Saudi Journal of Kidney Diseases and Transplantation

ORIGINAL ARTICLE
Year
: 2021  |  Volume : 32  |  Issue : 2  |  Page : 387--397

Plasma cell rich acute rejection: Risk factors, treatment and outcomes


Satish Mendonca1, Ananth Rao1, Manu Dogra1, Vivek Sood1, S Prakash1, G Batta1, A Dua1, A Joshi1, UK Sharma1, R Tiwari2,  
1 Department of Nephrology, Army Hospital (Research and Referral), New Delhi, India
2 Department of Pathology, Army Hospital (Research and Referral), New Delhi, India

Correspondence Address:
Ananth Rao
Department of Nephrology, Army Hospital (Research and Referral), New Delhi - 110 010
India

Abstract

Plasma cell-rich rejection is a rare and poorly defined entity. Its treatment is not clearly defined and has universally poor prognosis. More data should be published from various transplant centers around the world to identify the treatment that has the best outcomes and to formulate treatment guidelines for these cases. It is a retrospective analysis of kidney biopsies form 2008 to 2018. Four hundred biopsied were screened and 55 were found to have features of rejection and among them, 13 had plasma cell-rich rejection. Data of treatment given and the graft survival outcomes in these cases were retrieved by medical records. One patient had complete recovery, three had graft loss and the remaining nine had permanent decline in glomerular filtration rate. Decrease in immunosuppression and presence of infection are risk factors for plasma cell-rich acute rejection (PCAR). It can be acute cell-mediated rejection (ACR)/antibody-mediated rejection (AMR)/ACR+AMR. Resistant rejection, ACR+AMR, C4d positivity, and severe interstitial inflammation are poor prognostic factors. Overzealous decrease in immunosuppression should not be done. Management of immunosuppression during infection is most critical for the development of PCAR. Bortezomib is emerging as a therapeutic modality for the treatment of PCAR.



How to cite this article:
Mendonca S, Rao A, Dogra M, Sood V, Prakash S, Batta G, Dua A, Joshi A, Sharma U K, Tiwari R. Plasma cell rich acute rejection: Risk factors, treatment and outcomes.Saudi J Kidney Dis Transpl 2021;32:387-397


How to cite this URL:
Mendonca S, Rao A, Dogra M, Sood V, Prakash S, Batta G, Dua A, Joshi A, Sharma U K, Tiwari R. Plasma cell rich acute rejection: Risk factors, treatment and outcomes. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 Jul 6 ];32:387-397
Available from: https://www.sjkdt.org/text.asp?2021/32/2/387/335451


Full Text



 Introduction



Plasma cell-rich acute rejection (PCAR) is a distinct entity with interstitial inflammation consisting of plasma cells >10%.[1] Incidence of PCAR is 2%–14% of allograft biopsies.[2] Though PCAR is not classified as a separate entity in BANFF classification, it may have features of acute cell-mediated rejection (ACR) or antibody-mediated rejection (AMR) or both.[3] It is important to identify this entity in the biopsy due to its importance in the treatment and outcome.[4] Therapy in such cases is not clearly defined. Previous observational studies have shown very poor outcomes with graft loss occurring within six months in such cases.[5] Whereas, some have used bortezomib to treat such cases with some success.[6] Discontinuation of immunosuppressive drugs, especially tacrolimus and coexistent infection have been implicated in the development of PCAR.[7] More data should be published from various transplant centers around the world to identify the treatment that has the best outcomes and to formulate treatment guidelines for these cases.

 Methods



Our center is a tertiary center with active transplant program (both live and deceased donor) located in Delhi, North India. This study is a retrospective analysis of patients with plasma cell-rich rejection. We have evaluated the transplant kidney biopsies from 2008 to 2018. Four hundred biopsies were screened and 55 were found to have rejection and among them, 13 patients had plasma cell rich rejection. All biopsies were indication biopsies and none was protocol biopsy.

The clinical details were retrieved from the case files which consisted of the data till the last follow-up. The details were noted with respect to donor data, human leukocyte antigen (HLA) match, panel-reactive antibody (PRA), history of blood transfusion/ infection, serial creatinine levels, duration of follow-up and timing of rejection, biopsy report. The biopsies were classified according to BANFF 2007 classification by light microscopy – Hematoxylin, eosin, Periodic acid–Schiff stain, Methenamine silver stain, masons trichrome. Immunohistochemistry (IHC) was done for C4d, Simian virus 40 (SV 40), CD3, CD 20, CD 138, and immunofluorescence was done for IgG, IgM, IgA, C3c, albumin, kappa, and lambda.

As a protocol induction was done using basiliximab in live unrelated transplants and anti-thymocyte globulin (ATG) was given in the deceased donor. Maintenance immunosuppression consisted of tacrolimus (TAC), mycophenolate mofetil (MMF), and prednisolone. TAC C0 level was maintained 10–12 ng/mL in 1st month, 8–10 ng/mL in one to six months, and 3–7 ng/mL beyond 6 months. MMF was started at 1 g BD and dose reduced to 750 mg BD at six months, prednisolone is started at 30 mg OD and tapered to 7.5 mg OD by 6 weeks. Patients who had diarrhea due to MMF were shifted to azathioprine and those who had leukopenia, the dose of MMF was decreased and finally stopped if leukopenia persisted, everolimus was added in such cases. In those who had TAC toxicity, either azathioprine or everolimus was added. Those patients who had intolerance to two groups of drugs, dual immunosuppression was continued.

 Results



A total of 676 transplants were done at our center in the last 10 years from 2008 to 2018. Of them, 8% (55 patients) had rejection, among them 13 patients (23%) had plasma cell-rich rejection.

Patient baseline characteristics [Table 1]{Table 1}

Thirteen patients with PCAR were studied for this study. Of them nine were male (69%), mean age at the time of transplant was 31.8 ± 10.8 years. The most common cause of chronic kidney disease in this cohort was presumed chronic interstitial nephritis (9 patients); other causes were stone-related chronic interstitial nephritis, immunoglobulin A nephropathy diabetic nephropathy, and presumed chronic glomerulonephritis. The donor was HLA matched (mother/sister) in eight cases, spousal in four, and deceased on one transplant. One among the 13 was ABO-incompatible transplant. Induction was basiliximab in 10 cases, ATG in one case, and no induction was given in two cases and maintenance was with triple-drug immunosuppresion with TAC/MMF/prednisolone. Two patients had a history of noncompliance with medication. Mean serum creatinine at baseline was 1.4 ± 0.6 mg/dL and at the time of PCAR, it was 2.7 ± 1.1 mg/dL. While mean serum creatinine decreased to 2.5 ± 1.5 mg/dL following therapy, it increased to 3.9 ±3.1 mg/dL at the last follow-up.

Ten out of 13 patients had a history of decrease in immunosuppression and six patients had a history of infection before PCAR. Biopsy showed features of ACR in four, AMR in four and ACR+AMR in five cases. C4d was positive in 10 cases and negative in three cases (all 3 being ACR). Graft kidney biopsy was done in all cases following the rise in creatinine and none were protocol biopsies. Patients with only ACR were treated with intravenous methylprednisolone 500 mg × 5 doses and those who did not respond were treated with injection ATG 1.5 mg/kg × 5 doses. Treatment response was defined by decline in serum creatinine to within 30% of baseline. And those with features of AMR were treated with injection methylprednisolone, plasma exchange (PLEX) 50 mL/kg × 5 sessions, and each session was followed by intravenous immunoglobulin (IVIG) 100 mg/kg and injection bortezomib 1.3 mg/m2 × four doses on day 1, 4, 8, 11. Those cases with mixed rejection, with features of both ACR and AMR, were treated with ATG, PLEX, IVIG, Bortezomib. One patient had already developed features of transplant glome-rulopathy, hence immunosuppression was not given. Rituximab was not used in any of these cases.

Histopathological features of plasma cell-rich acute rejection [Table 2]{Table 2}

Histopathologic features of PCAR are shown in [Table 2]. There was minimal IFTA at the time of PCAR whereas in the repeat biopsy done at three months in 11 of these patients showed a significant increase in the interstitial fibrosis and tubular atrophy (IFTA) (mean IFTA increased from 17% baseline to 56% in the repeat biopsy). SV 40 staining by IHC was done in all cases, it was negative. There was no kappa/lambda restriction in any of the cases. C4d positivity was associated with higher creatinine at the time of rejection (2.9 vs. 2.1 mg/dL), following its treatment (2.7 vs. 1.8 mg/dL) and at last follow-up (2.8 vs. 2.5 mg/dL).

TAC C0 levels at the time of PCAR were available for nine patients and the mean Tac C0 level was 6.0 ng/mL. at the time of PCAR, six patients were on: TAC, MMF, prednisolone, and others were on varying combinations of: TAC, azathioprine, prednisolone, and everolimus as shown in [Table 2].

Clinical course in patients with plasma cell-rich acute rejection [Table 3]{Table 3}

Mean posttransplant follow-up of patients was for 53.8 ± 39 months with minimum 10 months to maximum of 110 months. Four patients had PCAR within 1st week of transplant (mean 4.5 days), five had between one week a one year (mean 5.6 months) and the remaining four had it after one year of transplant (mean 4.3 years). Mean time from transplant to onset of PCAR was 550 ± 912 days. The outcomes did not differ based on the timing of rejection (early/ late). Three patients had graft loss, nine had permanent decline in GFR and one patient complete recovery. The mean time to graft loss following PCAR was 3.3 months. Serum creatinine did not decrease the following therapy, and it showed gradual rise finally culminating in graft loss and re-initiation of dialysis by three months in two and four months in one patient. One patient who had good response to therapy and decline in serum creatinine had good graft function during follow-up whereas in the remaining 10 patients.

Serum creatinine at baseline or at the time of PCAR did not correlate with the outcome, however, serum creatinine at the end of therapy correlated well with the outcome [Figure 1].{Figure 1}

Sensitization status [Table 4]{Table 4}

PRA levels at the time of PCAR were available for 10 patients. Mean PRA class I was 17.4% ± 27% and class II was 35.1% ± 37.7%. PRA class I was >15% in four patients (40%) and PAR class II was >15% in seven patients (70%). Both PRA class I and II were >15% in three cases (30%). PRA was negative (both PRA class I and Class II - 0%) in two cases. PRA class I was >80% in one case, class II was >80% in three cases and both class I and class II were >80% in only one patient.

Donor-specific antibody (DSA) was done in six cases it was positive in three and negative in the remaining three cases. DSA was against class I HLA in one case (developed 4 months after transplant), against class II in one case (7 months after transplant) and against both in one case (after 6 years of transplant). Mean fluorescence index against class I was 3700 and against class II was 9656. Mean creatinine was more in DSA positive cases at time of rejection (2.3 vs. 3.2 mg/dL), following its treatment (4.1 vs. 1.7 mg/dL) and at last follow-up (7.4 vs. 2.3 mg/dL).

One among the 13 transplants was ABO incompatible. One case was 2nd transplant and she required graft nephrectomy due to graft intolerance.

Risk factors for plasma cell-rich acute rejection [Table 5]{Table 5}

There was a history of a decrease in immunosuppression in 10 cases. The reasons for decreasing MMF dose were leucopenia in three cases, diarrhea in two cases, and recurrent urinary tract infection (UTI) in one case. Steroid dose was decreased in one case as it caused growth retardation in her. TAC was stopped in one case due to drug toxicity in two cases.

There was a history of infection preceding PCAR in six cases. UTI in two cases, tuberculosis in two cases, herpes in one case, hepatitis C in two cases, hepatitis B in one case, viral upper respiratory infection in one case, cytomegalovirus (CMV) infection in two cases. Blood transfusion was done in seven cases before transplant. The mean duration of dialysis before transplant was 8 ± 9 months (range 2–36 months).

 Discussion



We have described the risk factors, clinical course, biopsy features, treatment, and outcomes of PCAR at a tertiary center teaching hospital in north India. Patients with ACR +A MR had the worst outcomes followed by those with AMR alone whereas patients with ACR alone had the best outcomes in our study. Previous studies have shown the doubtful contribution of AMR in PCAR.[6] But in our study it was clearly seen that PCAR has variable presentation, it can be ACR or AMR or ACR + AMR. The severity of interstitial involvement correlated with worse outcome in terms of serum creatinine at the last follow-up. Vascular involvement (Banff 2a/2b) was universally associated with poor outcomes and led to early graft loss in two cases. C4d positivity was also associated with poor response to treatment and worse outcomes. We have noticed that all patients except one had gradual worsening of renal function during follow up. Three patients had graft loss within three months of rejection. If serum creatinine at the end of therapy is higher than creatinine at the presentation of PCAR, indicating no response to therapy, it leads to early graft loss. Similarly, if the serum creatinine decreases the following therapy but does not reach baseline, it leads to gradual rise in creatinine leading to a short half-life of the graft. Serum creatinine reaching baseline after therapy predicted normal graft function at five years of follow-up. The presence of DSA was associated with poor outcome and graft loss in our study which is consistent with previous observations.[7]

Bortezomib was associated with good outcomes in one study.[2] They have used bortezomib in 10 patients with plasma cell-rich ACR. All of them also received ATG, plasma exchange, rituximab, methylprednisolone. We did not find such association in our study. The reason for this finding is probably we have used bortezomib in cases with AMR or ACR+AMR which are as such associated with poor prognosis and we have not used it in ACR which had better outcomes with the use of methylprednisolone/ATG alone. In the light of these findings, it is difficult to say, the good outcomes seen in the previous study are due to the effect of bortezomib or the other drugs used in these patients or it is due to the presence of ACR or borderline rejection (without the component of AMR) in those cases which are associated with good outcomes.

Recurrence of PCAR was not seen in any of our cases though has been rarely observed in some studies.[6] Poor compliance to medication is a risk factor.[8] This was not a predominant finding in our study and it was present in only two cases. It is difficult to know the true incidence of noncompliance as many patients do not reveal it and TAC levels may be normal if the patient has consumed the drug in the preceding three days even if he was previously non-compliant to the drug. There is no method to assess compliance to MMF and steroid. We have however noticed decrease in immunosuppression was present in 10 of our patients with PCAR for medical indications (diarrhea, leukopenia, infections). As a protocol, we decrease the dose of MMF to 750 mg BD from 1 g BD at 6 months post-transplant and around this period we also reduce TAC levels (Target C0 levels 3–7 ng/m) and it has led to rejection in six of our patients with PRA around 15%. We can conclude that patients with PRA as low as 15% are at risk of rejection around six months when immunosuppression is tapered.

Infections are associated with the development of PCAR.[9] In our study, infections preceded PCAR in six cases and immunosuppression was temporarily decreased in them. Two patients had CMV infection which is a known immuno-modulator leading to rejection. Two patients were on antitubercular therapy at the time of PCAR, rifampicin is known to interfere with TAC metabolism which could lead to rejection.

 Conclusion



Overzealous minimization of immunosuppression should not be done at six months, especially in patients with high PRA (> 15%) or other evidence of sensitization (DSA). TAC levels should be kept on the higher side (5–8 ng/mL) and MMF should be 1 g BD. How long to continue this dose is not clear, but at least one year seems reasonable in this cohort of high-risk transplant recipients. Management of immunosuppression around the time of infection is most critical. The dose of immunosuppression should be increased immediately after the infection is controlled. The role of infection prophylaxis for a longer period (up to 1-year post transplant) in such cases needs to be evaluated in prospective studies. Immunosuppression is a double-edged sword, increase leads to infection and decrease leads to rejection, balance has to be maintained. Longer antibiotic prophylaxis/valganciclovir/CMV monitoring pneumococcal vaccine may help maintain this balance. Whenever a new drug is added (Ex. ATT/rifampicin), drug levels of TAC should be monitored and the dose increased appropriately. Not all cases of PCAR are associated with graft loss. Early diagnosis and aggressive therapy are the most important factors. Poor response to treatment is invariably associated with graft loss. Whether the addition of bortezomib to standard therapy of ACR in cases without evidence of associated AMR has to be studied in prospective studies.

Conflict of interest: None declared.

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