9. MANAGEMENT OF THE COMPLICATIONS OF LONG-TERM IMMUNOSUPPRESSION

Although not specific to this group, many patients with a failing graft have been subject to long-term immunosuppression and we have covered some of the most common complications this treatment can cause.

9.1 Malignancy

9.1.1 Post-Transplant Lymphoproliferative Disorders (PTLD)

Statements of Recommendation

We recommend:

• All transplant recipients with PTLD receive joint care including a transplant physician and a specialist haematologist/haemato-oncologist. (1A)
• Sequential reduction in immunosuppression (RIS) with an initial withdrawal of anti-proliferative agent followed by a reduction of calcineurin inhibitor (CNI) dose by 30–50% whilst maintaining or reducing corticosteroids, with surveillance of graft function. (1B)
• Early disease response assessment (at 2–4 weeks) is recommended in those patients following RIS alone so that further treatment (chemotherapy) can be initiated in those that fail to respond. (1B)
• In the context of a failing kidney transplant, the objective of treatment should be to achieve complete remission of lymphoma with curative intent both to improve prognosis and to enable re-transplantation. (Ungraded)
• Re-transplantation can be considered after a minimum of 1-year disease-free period following remission, but a longer period may be needed in selected cases. (2C)

Recommendations for audit and research:

• Incidence of PTLD, histological subtypes, Epstein-Barr virus (EBV) and non-EBV associated lymphoma) in kidney transplant patients and characteristics including demographics, clinical presentation, management and outcomes.
• Re-transplantation rates and outcomes in patients with previous PTLD.
• The role of EBV-specific cytotoxic T-lymphocytes in the management of post-transplant lymphoma.

Rationale

Post-transplant lymphoproliferative disorders (PTLD) arise due to lymphoid or plasmacytoid proliferation in the context of immunosuppression (IS) following a solid organ transplant (SOT). PTLD accounts for 21% of all cancers in SOT recipients whereas lymphomas account for only 4-5% of all cancers in the immunocompetent population.^1,3Although most cases are reported within one year of transplant, presentation beyond one year is not uncommon. Compared to other organs, kidney transplant recipients (KTR) have the lowest incidence of PTLD (0.8-2.5%).^1,2The disease is usually EBV-driven diffuse large B cell lymphoma but Hodgkin’s lymphoma and non-EBV associated non-Hodgkin’s lymphoma are also described.  These patients need multidisciplinary care, and it is recommended that all patients are discussed with a haemato-oncology multidisciplinary team (MDT) with input from transplant physicians. For details on diagnosis, staging, grading and management, please refer to British Society of Haematology guidelines.³

The management of PTLD usually involves a sequential reduction in IS. The anti-proliferative agent (azathioprine or mycophenolate mofetil) is withdrawn and the calcineurin inhibitor (CNI) dose is reduced by 30-50% whilst maintaining corticosteroids (prednisolone 5-10mg once daily). Most patients require chemotherapy including Rituximab, either as a single agent or in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone). Mild, localised disease may respond to IS reduction alone and initial close observation. In high-risk cases with more advanced and aggressive disease (Ann Arbor stage ≥III, elevated LDH and more than one extra nodal disease), concomitant chemotherapy would be required along with RIS. A significant reduction or withdrawal of IS carries a risk of rejection and graft failure which is easier to manage for KTR than heart or lung transplant recipients where, unlike kidney failure, long term organ support therapies are not available.  In kidney transplant patients, the patient and graft specific factors to take into consideration while reducing/stopping immunosuppressive medications include graft function and urine output.

In the context of a failing kidney transplant, the management of PTLD should focus on achieving complete remission of lymphoma with curative intent both to improve patient prognosis and to enable re-transplantation. This usually means a more aggressive reduction or complete withdrawal of immunosuppression depending on the severity and extent of lymphoma followed by chemotherapy. Transplant nephrectomy should be considered in patients with poor graft function where the kidney is infiltrated by lymphoma.

With regards to retransplantation, the current joint guideline of the British Committee for standards in Haematology and the British Transplant Society recommends that patients with PTLD wait for at least one year after achieving complete metabolic remission prior to consideration of retransplantation.³ It is advisable to have undetectable or low EBV viral load prior to retransplantation as increased IS in the early post-transplant period can lead to an increase in viremia and consequent increased risk of B cell proliferation and development of lymphoma. However, due to a lack of evidence in this field, we are unable to recommend a threshold blood EBV level (viral load) prior to transplantation and there are reports of re-transplantation in patients with active EBV viremia.⁴ The risk-to-benefit ratio of proceeding with kidney transplantation in patients with previous PTLD and ongoing EBV viremia should be considered carefully on a case-by-case basis and decisions made in liaison with the haemato-oncologist.

For relapsed or refractory EBV positive B cell PTLD, adoptive immunotherapy with EBV -specific cytotoxic T cells (CTLs) offers another therapeutic option without the risk of graft rejection.  These EBV-specific cytotoxic T cells are either the recipient’s own T cells used to generate EBV-directed T cells (autologous) or from a bank of HLA-matched/partially matched EBV-specific T cells.^5,6,7 Although this treatment is currently not widely used, increasing safety and efficacy data could make it more available in the future.

References

1. Caillard S, Porcher R, Provot F, et al. Post-transplantation lymphoproliferative disorder after kidney transplantation: report of a nationwide French registry and the development of a new prognostic score. J Clin Oncol 2013;31:1302-9.
2. Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2004;4:222-30.
3. Shah N, Eyre TA, Tucker D, et al. Front-line management of post-transplantation lymphoproliferative disorder in adult solid organ recipient patients – A British Society for Haematology Guideline. Br J Haematol 2021;193:727-40.
4. Caillard S, Cellot E, Dantal J, et al. A French Cohort Study of Kidney Retransplantation after Post-Transplant Lymphoproliferative Disorders. Clin J Am Soc Nephrol 2017;12:1663-70.
5. Savoldo B, Goss JA, Hammer MM, et al. Treatment of solid organ transplant recipients with autologous Epstein Barr virus-specific cytotoxic T lymphocytes (CTLs). Blood 2006;108:2942-9.
6. Vickers MA, Wilkie GM, Robinson N, et al. Establishment and operation of a Good Manufacturing Practice-compliant allogeneic Epstein-Barr virus (EBV)-specific cytotoxic cell bank for the treatment of EBV-associated lymphoproliferative disease. Br J Haematol 2014;167:402-10.
7. Liu JY, Zhang JM, Zhan HS, Sun LY, Wei L. EBV-specific cytotoxic T lymphocytes for refractory EBV-associated post-transplant lymphoproliferative disorder in solid organ transplant recipients: a systematic review. Transpl Int. 2021; 34(12):2483-2493.

9.1.2 Solid Organ Cancers

Statements of Recommendation

We recommend that:

• Screening for cancer in patients with a failing kidney transplant should be done in accordance with national guidelines (for cervical, breast and colon cancer). Screening for renal cell cancer is not recommended. (2C)
• Patients should be aware of cancer risk and encouraged to report symptoms which may represent malignancy (breast lump, testicular lump, lower urinary tract symptoms, haematuria). (2D)
• Kidney transplant recipients with a failing graft and previously treated cancer should be considered for re-transplantation. (1B)
• Recommended time interval between remission from cancer and transplantation depends on the type, grade and stage of the cancer. (Ungraded)

Recommendations for audit and research:

• Outcomes of patients re-transplanted following treatment of solid organ cancer.
• Optimal IS regimens for kidney transplant recipients with solid organ cancers.

Rationale

Kidney transplant recipients are at higher risk of developing certain solid organ cancers, thought to be in part mediated by long-term IS and altered T cell anti-tumour immune surveillance. The risk varies for different cancers (summarised in the RA/BTS Clinical Practice Guideline Post-operative care in kidney transplant recipients¹). The main objective of the management of transplant recipients with cancer is to achieve complete remission/cure from cancer with surgery, chemotherapy, radiotherapy and immunotherapy as required. Preservation of renal function facilitates adequate cancer treatment and improves tolerance to chemotherapy. Therefore, preserving renal function and residual urine output with continuation of low-level IS should be considered while the patient undergoes active treatment for cancer under surgical and oncology teams.  Complete withdrawal of IS can lead to severe rejection with consequent hyperinflammatory state, anaemia and return to dialysis which is an undesirable outcome for patients undergoing treatment for cancer. Liaison with the oncology team is recommended when considering any augmentation of IS.

Patients with a failing kidney transplant and a history of successfully treated cancer can be considered for kidney re-transplantation. However, it is important to estimate the risk of cancer recurrence and the patient needs to be counselled accordingly before being placed on the deceased donor waiting list for a second or subsequent transplant or proceeding with living donor transplantation. Solid organ cancer recurrence is dependent on tumour type and the time interval between remission/cure and transplantation with a longer interval associated with a lower risk of recurrence. Overall, 53% of recurrences occur in patients transplanted within 2 years of cancer treatment, falling to 34% if the interval is 2-5 years and 13% if the interval is > 5 years but this is dependent on the organ involved, stage and histological grade at the time of diagnosis and the response to treatment. ^2,3

Appendix 9.1 recommends the waiting time following curative treatment of malignancy prior to proceeding to re-transplantation, adapted from a recent American consensus expert opinion.² It is essential to make decisions following discussions with the treating Oncologist and Surgeon. Most recurrences occur within 3 years; generally, once a disease-free interval of 3–5 years after all treatments has been completed, patients could be considered as transplant candidates.

References

1. Renal association and British Transplantation Society clinical practice guideline on post-operative care in the kidney transplant recipient. Richard J Baker, Patrick B Mark, Rajan K Patel, Kate K Stevens, Nicholas Palmer. BMC Nephrol. 2017; 18: 174 (https://bts.org.uk/wp-content/uploads/2017/06/FINAL_PostOperative_Care_Guideline.pdf)

2. Al-Adra DP, Hammel L, Roberts J, et al. Pretransplant solid organ malignancy and organ transplant candidacy: A consensus expert opinion statement. Am J Transplant 2021;21:460-74.
3. Acuna SA, Sutradhar R, Kim SJ, Baxter NN. Solid Organ Transplantation in Patients With Pre-existing Malignancies in Remission: A Propensity Score Matched Cohort Study. Transplantation 2018;102:1156-64.

Appendix 9.1

Recommended wait time for transplant candidates with prior history of:

Breast cancer

Risk/Stage	Recommended time interval to transplant	Additional considerations
Low risk: Ductal carcinoma in situ and stage I	No wait time	Continuation of endocrine therapy is not a contraindication for transplantation. Oestrogen receptor-negative disease may have a slightly higher rate of recurrence in the first 2-3 years
Intermediate Risk Stage II	2 Years	Oestrogen receptor-negative disease may have slightly higher rate of recurrence in first 2-3 years
High risk Stage III	3-5 Years	Oestrogen receptor-negative disease may have slightly higher rate of recurrence in first 2-3 years. Inflammatory breast cancer likely has a higher risk of recurrence and worse survival

 

Colon cancer

Risk/Stage	Recommended time interval to transplant	Additional considerations
Low risk Stage I (T1 or T2, N0, M0)	1 Year	High-risk features: Poorly differentiated histology, bowel obstruction, tumour perforation
Low Intermediate risk Stage II (T3, N0, M0)	2 Years, longer if high-risk features present
High Intermediate risk Stage II (T4, N0, M0) Stage III (Any T, N+, M0)	3 years, 5 years if high-risk features present
High risk Stage IV (Any T, Any N, M+)	5 years In patients with residual disease/metastasis, transplantation is not recommended

 

Rectal cancer

Risk/Stage	Recommended time interval to transplant	Additional considerations
Low risk Stage I (T1 or T2, N0, M0)	1 year, consider 2 years if high risk features are present	Poorly differentiated histology, bowel obstruction, tumour perforation, lower 1/3rd of rectum
High intermediate risk Stage II (T3, T4, N0, M0) Stage III (Any T, N+, M0)	3 years, 5 years if high-risk features are present
High Risk Stage IV (Any T, Any N, M+)	5 years. In patients with residual disease/metastasis, transplantation is not recommended

 

Urological malignancies

Prostate Cancer

Risk/Stage	Recommended time interval to transplant	Additional considerations
Very Low Risk and low risk -PSA<10ng/mL -3 or fewer cores of Gleason 6 (grade group 1); no greater than 50% of individual core -T1c-T2a	None	Surveillance recommended post-transplant
Low- volume Intermediate risk One of the following criteria: -PSA >10ng/mL, Gleason 7 (grade group 2 or 3), T2b	If decision is surveillance only, no wait time If treatment is initiated and nomogram (www.nomograms.org) predicts cancer-specific death over the next 15 years <10%, no wait time	Post-transplant, surveillance and treatment if required depending on patient and cancer characteristics
High-Volume Intermediate risk, High Risk or Very High Risk -PSA>20ng/mL or High volume Gleason 7 or any Gleason 8-10, T3	If treated, deemed cured and nomogram predicts cancer-specific death over the next 15 years <10%, no further wait time	May require treatment post-transplant if there is disease recurrence
Metastatic disease	Transplantation is not recommended	Castration-sensitive metastatic disease, treated with local and systemic therapy, stable disease for 2 years, may consider transplant

 

Renal cell carcinoma

Risk/Stage	Recommended time interval to transplant	Additional considerations
T1a (≤4 cm), N0, M0	No wait time	Resection/nephrectomy before listing is the standard approach but in selected cases, active surveillance can be an option. A biopsy can be useful in guiding management.
T1b (>4cm ≤7cm), N0, M0	1-2 years based on histology (Fuhrman grade)	Fuhrman grade (FG)1 -2: consider no wait time, FG 3-4: 1-2 years
T2 (7-10 cm), N0, M0	2 Years
T3, N0, M0	2-3 years
T4, N0, M0	2-3 years
Any T, Node positive, metastatic disease	Not a candidate	If solitary metastasis is resected and disease free for 2-3 years, MDM discussion

Bladder cancer

Risk/Stage	Recommended time interval to transplant	Additional considerations
Non-muscle invasive bladder cancer, low and Intermediate risk	6 months
Non-muscle invasive bladder cancer, High Risk	2 years
Muscle invasive, post radical cystectomy	2 Years
Muscle invasive, post chemo and radiotherapy	Not a transplant candidate

Gynaecological cancer

5-Year recurrence risk	Type and stage	Recommended time interval to transplant
Low risk (<5% risk of recurrence)	Stage I/IB, grade 1-2 endometrial cancer without lymph-vascular space invasion	No waiting period after the completion of primary treatment
	Stage IA/IB/IC Grade 1-2 ovarian cancer
	Stage IA1, IA2 squamous/ adenocarcinoma of the cervix
Intermediate Risk 5-15% risk of recurrence	Stage II endometrial cancer	2-3 years after completion of treatment
	Stage IB squamous/adenocarcinoma of the cervix
High Risk >30% risk of recurrence	Endometrial cancer: Aggressive/high-grade histology, any stage Stage III endometrial cancer	5 years after completion of treatment 5 years after completion of treatment
	Stage II/III Ovarian cancer
	Stage II/III Squamous cell/adenocarcinoma of cervix
Very high risk	Stage IV endometrial cancer (all grades) Recurrent or metastatic endometrial cancer	Not a transplant candidate
	Stage IV Ovarian cancer (any grade) Recurrent or metastatic Ovarian Cancer
	Stage VI Cervical cancer Recurrent or metastatic cervical cancer

Lung cancer

Stage	Recommended wait time
I (T1a, 1b, N0)	≥3 years
I (T1c N0)	3-5 years
IB (T2aN0)	5 years
IIA (T2bN0)	5 years
IIB (T3N0)	5 years
IIIA	5 years
Stage IIIB and higher	Not a transplant candidate

9.1.3   Skin cancers

The recommendations that are in place in the BTS/RA Clinical Practice Guideline ‘Post-operative care in the kidney transplant recipient’ should be continued for the management of skin disorders in the failing graft.⁶

Statements of Recommendation

We recommend that:

• Renal transplant recipients should be educated about the adverse effects of sun exposure. (1C)
• Patients should be encouraged to cover their skin in direct sunlight and to use total sunblock (Sun Protection Factor ≥50). (1D)
• Self-examination should be encouraged with guidance provided. This should be supplemented by a biannual review by a trained healthcare professional up to 5 years post-transplant and an annual review from 5 years. (2C)
• After initial screening, the frequency of subsequent reviews can be guided by a dermatologist based on risk assessment (skin type, previous history of skin cancers, immunosuppressive burden and any premalignant lesions). (Ungraded)
• Prescription of acitretin as chemoprophylaxis to be considered in those with ≥2 previous non-melanoma skin cancers (NMSC) if there are no contraindications. (2B)
• IS should be reduced if neoplasia develops. (2C)
• Following re-transplantation, CNI to mTOR inhibitor (Sirolimus or Everolimus) switch should be considered for recipients with a history of skin cancers, particularly squamous cell skin cancer. (2C)
• No waiting period before re-transplantation is required for basal or low-risk squamous cell carcinoma of the skin (surgical excision with clear margins), in situ melanoma following curative wide local excision. (1B)
• Following surgical excision with clear margins, high-risk squamous cell carcinoma of the skin without perineural invasion requires a two-year waiting period before re-transplantation. If the perineural invasion is found or adjuvant radiation therapy is required, a two- to three-year waiting period is required. (1B)
• Localised Merkel cell carcinoma of the skin treated with wide local excision requires a two-year, cancer-free period before re-transplantation (1B)
• A stage Ia melanoma treated with wide local excision requires a two-year, disease-free period. Other more advanced melanoma may require a five-year waiting period or maybe a contraindication to re-transplantation. (1B)

Recommendations for audit and research:

• Recurrence of skin cancers following re-transplantation in patients with a previous history of treated skin cancers
• Optimal immunosuppressive regimen in patients with a history of skin cancers following re-transplantation

Rationale

The incidence of cutaneous neoplasia is significantly increased in kidney transplant recipients compared to the general population.^1,2,3,4 The relative risk of developing melanoma and non-melanoma skin cancers are summarised in the BTS guideline on post-operative care of kidney transplant recipient.⁶  Patients with a failing kidney transplant are at higher risk of skin cancers due to a longer duration of immunosuppression exposure.⁵ A variety of factors, including the intensity and duration of IS, the patient’s ethnic background, sun exposure history, and geographic location, influence the likelihood of the development of skin cancer in these patients.

Regardless of graft function, the mainstay of management is the same with regular surveillance, reduction in IS and specific management by the dermatology/surgical team. Part of the treatment will involve the minimisation or modification of immunosuppressive therapy.  After re-transplantation, a switch to mTORi should be considered in patients with previously treated skin cancers, particularly squamous cell skin cancer. ^{12, 13}

The recommended twice-a-year review by a dermatologist for 5 years followed by an annual review is a target that is often not met in most centres. A survey published in 2020 found wide variations in skin surveillance for kidney transplant patients in the UK. Of the 51 (86%) centres responding, only 28 (55%) provided skin cancer surveillance post-transplantation.^10,11 There are wide variations in the frequency of monitoring and a recommended biannual assessment is often not achieved. Patients with a failing kidney transplant would have been exposed to immunosuppression for prolonged periods of time and therefore, it is advisable to ensure annual skin surveillance or at a frequency determined by the dermatologist. Following second and subsequent transplants, at least one dermatology review within the 1^st post-transplant year, followed by a review at intervals advised by the dermatology team (based on the previous history of skin cancers, skin type and current skin assessment) where bi-annual assessment is not possible could be a practical approach to achieve adequate dermatology surveillance. Patients should be encouraged to inspect their skin and report any new lesions.

The role of specific immunosuppressants on skin malignancies is unclear although limited evidence suggests that mycophenolic acid compounds may be less likely to cause NMSC compared to azathioprine. mTOR inhibitors may reduce the risk for NMSC in renal transplant patients compared with other immunosuppressive regimens.¹² The use of these agents should be carefully balanced with adverse effects and impact on graft function on a case-by-case basis.

References

1. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003 Apr 24;348(17):1681-91. doi: 10.1056/NEJMra022137. PMID: 12711744.
2. Greenberg JN, Zwald FO. Management of Skin Cancer in Solid-organ Transplant Recipients: A Multidisciplinary Approach. Dermatol Clin. 2011 Apr;29(2):231-41, ix. doi: 10.1016/j.det.2011.02.004. PMID: 21421148.
3. Chen QP, Aw DC. Epidemiology of skin diseases in renal transplant recipients in a tertiary hospital. Ann Acad Med Singap. 2010 Dec;39(12):904-5. PMID: 21274486.
4. Garrido PM, Borges-Costa J. Skin disorders in renal transplant recipients: a retrospective study. An Bras Dermatol. 2017;92(5):638-41.
5. British Transplantation Society. Management of the Failing Kidney Transplant. Available at:https://btsorguk/wp-content/uploads/2016/09/13_BTS_Failing_Graft-1pdf
6. Baker R J et al, Post operative care in the kidney transplant recipient, British Transplantation Society, February 2017
7. Garg S, Carroll RP, Walker RG, Ramsay HM, Harden PN. Skin cancer surveillance in renal transplant recipients: re-evaluation of U.K. practice and comparison with Australian experience. Br J Dermatol 2009;160:177-9.
8. Ramsay HM, Reece SM, Fryer AA, Smith AG, Harden PN. Seven-year prospective study nonmelanoma skin cancer incidence in U.K. renal transplant recipients. Transplantation 2007;84: 437-439
9. Zwald F, Leitenberger J, Zeitouni N, Soon S, Brewer J, Arron S, Bordeaux J, Chung C, Abdelmalek M, Billingsley E, Vidimos A, Stasko T. Recommendations for Solid Organ Transplantation for Transplant Candidates With a Pretransplant Diagnosis of Cutaneous Squamous Cell Carcinoma, Merkel Cell Carcinoma and Melanoma: A Consensus Opinion From the International Transplant Skin Cancer Collaborative (ITSCC). Am J Transplant. 2016 Feb;16(2):407-13. doi: 10.1111/ajt.13593. Epub 2016 Jan 28. PMID: 26820755.
10. https://www.kidneycareuk.org/news-and-campaigns/news/kidney-clinic-skin-deep-skin-cancer-aftertransplant
11. Skin cancer screening in organ transplant centres in the United Kingdom: A national survey. Andrea Cordaro, Thomas D. Dobbs, John A. G. Gibson, Sairan Whitaker& Iain S. Whitaker. European Journal of Dermatology volume 30, pages372–376 (2020)
12. Robert P Carroll, Joanna Hester, Kathryn J Wood, Paul N Harden. Conversion to sirolimus in kidney transplant recipients with squamous cell cancer and changes in immune phenotype. Nephrol Dialy Transplant 2013 Feb;28(2): 462-465
13. Salgo R, Gossmann J, Schofer H, et al. Switch to a sirolimus-based immunosuppression in long-term renal transplant recipients: reduced rate of (pre-) malignancies and non-melanoma skin cancer in a prospective, randomised, assessor-blinded, controlled clinical trial. Am J Transplant. 2010;10:1385-93

9.2 BK Virus and Nephropathy

Statements of Recommendation

We recommend that:

• Re-transplantation can be safely considered in patients who develop BK viraemia or nephropathy in an earlier graft. (2C)
• Clearance of viraemia is desirable prior to re-transplantation. (2C)

Recommendations for audit and research:

• Prevalence and long-term outcomes of BK viraemia and BK nephropathy (BKVN) in renal transplant patients and following re-transplantation.

Rationale

The BK polyoma virus infection can cause viraemia, BKV nephropathy and transplant ureteric stenosis in the kidney transplant patient. The reported prevalence is up to 10% with 15-20% of patients losing their allograft due to BKV nephropathy.¹ Reduction in immunosuppression is the mainstay of BKVN treatment. Usual practice is withdrawal of antiproliferative agents such as mycophenolate mofetil and azathioprine and maintaining tacrolimus levels between 4-6µg/L (or Ciclosporin A 50-100 µg/L) with or without prednisolone but evidence supporting this is limited.^2,3,4Specific agents such as quinolones, leflunomide and cidofovir have been used to treat BKV nephropathy with limited evidence.² Leflunomide, an immunosuppressive agent with antiviral activity, is often a preferred choice due to better tolerability with no nephrotoxicity.⁵

In the context of the failing renal allograft, the indications for screening and treatment strategy largely remain the same. There is no evidence that allograft loss due to BKN adversely affects the outcome of a subsequent graft.⁷Clearance of viraemia is recommended prior to re-transplantation², but the presence of a low-grade viraemia despite appropriate reductions or withdrawal of immunosuppression in the context of failing transplant kidney is not an absolute contra-indication for re-transplantation.⁶ Currently, there is not enough evidence to support graft nephrectomy to eliminate a potential reservoir of BKV and a source of future infection prior to re-transplantation.

References

1. Renal association and British Transplantation Society clinical practice guideline on post-operative care in the kidney transplant recipient. Richard J Baker, Patrick B Mark, Rajan K Patel, Kate K Stevens, Nicholas Palmer. BMC Nephrol. 2017; 18: 174
2. BK virus infection: an update on diagnosis and treatment. Deirdre Sawinski, Simin Goral. Nephrol Dial Transplant. 2015;30: 209-217
3. Weiss AS, Gralla J, Chan L, et al. Aggressive immunosuppression minimisation reduces graft loss following diagnosis of BK virus-associated nephropathy: a comparison of two reduction strategies. Clin J Am Soc Nephrol. 2008; 3: 1812-1819
4. Hardinger KL, Koch MJ, Bohl DJ et al. BK virus and the impact of pre-emptive immunosuppression reduction: 5 year results. Am J Transplant. 2010; 10: 407-415
5. Williams JW, Javaid B, Kadambi PV, et al. Leflunomide for polyomavirus type BVK nephropathy. N Engl J Med 2005; 352: 1157-1158
6. Geetha D, Sozio SM, Ghanta M, Josephson M, Shapiro R, Dadhania D, Hariharan S. Results of repeat renal transplantation after graft loss from BK virus nephropathy. Transplantation. 2011 Oct 15;92(7):781-6. doi: 10.1097/TP.0b013e31822d08c1. PMID: 21836535.
7. Dharnidharka VR, Cherikh WS, Neff R, et al. Re transplantation after BK virus nephropathy in prior kidney transplant: an OPTN database analysis. Am J Transplant. 2010; 10: 1312-1315

 

9.3 Recurrent Primary Disease

Statements of Recommendation

We recommend:

• Re-transplantation should be considered for patients with a failing kidney transplant due to recurrent glomerulonephritis despite the potential for recurrent disease. (1D)
• Prior to re-transplantation, appropriate counselling should be given to patients with conditions known to recur quickly and severely in a kidney transplant, namely FSGS, atypical HUS and other complement abnormalities (C3GN and Dense Deposit Disease). (1D)
• Patients with recurrent FSGS in the transplanted kidney should be considered for treatment with plasma exchange and rituximab. (ungraded)
• Prophylactic plasma exchange and rituximab for patients with FSGS to prevent recurrence are not recommended. (1D)
• Patients with MCGN due to complement abnormalities (C3GN and Dense Deposit Disease) should be discussed in a regional multidisciplinary meeting pre-transplantation to determine a plan for recurrent disease. (ungraded)
• Patients with atypical HUS with defined complement abnormalities and C3GN should be discussed with the UK national atypical HUS service before transplantation to have a clear management plan in case of disease recurrence post-transplant. (1C)
• Eculizumab may be helpful in reducing the risk of recurrent C3GN and atypical HUS. (ungraded)
• If advanced interstitial fibrosis and tubular atrophy are present on kidney biopsy, specific treatments for recurrent disease are not recommended. (2D)
• Patients with recurrent glomerulonephritis and proteinuria should be treated with RAS blockade to control proteinuria and hypertension. (1C)

Recommendations for audit and research:

• Studies to determine the optimum dosing schedule for rituximab and plasmapheresis for FSGS post-recurrence.
• Re-transplantation rates and outcomes for patients with graft failure due to recurrent atypical HUS or complement defect associated with MCGN.
• The safety and efficacy of SGLT2 inhibitors in patients with recurrent proteinuric disease in the kidney transplant.

Rationale

Recurrent primary glomerular disease in the transplanted kidney is a common histological occurrence but does not inevitably lead to accelerated graft failure. For example, 50% of patients with diabetes mellitus pre-transplant show mesangial expansion on renal transplant biopsy 5 years post-transplant.¹ Renal Registry data from the UK indicates around 3.5% of kidney transplants fail due to recurrent disease.² However, other studies quote a higher rate, with 18-22% graft losses due to recurrent or de novo glomerulonephritis.³ Histological patterns in a failing transplant kidney are often driven by more than one pathology, including chronic rejection (T cell and antibody-mediated), chronic CNI toxicity, hypertension, vascular disease, diabetes, and recurrent glomerular disease. Consequently, it is often difficult to attribute graft failure to recurrent disease alone.⁴ Recurrent FSGS, C3 Glomerulopathy (subdivided into dense deposit disease, formerly Type2 mesangiocapillary glomerulonephritis and C3 glomerulonephritis), membranous nephropathy and IgA nephropathy all increase the risk of allograft loss.⁵ FSGS and C3G typically recur in the early post-transplant period whereas the risk of recurrence of other forms of glomerulonephritis increases with time post-transplantation.⁶ Although disease recurrence may shorten graft survival, long-term outcome data support transplantation (both deceased and living donor) in patients with primary glomerulonephritis.⁷Renal registry data from Australia and New Zealand, collected over a 28-year follow-up period, has demonstrated the recurrence rates for primary glomerulonephritis after first and subsequent transplants (table 1).

Table 1. Recurrence rates for primary glomerulonephritis

	FSGS n (%) (n = 975)	IGAN n (%) (n = 2393)	MCGN n (%) (n = 348)	MN n (%) (n = 309)	Other GN n (%) (n = 3211)
Total	101 (10.4%)	231 (9.7%)	54 (15.5%)	38 (12.3%)	87 (2.7%)
First graft	79 of 861 (9.1)	210 of 2162 (9.7)	48 of 288 (16.6)	38 of 278 (13.6)	76 of 2886 (2.6)
Second graft	19 of 98 (19.3)	20 of 215 (9.3)	6 of 55 (10.9)	0 of 30 (0)	10 of 288 (3.4)
Subsequent grafts	3 of 16 (18.7)	1 of 16 (6.2)	0 of 5 (0)	0 of 1 (0)	1 of 37 (2.7)

Recurrent FSGS in the first kidney transplant increases the risk of recurrent FSGS in a subsequent transplant/s with a shorter duration from diagnosis to kidney failure often associated with a higher risk of early recurrence post-transplant. Some studies have suggested this risk is upwards of 60-80%.⁸

Other important causes of recurrent diseases include primary oxalosis, atypical haemolytic uraemic syndrome, C3G and Fabry disease.

Appropriate counselling with specific reference to high rates of recurrence and graft failure (in those with aggressive recurrence) in patients with FSGS is essential pre-transplant and should be part of donor counselling for living donor kidney transplants. Patients with atypical HUS and C3G are at high risk of recurrence in transplant kidney⁹and should also receive appropriate counselling pre-transplant with a clear management plan discussed and decided pre-transplant at a multidisciplinary meeting.

Early recurrence with nephrotic range proteinuria and rapidly declining kidney function can occur in recurrent FSGS (with up to 60% graft loss) and this merits consideration of aggressive management options that include plasmapheresis and Rituximab.¹⁰ The usual regime used is 5 sessions of plasmapheresis followed by 2 doses of Rituximab of 1g each given 2 weeks apart. Some patients require repeat sessions of plasmapheresis and Rituximab depending on their clinical course. A prophylactic strategy to give plasmapheresis and Rituximab for prevention of FSGS recurrence is not recommended.¹¹ Patients with atypical HUS with defined complement abnormalities and MCGN with associated complement abnormalities (C3 glomerulonephritis and dense deposit disease) should be discussed at regional transplant multidisciplinary meetings and UK national atypical HUS service before transplantation to have a clear management plan in case of disease recurrence post-transplant. Selective complement inhibition with Eculizumab has been shown to be an effective preventive strategy for patients at high risk of recurrence (based on the clinical history and complement defects) and for the management of recurrent disease.¹² However, given the high cost of this therapy and uncertainties around the duration of therapy post-transplant, it is important to establish a clear management plan pre-transplant.

No specific recommendation can be made for the management of recurrent IgA nephropathy apart from the general management of hypertension and proteinuria with renin-angiotensin system (RAS) blockade. Emerging new therapies for IgA disease could potentially change this.

Other diseases that can rarely recur in the transplanted kidney include membranous nephropathy, ANCA-associated vasculitis and SLE. Specific treatment similar to that used for the disease in the native kidney may be indicated.  Persistent seropositivity for disease-associated autoantibodies (eg, anti-PLA2R or ANCA) is not a contra-indication to re-transplantation in patients in clinical remission.  Management of these patients will need to be decided on a case-by-case basis.

In the context of a failing transplant kidney with progressive decline in eGFR and advanced tubulointerstitial fibrosis on biopsy, specific treatment targeted to recurrent glomerular disease is not recommended. The management in this situation should be focused on blood pressure control, optimisation of diabetes treatment, attention to other cardiovascular risk factors (smoking and lipids), weight management and management of complications associated with CKD (anaemia and bone disease). Their care may be best coordinated in a low-clearance transplant clinic.

References

1. Coemans, M., et al., Occurrence of Diabetic Nephropathy After Renal Transplantation Despite Intensive Glycemic Control: An Observational Cohort Study. Diabetes Care, 2019. 42(4): p. 625-634.
2. Burton, H., et al., Causes of renal allograft failure in the UK: trends in UK Renal Registry and National Health Service Blood and Transplant data from 2000 to 2013. Nephrology Dialysis Transplantation, 2018. 34(2): p. 355-364.
3. Cosio, F.G. and D.C. Cattran, Recent advances in our understanding of recurrent primary glomerulonephritis after kidney transplantation. Kidney Int, 2017. 91(2): p. 304-314.
4. Naesens, M., et al., The histology of kidney transplant failure: a long-term follow-up study. Transplantation, 2014. 98(4): p. 427-35.
5. Jiang, S.H., A.L. Kennard, and G.D. Walters, Recurrent glomerulonephritis following renal transplantation and impact on graft survival. BMC Nephrol, 2018. 19(1): p. 344.
6. Sellarés, J., et al., Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant, 2012. 12(2): p. 388-99.
7. Pippias, M., et al., Long-term Kidney Transplant Outcomes in Primary Glomerulonephritis: Analysis From the ERA-EDTA Registry. Transplantation, 2016. 100(9): p. 1955-62.
8. Artero, M., et al., Recurrent focal glomerulosclerosis: natural history and response to therapy. Am J Med, 1992. 92(4): p. 375-83.
9. Regunathan-Shenk, R., et al., Kidney Transplantation in C3 Glomerulopathy: A Case Series. Am J Kidney Dis, 2019. 73(3): p. 316-323.
10. Alasfar, S., et al., Rituximab and Therapeutic Plasma Exchange in Recurrent Focal Segmental Glomerulosclerosis Postkidney Transplantation. Transplantation, 2018. 102(3): p. e115-e120.
11. Boonpheng, B., et al., Rituximab or plasmapheresis for prevention of recurrent focal segmental glomerulosclerosis after kidney transplantation: A systematic review and meta-analysis. World J Transplant, 2021. 11(7): p. 303-319.
12. Zuber, J., et al., Use of Highly Individualized Complement Blockade Has Revolutionized Clinical Outcomes after Kidney Transplantation and Renal Epidemiology of Atypical Hemolytic Uremic Syndrome. J Am Soc Nephrol, 2019. 30(12): p. 2449-2463.