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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 16  |  Issue : 4  |  Page : 419-424

Clinicopathological correlation of transplant nephrectomies in elusive graft dysfunction - An observational study


1 Department of General Medicine, Chettinad Hospital and Research Institute, Chennai, Tamil Nadu, India
2 Department of Nephrology, Madras Medical Mission, Chennai, Tamil Nadu, India
3 Department of Pathology, Madras Medical Mission, Chennai, Tamil Nadu, India
4 Department of Transplant and Vascular Surgery, Madras Medical Mission, Chennai, Tamil Nadu, India
5 Department of Urology, Madras Medical Mission, Chennai, Tamil Nadu, India

Date of Submission06-Aug-2020
Date of Acceptance27-Jun-2022
Date of Web Publication30-Dec-2022

Correspondence Address:
Dr. Georgi Abraham
Madras Medical Mission, 4th A St, Dr J, Jayalalithaa Nagar, Mogappair, Chennai - 600 037, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_94_20

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  Abstract 


Aim: The objective of this study is to review the pathology and outcome of kidney allograft nephrectomies performed in a single renal transplant center in South India. In our regional center, a total of 721 renal transplants were done between January 2001 and March 2020, of which 18 underwent transplant nephrectomy (TN). Materials and Methods: Clinical data concerning patient characteristics, duration of allograft functions, indications, complications, and subsequent follow-up details were assessed. The median age of patients at the time of transplantation who underwent TN was 35 years. Among the 18 allografts, 16 were from live-related donors and a deceased donor after circulatory/brain death in two patients. Associated comorbidities found at the time of transplantation mainly consist of diabetes mellitus, hypertension, and coronary artery disease. A standard triple immunosuppressive regimen along with mTOR inhibitors was followed in all patients. The morphology of the allograft nephrectomy was studied in elusive graft dysfunction. Results: In our study, while the infection was found to be the leading cause of renal allograft failure clinically, on pathological examination of TN specimens, rejection (44.44%) contributed to failure the most. Early graft failure (55.56%) was related to hyperacute rejection or vascular complications. Late graft failure (44.44%) was associated with infection and rejection. No significant mortality was observed in our study. Conclusion: Clinicopathological correlation to arrive at a diagnosis for graft failure contributes to more effective postnephrectomy care of the patient since often the underlying pathology is masked by other incidental occurrences. It also aids in gauging the patient's chances of undergoing further transplant and graft survival.

Keywords: Allograft nephrectomy, histopathology of allograft, irreversible graft dysfunction, kidney transplantation


How to cite this article:
Anupama SH, Pradeep I, Mathews S, Abraham G, Parthasarathy R, Mathew M, Sundaraja S, Kurien A, Palaniappan N. Clinicopathological correlation of transplant nephrectomies in elusive graft dysfunction - An observational study. Indian J Transplant 2022;16:419-24

How to cite this URL:
Anupama SH, Pradeep I, Mathews S, Abraham G, Parthasarathy R, Mathew M, Sundaraja S, Kurien A, Palaniappan N. Clinicopathological correlation of transplant nephrectomies in elusive graft dysfunction - An observational study. Indian J Transplant [serial online] 2022 [cited 2023 Feb 3];16:419-24. Available from: https://www.ijtonline.in/text.asp?2022/16/4/419/364630




  Introduction Top


Renal transplantation results in significant improvement in the survival of patients with end-stage renal disease (ESRD). The incidence of ESRD in India is estimated to be between 150 and 230 per million population.[1] In India, over 7500 renal transplantations are performed at 250 centers predominantly live, and a small percentage consists of deceased donor transplantation.[2] Renal allograft/transplant nephrectomy (TN) is performed following irreversible graft vessel thrombosis, hyperacute rejection, refractory pyelonephritis and renal abscess, graft artery aneurysm and pseudoaneurysms, and rarely due to untreatable malignancies in the allograft. Allograft nephrectomy may be performed either in the early part following transplantation or late. In addition to being associated with significant mortality and morbidity, TN also influences the subsequent outcome of re-transplantation due to increased production of antibodies against any mismatched antigens limiting future transplantation. The purpose of this study is to analyze the clinical features, pathology, and outcome of renal allograft nephrectomies performed in a single renal transplant center in South India. Here, we describe our experience of clinicopathological correlation of transplant nephrectomies in elusive graft dysfunction over 19 years.


  Materials and Methods Top


Among a total of 721 renal transplants done in our center between January 2001 and March 2020, 17 patients underwent 18 TN. Before undergoing nephrectomy, the patient underwent an ultrasound Doppler, a nuclear medicine scan to assess the status of blood flow to the allograft and a computed tomography (CT) scan or magnetic resonance imaging. Clinical data regarding patient characteristics, duration of allograft function, indications, complications, and subsequent follow-up details were obtained from the computer database and medical records section. The histopathology slides were retrieved and reviewed using the Banff classification (2018) of renal allograft pathology.

Declaration of patient consent

The patient consent has been taken for participation in the study and for the publication of clinical details and images. Patients understand that the names and initials would not be published, and all standard protocols will be followed to conceal their identity.

Ethics statement

The study was performed according to the guidelines in Declaration of Helsinki. As it was an analysis of records EC approval was not deemed necessay.


  Results Top


Clinical

A total of 18 TNs were done in 17 patients (ten males and seven females; one male patient underwent TN twice). The median age was 35 years. Allografts retrieved were from live-related donors in 15 patients and from deceased donors after circulatory/brain death in two patients. Associated comorbidities found at the time of transplantation include hypertension (94.11%), diabetes mellitus (23%), and hypothyroidism (11.7%). Demyelinating polyradiculopathy and chronic heart failure were seen in one patient each. One patient gave a history of pulmonary tuberculosis. A 27-year-old young African male underwent transplantation twice, having developed hyperacute rejection on both occasions, was followed up by transplant nephrectomies. Another 22-year-old female patient with IgA nephropathy showed antibody-mediated rejection (ABMR) posttransplantation and was advised against nephrectomy. She underwent TN elsewhere, for elevated panel reactive antibodies (PRA) against Class I and II antigens. Despite the nephrectomy, PRA levels remained high, and the patient returned to our center and was maintained on hemodialysis. [Table 1] describes the demographic data of the patients included in the study as well as the clinical and pathological diagnosis of the patients' prenephrectomy and postnephrectomy.
Table 1: Demographic data of the patients showing clinicopathological diagnosis and findings

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The standard maintenance immunosuppressive regimen followed in all our patients was calcineurin inhibitors (cyclosporin or tacrolimus), mTOR inhibitors, mycophenolate mofetil, and prednisolone. Induction therapy consisted of interleukin-2 R-inhibitor basiliximab initially and since 2007 onward, thymoglobulin. All patients had complement-dependent cytotoxicity crossmatch and human leukocyte antigen typing for Class 1 and 2 antigens before transplantation. The vascular anastomosis consisted of end-to-side of the renal vein to the external iliac vein and renal artery to the external iliac artery. Clamps were applied above, and below the external iliac vein then a venotomy was performed. End-to-side anastomosis of the vein was done with continuous 5–0 prolene sutures. Clamps were applied above and below the external iliac artery, and small arteriotomy was performed, 4.5 or 5 punch was used to make a circular hole in the artery, nicely flushed with heparinized saline then papaverine followed by an end-to-side anastomosis with 6–0 prolene sutures. Clamps were released except the lower arterial clamp which was released after thoroughly perfusing the kidney and hemostasis was secured before starting the ureteric anastomosis. The donor kidney function assessment included serum creatinine, isotope renogram for glomerular filtration rate, and CT angiogram to look for the number of donor renal blood supply.

The left kidney was harvested in the majority of patients unless there was a complex abnormality of the renal vasculature or diminished function. In our setup, during a live transplant, the initial warm ischemia time accounts for around 3 min following which the cold ischemia time ranges from 20 to 30 min. The subsequent warm ischemia time is about 32 min. If there was a delay in graft function, a Doppler ultrasound and nuclear medicine scans were used to study blood flow. Early graft failure was seen in 12 TNs with almost all of them showing irreversible graft loss within 3 months related to hyperacute rejection or vascular complications (vascular thrombosis and anastomotic site leak/pseudoaneurysm). Late graft failure (≥1 year) was seen in the remaining 6 TNs and was associated with rejection and accompanying intractable infection. These patients returned to maintenance hemodialysis. [Figure 1] shows a gross specimen of a TN (a) and a specimen of allograft showing kidney abscess (b).
Figure 1: (a) Transplant nephrectomy specimen. (b) A 37 year old male with renal graft abscess (yellow arrows)

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Histopathology

The hematoxylin-eosin stain, special stains including periodic acid–Schiff, silver methenamine and Masson trichrome, and immunohistochemistry for C4d and SV-40 were done in all cases, and two competent nephropathologists made interpretation independently by the Banff classification for renal allograft biopsies (2018) Histopathological diagnosis is as summarized in [Table 2] and stain images are shown in [Figure 2]. Eight patients had rejection, of which one patient had acute T-cell-mediated rejection (aTCMR), two patients had aTCMR with c4d-positive active ABMR, and one patient had active ABMR. Four patients had hyperacute rejection with diffuse cortical necrosis. Two patients with late graft failure developed acute on chronic pyelonephritis. Six patients had diffuse cortical necrosis due to arterial thrombus, and one patient developed anastomotic site pseudoaneurysm which was repaired with polytetrafluoroethylene graft which grew multidrug-resistant Pseudomonas aeruginosa. One patient developed diffuse cortical necrosis with no evident underlying etiology detected in histopathology. All patients with ABMR in our series had serum donor-specific antibodies and C4d positive. There was no evidence of recurrence of native kidney disease in any of the specimens in whom native kidney disease was earlier diagnosed.
Table 2: Pathological diagnosis of transplant nephrectomy of the study population

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Figure 2: (a and b) A 47-year-old with renal artery thrombus resulting in diffuse cortical necrosis. (c) A 63-year-old male with Acute Pyelonephritis. (d) A 34-year-old presenting with hyperacute rejection with cortical necrosis and neutrophil-rich interstitial inflammation. (e and f) A 39-year-old with acute antibody-mediated rejection with glomerulitis, interstitial plasma cell-rich inflammation, hemorrhage, and C4d positivity (immunohistochemistry)

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  Discussion Top


In addition to the increase in kidney transplantations, there has also been a surge in the number of patients reverting to dialysis, owing to graft failure. Vascular complications due to arterial thrombosis and anastomotic site leak due to pseudoaneurysm were attributed to most of the patients with early graft failure.[3] The probability of developing renal allograft thrombosis may be tripled with the presence of factor V Leiden, prothrombin G20210A mutation, or antiphospholipid antibodies (APA).[3] These patients also tend to show more risk of graft loss due to the aggravation or induction of the prothrombotic state resulting in immunological insult on the vessel wall. Patients with chronic kidney disease secondary to systemic lupus erythematosus appear to be at a higher risk of thrombosis, especially in the presence of APA or beta 2-glycoprotein-1.[3]

The majority of early graft thrombus is found within 48 h postoperatively. However, they may evolve until after the 1st week. While most originate in the renal vein, and less commonly in the renal artery, in some cases, their origin is difficult to determine. In renal artery thrombosis, the presence of an atheroma is the only known independent factor. Elderly donors are associated with an increased risk of graft thrombosis most likely attributed to donor hypotension coupled with reperfusion injury leading to activation of procoagulant cytokines and the target immune response in atherosclerotic vessels.[4] The use of monoclonal antibody OK3 and the resultant induction of procoagulant activity may increase the risk of renal artery thrombosis.[4] The risk is accentuated by the use of high-dose intravenous methylprednisolone. Late thrombosis in renal allograft is defined as occurring later than 14 days but may rarely form up to a few months' posttransplantation with the most common etiological factor being trauma. It may also arise as a complication of intra-abdominal surgery. There may be slow progressive development of renal artery thrombosis in patients with vascular abnormalities, late hemolytic uremic syndrome, or antiphospholipid antibody carriers. Allograft renal vein thrombosis may be caused by renal vein kinking, compression, and often from the extension of deep vein thrombosis to the allograft vein. According to the USRDS data, the incidence of deep vein thrombosis in renal transplant recipients is 2.9 episodes/100 person-year.[4] This risk is increased in patients with renal insufficiency, nephrotic syndrome, increased packed cell volume, infection, rejection, or factor V Leiden mutation.[4] Vascular complications can also be attributed to the comorbidities and technical difficulties encountered during transplantation. TN for late graft failure patients in our center is evaluated on an individual basis due to risks associated with sensitization and donor-specific antibody development in failing re-transplanted kidneys. Infection and rejection of graft kidneys were seen in more than 90% of late graft failure patients. The incidence of pyelonephritis among other infections is higher in renal allografts due to the absence of Gerota's fascia. Allograft pyelonephritis was resistant to therapy in seven of our patients.[5] Among our study population having pyelonephritis, infection with extended spectrum beta-lactamase was observed in 71.4%. A common complication seen with 50%–86% of kidney allografts is vesicoureteral reflux which in turn increases the risk or transplant pyelonephritis by 8-fold.[6] A wide ureteroneocystostomy is preferred by surgeons over a tunneled re-implantation to reduce the risk of urethral stenosis. Inadequate titration of immunosuppression in the late posttransplant period, due to poor compliance for periodic follow-up also adds to the burden. Socioeconomic factors play a vital role in the accessibility for specialty clinical care in our part of the country. Our study is, however, limited by the small size of the retrospective cohort with few comorbidities and younger group of patients. Hyperacute rejection hypothesized to be caused by preformed cytotoxic antibodies occurs within 48 h after transplant and is characterized by ischemia and necrosis of the graft. Studies also implicate the action of endothelial monocyte alloantigen system, the anti-vascular immunoglobulin G endothelial cell antibodies, and the immunoglobulin M antibodies that are reactive against endothelial cells as provocative factors in the induction of hyperacute rejection.[7] These antibodies may not be detectable by the conventional lymphocytotoxic crossmatch methods done before transplantation.[7] Accelerated renal allograft rejection usually occurs within 24 h after transplantation but could happen within a few days.[8] Hyperacute rejection leading to graft failure is seen in only 0.7% of all index or subsequent transplant patients according to the latest NAPRTCS report.[9] The clinical presentation of hyperacute rejection includes high-grade temperature and general malaise. Medical management consists of plasmapheresis, albeit hyperacute rejection is unresponsive to treatment and ultimately leads to TN.[7] The incidence of posttransplant pyelonephritis in recipients is known to be between 10% and 25% with almost 50% being asymptomatic. Transplant pyelonephritis shows histopathological similarity to acute cellular rejection (ACR) showing interstitial infiltrates and tubulitis, thereby masking the detection of ACR. Acute graft pyelonephritis (AGPN) is seen in patients' posttransplant with an incidence of 10% and 25%.[10] The incidence of urinary tract infection (UTI) in patients' postkidney transplant is reported to be between 10% and 85%.[10] UTI occurring posttransplant can cause graft dysfunction, through mechanisms such as free-radical production, inflammatory cytokine response, cytomegalovirus infection reactivation, and pyelonephritis resulting in scarring. Furthermore, a study by Khanna et al. showed 14.4% of patients with acute rejection requiring higher immunosuppression may develop UTI.[11] UTI, as well as AGPN, can progress to bacteremia, subsequently increasing the risk of morbidity and mortality notably in the initial 6 months following transplantation.[12]

Several studies demonstrate a higher risk of infection in patients with transplant ureteric stenting as opposed to those without stents by Branitz et al. and Ranganathan et al.[13],[14] Further they showed that patients who sustained UTI with stent in situ were at a higher risk to develop UTI even poststent removal.[15] In up to 20% of deceased-donor kidney transplants, delayed graft function may occur requiring, peritoneal dialysis in continuous ambulatory peritoneal dialysis patients. However, an indwelling peritoneal dialysis catheter has been associated with a higher risk of infections.[16] The prevalence of kidney allograft rupture ranges from 0.3% to 9.6% with a mean of 3.4%.[17] It is known to occur within 3 weeks of transplantation.[18] The most common cause and primary predisposing factor in almost 60%–80% of cases of kidney graft rupture is acute rejection followed by ischemic acute kidney injury, acute tubular necrosis, injury to hilar lymphatic channels, renal vein thrombosis, urethral obstruction with resultant hydronephrosis, allograft kidney biopsy, trauma, nephrostomy tubes, and renal cell carcinoma.[19] Although some ruptures can be successfully repaired others require graft nephrectomy as seen is some of our earlier patients.[20],[21] The presence of multiple renal arteries is not known to impact the presence of long-term graft survival and function adversely.[22]

Clinicopathological correlation to arrive at a diagnosis for graft failure contributes to more effective postnephrectomy care of the patient since often the underlying pathology is masked by other incidental occurrences. It also aids in gauging the patients chances of undergoing further transplant and graft survival.


  Conclusion Top


In our study, while the infection was found to be the leading cause of renal allograft failure clinically, on pathological examination postnephrectomy, rejection (44.44%) contributed to failure the most. Majority of TNs are due to early graft failure (55.56%) secondary to vascular complications or rejection. Late graft failure (44.44%) was mostly attributed to infections. There is no significant mortality and morbidity observed in our series.

Limitations

The number of cases in the study may reduce the chance of randomization. There are no other limitations to this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Modi G, Jha V. Incidence of ESRD in India. Kidney Int 2011;79:573.  Back to cited text no. 1
    
2.
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Irish A. Hypercoagulability in renal transplant recipients. Identifying patients at risk of renal allograft thrombosis and evaluating strategies for prevention. Am J Cardiovasc Drugs 2004;4:139-49.  Back to cited text no. 3
    
4.
Ponticelli C, Moia M, Montagnino G. Renal allograft thrombosis. Nephrol Dial Transplant 2009;24:1388-93.  Back to cited text no. 4
    
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Abraham G, Anupama S, Mathew M, Rohit A, Kurien A. Multidrug-resistant coinfection and emphysematous pyelonephritis in a deceased donor allograft – Treatment dilemma. Indian J Transplant 2019;13:127.  Back to cited text no. 5
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Aristizabal-Alzate A, Salazar-Villa G, Yepes-Delgado C, Serna-Higuita LM, Nieto-Rios JF, Ocampo-Kohn C, et al. Vesicoureteral reflux management with subureteral injection of polydimethylsiloxane in cases of recurrent pyelonephritis in transplanted kidneys. World J Nephrol Urol 2016;5:71-8.  Back to cited text no. 6
    
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Smith JM, Martz K, Blydt-Hansen TD. Pediatric kidney transplant practice patterns and outcome benchmarks, 1987-2010: A report of the North American Pediatric Renal Trials and Collaborative Studies. Pediatr Transplant 2013;17:149-57.  Back to cited text no. 9
    
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Khanna P, Abraham G, Mohamed Ali AA, Miriam PE, Mathew M, Lalitha MK, et al. Urinary tract infections in the era of newer immunosuppressant agents: A tertiary care center study. Saudi J Kidney Dis Transpl 2010;21:876-80.  Back to cited text no. 11
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Fiorante S, Fernández-Ruiz M, López-Medrano F, Lizasoain M, Lalueza A, Morales JM, et al. Acute graft pyelonephritis in renal transplant recipients: Incidence, risk factors and long-term outcome. Nephrol Dial Transplant 2011;26:1065-73.  Back to cited text no. 12
    
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Ranganathan M, Akbar M, Ilham MA, Chavez R, Kumar N, Asderakis A. Infective complications associated with ureteral stents in renal transplant recipients. Transplant Proc 2009;41:162-4.  Back to cited text no. 14
    
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Akoh JA, Rana T. Effect of ureteric stents on urological infection and graft function following renal transplantation. World J Transplant 2013;3:1-6.  Back to cited text no. 15
    
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Szenohradszky P, Smehák G, Szederkényi E, Marofka F, Csajbók E, Morvay Z, et al. Renal allograft rupture: A clinicopathologic study of 37 nephrectomy cases in a series of 628 consecutive renal transplants. Transplant Proc 1999;31:2107-11.  Back to cited text no. 18
    
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