Sood V, Kashif AW, Nada R, Sharma A, Ramachandran R. Hyperacute rejection in a blood group incompatible renal transplant recipient – enigma of unfathomable thrombotic microangiopathy!. Indian J Transplant [serial online] 2019 [cited 2020 Apr 8];13:307-10. Available from: http://www.ijtonline.in/text.asp?2019/13/4/307/274612




  Introduction Top


Transplantation-associated thrombotic microangiopathy (TA-TMA) following renal transplant although uncommon is a well-recognized complication, resulting in poor graft and patient outcomes with over 80% mortality at 3 years.[1] The two categories[2] of TA-TMA exist as follows: first, recurrent TMA with an atypical hemolytic uremic syndrome (aHUS) being the most frequent etiology, primarily associated with mutations (60%) or autoantibodies.[3] The second category constitutes de novo TMA which represents an overwhelming majority, a substantially more complex entity with varied etiology and includes antibody-mediated rejection (ABMR), infections, drugs (calcineurin inhibitor [CNI], mammalian target of rapamycin inhibitor [mTORi]), and pregnancy. Clinical presentation of TA-TMA is highly variable, usually results in renal-limited TMA[4] with few or no systemic manifestations mandating allograft biopsy. TA-TMA mostly is encountered in the first 3 months and[2] infrequently has been described as early as the second day[5] postrenal transplantation. In this regard, we describe a blood group incompatible renal transplant recipient who unfortunately ended up with early graft loss (primary nonfunction) consequent to TA-TMA mimicking hyperacute rejection (occurring as early as 1st-h postperfusion); cause of same remained elusive despite comprehensive evaluation.


  Case Report Top


A 26-year-old male patient was referred to our unit for evaluation of diffuse headache of 1-month duration. The patient denied history of vomiting, fever, vertigo, or focal neurological deficits. Clinically, patient had accelerated hypertension (blood pressure [BP] – 190/110 mm Hg) and workup revealed renal involvement (serum creatinine – 4.6 mg/dL and active sediments in urine and normal-sized kidneys). He further denied history of oliguria, gravelluria, hematuria, frothuria, intake of alternative medications, or over-the-counter analgesics, and family history was not contributory. Renal biopsy suggested IgA nephropathy (M1E0S1T2C0) with global sclerosis in 6 out of 11 glomeruli (G), tuft sclerosis and mesangial matrix expansion in 3G, and interstitial fibrosis with tubular atrophy of over 60%. Arteries had medial thickening. Immunofluorescence revealed 13G with IgA (3+), C3 (1+), IgM, IgG, and C1q were negative and equivocal kappa and lambda restriction (1+). The patient failed a trial of oral steroids (1 mg/kg) and progressed to end-stage renal disease (ESRD) over the next 6 months, requiring initiation of hemodialysis (HD). With no blood group compatible donors in family, patient was worked up for the most suitable blood group incompatible donor (maternal aunt, 48 years, A1B+ to B+). During pretransplant workup, his BP and hemoglobin were optimized. Preoperative immunological evaluation showed negative complement-dependent cytotoxicity (CDC) and flow cytometric crossmatch test (FCXM). Baseline IgM and IgG anti-A titer of 1:64 and 1:128, respectively (gel card), mandated desensitization with single dose of rituximab (375 mg/m2), mycophenolate mofetil (MMF), and plasmapheresis (PLEX) (five sessions with 100 mg/kg of IVIG following the last session of PLEX) after which IgM and IgG anti-A titer decreased to 1:1 and 1:4, respectively. His CD19 remained undetectable before transplant. The patient proceeded for renal transplantation with anti-thymocyte globulin (1 mg/kg × 3 days – cumulative dosage – 175 mg) induction after 3 months of dialysis vintage. Intraoperatively, there was initial brisk diuresis for 10 min, following declamping, after which allograft kidney turned blue with decreased urine output thereafter with spontaneous graft perfusion and diuresis within 30 min. However, patient had low urine output in the immediate postoperative period, and color doppler showed nil vascularity of the allograft with normal perfusion in main renal vessels. Meanwhile, implantation allograft biopsy suggested TMA [Figure 1]a with 4 out of 20G showing intraglomerular fibrin thrombi with mesangiolysis with no evidence of acute rejection. Maintenance immunosuppression included tacrolimus, prednisolone, and MMF with alternate day HD in view of delayed graft function. Although anti-A titer did not rebound (maximum IgM-1:2 and IgG-1:2), in light of systemic TMA (microangiopathic hemolysis with hemoglobin drop [from 9 g/dL to 5 g/dL], new-onset thrombocytopenia, and raised lactate dehydrogenase) [Table 1]a, the patient received further PLEX (6 sessions), methylprednisolone pulse (500 mg × 3 days), an additional dose of rituximab, blood transfusion (3 units), and switched over to everolimus as CNI sparing drug. Exhaustive etiological workup of TMA was inconclusive [Table 1]b. The patient remained dialysis-dependent, and repeat allograft biopsy on the 18th day showed persistent florid glomerular and vascular TMA (endothelial swelling, fibrin thrombi, and reticulated mesangium in all 15 G), acute cortical necrosis in 25% of the cores, global sclerosis in 3G with no evidence of rejection, or CNI toxicity [Figure 1]b and [Figure 1]c. Computed tomography angiography did not reveal allograft vascular thrombosis. Given HD dependence for 6 weeks, the patient was declared graft loss and maintained on curtailed immunosuppression (prednisolone 10 mg). He underwent allograft nephrectomy at 3 months posttransplant [Figure 1]d for graft intolerance and microscopy revealed substantial cortical necrosis with extensive glomerular and vascular thrombi [Figure 1]e and [Figure 1]f. Six months later, the patient underwent second renal transplant with a blood group compatible deceased donor and has normal graft function at 2 years of follow-up.
Figure 1: (a) Implantation renal biopsy: Glomeruli exhibit mesangiolysis and capillary thrombosis indicating glomerular thrombotic microangiopathy. (b and c) Allograft biopsy on D18: Glomeruli display capillary thrombosis (b, H and E, ×20) while the small arteries also show acute thrombotic microangiopathy in form of fibrin thrombi and near-total luminal occlusion (c, H and E, ×20). (d-f) Nephrectomy specimen: numerous pinpoint hemorrhages along with patches of pale infarcts, largest measuring 2.0 cm × 1.5 cm (d). Sections demonstrate large areas of cortical necrosis with widespread glomerular and vascular fibrin thrombi (e, H and E, ×10). Many arteries showed transmural lymphocyte infiltration, endothelial swelling, and medial smooth muscle necrosis along with fibrin thrombi (f, MSB stain, ×40)

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  Discussion Top


In the current manuscript, we report a case of presumed de novo TA-TMA in a blood group incompatible renal transplant presenting within the 1st h of posttransplant, thereby mimicking hyperacute rejection, probably due to an interaction between the endothelial cells of renal allograft and anti-donor hemagglutinin antibodies and hence reported for its newfangled contraption.

The diagnosis of TA-TMA be it systemic or renal limited requires careful reevaluation of the underlying etiology of ESRD, with particular attention to the fact that TMA can complicate various glomerulonephritis and small-vessel vasculitis syndromes. The index patient had biopsy-proven IgA nephropathy with significant chronicity. It is worth emphasizing that the diagnosis of aHUS may be overlooked in native kidneys in the absence of systemic signs of TMA and subsequent recurrence in allograft may be misclassified as de novo. However, genetic analysis done retrospectively did not reveal any of the currently implicated mutations or autoantibodies, and normal alternate pathway functional assay ruled out activation of the complement cascade.

With negative CDC as well as FCXM, successful desensitization (undetectable IgG anti-A titer as well as CD19 in posttransplant period), serial allograft biopsies not suggesting rejection, and insignificant Class 1 or 2 anti-human leukocyte antigens antibodies, and hyperacute or accelerated acute ABMR appeared less likely.

Tacrolimus is associated with renal-limited TMA, in approximately 1% of solid-organ transplant recipients. However, normal trough levels, an absence of acute tacrolimus toxicity on allograft biopsy, florid systemic TMA despite drug withdrawal made this possibility unlikely.

Although clinical and pathological profile (hypertension, systemic TMA, renal dysfunction, and allograft biopsy) resembled antiphospholipid syndrome nephropathy (APSN);[6] however, severe thrombocytopenia, absence of proteinuria, dialysis-requiring renal dysfunction in the absence of allograft vascular thrombosis, and undetectable antiphospholipid antibodies made APSN an inconceivable possibility in the index case.

Exhaustive workup [Table 1]b for other albeit rarer differentials for TMA (including thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, and sepsis) were negative.

Last but not the least, even blood group incompatible transplantation may itself be a risk factor for TA-TMA, as demonstrated in ABO-incompatible liver transplantation,[7] whereby interaction between anti-donor hemagglutinin antibodies and endothelial cells of allograft activates compliment cascade resulting in microthrombi,[8] akin to cadaveric transplantation, where prolonged cold ischemia time and reperfusion injury results in endothelial damage and consequent TMA.

With no clear guidelines on the management of de novo TA-TMA in the early postoperative period, treatment options remain debatable. CNI withdrawal with a switch to belatacept[9] or mTORi[10] with PLEX[5] has been reported to be relatively effective with a graft salvage rate of 80% and early eculizumab initiation in aHUS recurrence after transplantation[11] seems promising.

In the absence of plausible alternative etiology for florid TA-TMA following blood group incompatible renal transplantation at first instant, subsequent normal graft function after blood group compatible deceased donor renal transplantation and applying principle of Occam's razor, it may be conceivable to attribute first allograft loss in index case to blood group incompatible renal transplantation itself, thereby implicating the role of anti-donor hemagglutinin antibodies.[12] These antibodies even though in low titers, can still be pathogenic and contribute to allograft loss, even in the absence of complement activation, as evident in index patient, however, requires further deliberation.

To conclude, for reasons unknown, an incongruous interaction between anti-donor hemagglutinin antibodies and endothelial cells remains underreported in blood group incompatible renal transplantation till date. We, therefore, suggest that patients willing to proceed for blood group incompatible renal transplantation need to be preemptively apprised of this albeit infrequent, yet devastating entity during pretransplant counseling.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.

Acknowledgment

  • Nephrology – Prof. KL Gupta, Prof. HS Kohli, Prof. Manish Rathi, Dr Vivek Kumar and Dr Navin P
  • Transplant surgery – Dr. SP Singh and Dr Deepesh Kenwar
  • Transfusion Medicine – Prof. RR Sharma.


Financial support and sponsorship

Nil.

Conflicts of interest

There are nao conflicts of interest.



 
  References Top

1.
Reynolds JC, Agodoa LY, Yuan CM, Abbott KC. Thrombotic microangiopathy after renal transplantation in the United States. Am J Kidney Dis 2003;42:1058-68.  Back to cited text no. 1
    
2.
Abbas F, El Kossi M, Kim JJ, Sharma A, Halawa A. Thrombotic microangiopathy after renal transplantation: Current insights in and and recurrent disease. World J Transplant 2018;8:122-41.  Back to cited text no. 2
    
3.
Nester CM, Barbour T, de Cordoba SR, Dragon-Durey MA, Fremeaux-Bacchi V, Goodship TH, et al. Atypical aHUS: State of the art. Mol Immunol 2015;67:31-42.  Back to cited text no. 3
    
4.
Schwimmer J, Nadasdy TA, Spitalnik PF, Kaplan KL, Zand MS. De novo thrombotic microangiopathy in renal transplant recipients: A comparison of hemolytic uremic syndrome with localized renal thrombotic microangiopathy. Am J Kidney Dis 2003;41:471-9.  Back to cited text no. 4
    
5.
Karthikeyan V, Parasuraman R, Shah V, Vera E, Venkat KK. Outcome of plasma exchange therapy in thrombotic microangiopathy after renal transplantation. Am J Transplant 2003;3:1289-94.  Back to cited text no. 5
    
6.
Turrent-Carriles A, Herrera-Félix JP, Amigo MC. Renal Involvement in Antiphospholipid Syndrome. Front Immunol 2018;9:1008.  Back to cited text no. 6
    
7.
Tamura S, Sugawara Y, Matsui Y, Kishi Y, Akamatsu N, Kaneko J, et al. Thrombotic microangiopathy in living-donor liver transplantation. Transplantation 2005;80:169-75.  Back to cited text no. 7
    
8.
Miyata R, Shimazu M, Tanabe M, Kawachi S, Hoshino K, Wakabayashi G, et al. Clinical characteristics of thrombotic microangiopathy following ABO incompatible living donor liver transplantation. Liver Transpl 2007;13:1455-62.  Back to cited text no. 8
    
9.
Cicora F, Paz M, Mos F, Roberti J. Use of belatacept as alternative immunosuppression in three renal transplant patients with de novo drug-induced thrombotic microangiopathy. Case Rep Med 2013;2013:260254.  Back to cited text no. 9
    
10.
Cortina G, Trojer R, Waldegger S, Schneeberger S, Gut N, Hofer J. De novo tacrolimus-induced thrombotic microangiopathy in the early stage after renal transplantation successfully treated with conversion to everolimus. Pediatr Nephrol 2015;30:693-7.  Back to cited text no. 10
    
11.
Ikeda T, Okumi M, Unagami K, Kanzawa T, Sawada A, Kawanishi K, et al. Two cases of kidney transplantation-associated thrombotic microangiopathy successfully treated with eculizumab. Nephrology (Carlton) 2016;21 Suppl 1:35-40.  Back to cited text no. 11
    
12.
Jackson AM, Sigdel TK, Delville M, Hsieh SC, Dai H, Bagnasco S, et al. Endothelial cell antibodies associated with novel targets and increased rejection. J Am Soc Nephrol 2015;26:1161-71.  Back to cited text no. 12
    


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This article has been cited by
1 Thrombotic microangiopathy and rejection in blood group incompatible renal transplantation
PraveenKumar Etta
Indian Journal of Transplantation. 2020; 14(1): 5
[Pubmed] | [DOI]



 

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