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ARTICLE
Alemtuzumab Induction and Steroid Minimization in IgA Nephropathy: A Matched-Cohort Analysis

Objectives: Immunoglobulin A nephropathy is the most common primary glomerulonephritis in adults. Transplant can be complicated by immunoglobulin A nephropathy recurrence in up to 60% of allografts, sometimes causing graft loss. The use of alemtuzumab for induction therapy in the setting of steroid minimization for recipients with immunoglobulin A nephropathy is unclear. Here, we investigated patient and graft outcomes in patients with this condition who were induced with alemtuzumab and a steroid minimization protocol.

Materials and Methods: We performed a retrospective analysis of a database containing 29 patients with immunoglobulin A nephropathy and 646 other recipients who underwent transplant and were induced with alemtuzumab and steroid minimization treatment between March 2006 and May 2015. A matched cohort generated using propensity scoring was also analyzed.

Results: Recipients with immunoglobulin A nephro­pathy were significantly younger at transplant (37.3 ± 11.9 vs 55.6 ± 13.4 years; P < .001), less likely to be African American (6.9% vs 23.2%; P = .04), less likely to have diabetes mellitus (10.3% vs 39.8%; P < .001), and more likely to have private insurance (72.4% vs 45.9%; P = .007). There were no significant differences in graft and patient survival. Recipients with immunoglobulin A nephropathy experienced a higher rate of 1-year rejection (24.1% vs 21.4%; P = .043). Of the 29 patients with immunoglobulin A nephropathy, 8 experienced recurrence (27.6%; average time of 1120.5 ± 982.9 days), with all 8 patients having allograft loss. Matched pair analyses did not yield significant differences in outcomes.

Conclusions: Recurrence rate of immunoglobulin A nephropathy in those induced with alemtuzumab in the setting of steroid minimization is similar to previously reported rates. Although recipients with immunoglobulin A nephropathy had significantly higher 1-year rejection rate, no other differences in graft or patient survival were shown versus recipients without this condition.


Key words : Allograft loss, End-stage renal disease, Glomerulonephritis, Kidney transplant

Introduction

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis in adults.1 End-stage renal disease occurs in 50% of IgAN patients after 20 to 30 years.2 Kidney transplant is the treatment of choice and is associated with improved quality of life, better patient survival, and lower health care costs.3-5 Unfortunately, IgAN recurrence may result in chronic graft dysfunction and the subsequent need for retransplant. The recurrence rate of IgAN ranges from 13% to 50%, and graft loss occurs in up to 16%.6 The risk of recurrence is increased with living-related donation7 and is associated with younger recipient age.8

Recurrence risk is reduced in the presence of long-term steroid therapy.9 However, steroid withdrawal and steroid minimization, especially in the setting of induction immunosuppression, have recently become more popular among transplant practi­tioners given the adverse effects of steroid therapy.

Alemtuzumab is an induction agent utilized in the setting of steroid minimization. It is a humanized monoclonal antibody that targets the CD52 glyco­protein and results in lymphocyte depletion.10 The use of alemtuzumab induction in the setting of steroid minimization for kidney transplant recipients with IgAN has not been well demonstrated. Therefore, we evaluated the long-term patient and graft outcomes of these individuals.

Materials and Methods

We performed an institutional review board-approved retrospective analysis of a database of 464 kidney transplant recipients who were induced with alemtuzumab at the University of Toledo Medical Center (Toledo, OH, USA) between March 2006 and May 2015. We only included recipients of deceased-donor allografts to make outcomes more comparable. Data were reviewed using TransChart (TransChart LLC, Dublin, OH, USA) electronic medical record software. Donor information included age, ethnicity, presence of hypertension, presence of diabetes mellitus, and type of donor. Recipient information included sex, age, ethnicity, type of graft received, panel reactive antibody, and number of transplants.

All recipients were negative cross-matches for both T and B cells. All cases of acute rejection and IgAN recurrence were biopsy-proven. Biopsies were only performed in the presence of allograft dysfunction.

Patients were pretreated with 25 mg of diphen­hydramine intravenously. At the time of the procedure, induction immunosuppression with intravenous methylprednisolone 500 mg (Solu-Medrol, Pfizer, New York, NY, USA), oral myco­phenolate sodium 540 mg (Myfortic, Novartis Pharmaceuticals, Basel, Switzerland or CellCept, Genentech, San Francisco, CA, USA), and intravenous alemtuzumab 30 mg was administered. Before 2011, we used alemtuzumab induction alone. After 2011, a steroid bolus and taper were added to the protocol.

The postoperative steroid taper consisted of intravenous methylprednisolone 250 mg on post­operative day 1, intravenous methylprednisolone 125 mg on postoperative day 2, oral prednisone 60 mg on postoperative day 3, oral prednisone 40 mg on postoperative day 4, and oral prednisone 20 mg on postoperative day 5. Starting in 2015, patients at high-risk for rejection were continued indefinitely on oral prednisone (5-10 mg).

On postoperative day 1, oral tacrolimus 1.5 mg (Prograf, Astellas Pharma, Tokyo, Japan) and oral mycophenolate sodium 540 mg twice per day were administered. Tacrolimus levels were measured and titrated to the correct dose. When side effects permitted, mycophenolate sodium was administered at 2/3 dose until the white blood cell counts returned to normal.

Antimicrobial prophylaxis was started post­operatively with 1 oral tablet of sulfamethoxazole (800 mg)-trimethoprim (160 mg) (Bactrim DS, AR Scientific, Philadelphia, PA, USA) 3 times per week and clotrimazole troche 10 mg dissolved in the mouth 4 times per day following oral care. Daily valganciclovir (Valcyte, Hoffman-La Roche, Basel, Switzerland) was prescribed for cytomegalovirus prophylaxis.

Statistical analyses
Continuous variables such as age, length of dialysis, cold ischemia time, and kidney donor profile index were presented in medians and were compared using t tests or the Mann-Whitney U test when appropriate. Categorical variables, including sex, ethnicity, education level, delayed graft function, and early rejection, were presented in terms of percentage of the total numbers within the group. These results were compared with the Pearson chi-square or Fisher exact test. Survival curves were generated using the life table method, with statistical comparisons computed with the log-rank method. Multivariate survival analysis was done using Cox regression analysis with multivariate factors selected from univariate results and with patient ethnicity included for comparison. Type I error level was set at .05. All statistical analyses were conducted using IBM SPSS version 23 (IBM Corp., Armonk, NY, USA). Additionally, a matched cohort analysis was generated using propensity scoring for the major statistically significant demographic differences using regression.

Results

Recipient and donor characteristics are shown in Table 1. Of the 675 total recipients, 29 (4.3%) received a transplant due to IgAN. These recipients were significantly younger at time of transplant (37.3 ± 11.9 vs 55.6 ± 13.4 y; P < .001) and more likely to have private health insurance (72.4% vs 45.9%; P = .007). The IgAN group was less likely to be African American (6.9% vs 23.2%; P = .001) or to have diabetes mellitus (10.3% vs 39.8%; P = .001).

Donors to IgAN recipients were significantly younger (29 ± 13.6 vs 41 ± 14.9 y; P = .025) and had lower terminal creatinine (0.8 ± 0.3 vs 1 ± 0.9 mg/dL; P = .049). These donors were less likely to be deceased (44.8% vs 75.4%; P = .001), although living donors were excluded from our analysis. Matched pair analysis was completed but did not yield statistically significant differences in recipient or donor factors. Recipient and donor factors are listed in Table 2.

Outcomes
Transplant recipients with IgAN were more likely to experience rejection at 1 year (24.1% vs 21.4%; P = .043). No significant differences were noted for rejection at 3 years (28.4% vs 26.4%; P = .898) or at 5 years (35.5% vs 29.1%; P = .734), for delayed graft function (6.9% vs 9.8%), or for death-censored graft survival at 1 year (100% vs 94.8%; P = .215), 3 years (91.1% vs 89.3%; P = .588), or 5 years (85.7% vs 84.8%; P = .778). One recipient with IgAN died at 104 months posttransplant due to metastatic lung cancer at age 74.6 years. Cox proportional hazards model determined that IgAN status was not an independent predictor of rejection within 1 year (hazards ratio of 1.26; 95% confidence interval, 0.571-2.777; P = .567). General outcomes are listed in Table 3. Matched pair analysis did not yield significant differences in outcomes. Matched pair outcomes are listed in Table 4.

Recurrence results
Of the 29 recipients with IgAN, 8 (27.5%) experienced IgAN recurrence. These 8 individuals eventually lost their allografts after diagnosis of IgAN recurrence. The average time to recurrence was 1120.5 ± 982.9 days. Recipient factors for those who experienced recurrence did not vary with any significance. Those who experienced recurrence were more likely to have female donors (87.5% vs 42.9%; P = .044), but donor-recipient male-female mismatch was not significant (37.5% vs 23.8%; P = .646). Recurrence was associated with significantly lower donor terminal creatinine (0.65 ± 0.13 vs 0.93 ± 0.30 mg/dL; P = .01). Three patients experienced both graft rejection and IgAN recurrence. These incidences recurred at a signi­ficantly earlier time versus recipients with IgAN (775 ± 532.5 vs 1774 ± 1033.6 days; P = .017). Recurrence demographics are listed in Table 5.

Rejection results
The rate of graft loss due to rejection did not differ significantly between IgAN and controls. However, IgAN recipients were more likely to experience all-cause graft loss (P = .043). Rejection outcomes are listed in Table 6. The IgAN group had significantly more eosinophils on biopsy than the control group (22.2% vs 5.6%; P < .05). Other cell types did not vary with any significance. There were no significant differences in the type of rejection (acute cellular vs antibody-mediated) or in Banff score between the IgAN and control groups (P = .298 and P = .285, respectively). Regarding those who experienced recurrence, there were no significant differences in cell type (P = .308), type of rejection (P = .464), or Banff score (P = .624) compared with those who did not experience recurrence.

Discussion

Immunoglobulin A nephropathy is the most common cause of glomerulonephritis worldwide. Kidney transplant is associated with superior outcomes compared with chronic dialysis. However, the recurrence of IgAN in renal allograft recipients remains a substantial complication, frequently leading to graft failure and return to wait list.

In the setting of alemtuzumab induction and steroid minimization, we demonstrated no significant differences in death-censored graft survival between recipients with IgAN and the control group at 1, 3, and 5 years. Our initial analysis demonstrated an elevated rate of rejection at 1 year in the IgAN group. However, our matched cohort analysis did not yield statistically significant differences in either death-censored graft survival or rejection between patients with a kidney transplant due to IgAN matched against patients who underwent kidney transplant for other reasons.

Similarly, Choy and associates and Kim and associates both reported that long-term graft survival rates in IgAN patients do not differ significantly from graft survival in recipients with renal diseases from other causes.7,11 However, it has been postulated that IgAN graft survival diminishes beyond 10 years compared with other patients, although long-term studies are needed.8

Regarding recurrence, our rate was 27.5%. In a recent review, Wyld and associates reported rates ranging from 8% to 53%.12 Others have suggested that younger age, rapid progression of the innate disease, degree of proteinuria, and various donor factors are associated with increased recurrence rates.13-15 Demographically, there were no clinically significant differences between recipients with IgAN who experienced recurrence and those who did not. Recipients who experienced recurrence were more likely to have a female donor. This finding is somewhat surprising given that it has been demonstrated that having a female donor is associated with improved graft survival.16 However, given the small number of recipients who experienced recurrence, the statistical power of this finding was likely low.

It is important to note that our recurrence rate could be falsely low given that we performed no screening biopsies for recurrence. We performed biopsies only in the presence of graft dysfunction, which was defined as elevated creatinine and proteinuria. However, Odum and associates demonstrated that more than one-half of their patients who experienced biopsy-proven recurrence had stable renal function and almost 20% had negative urinalysis results.17 Furthermore, Ortiz and associates found clinical signs such as hematuria were absent in 64% of patients with biopsy-proven disease recurrence.18 Given that all of our patients who experienced recurrence ultimately lost their graft, it is reasonable to conclude that our current biopsy protocol needs to be adjusted to identify recurrence at an earlier stage and to better manage it.

Although our recurrence rate was relatively similar to previously reported rates in the literature, few studies have reported on outcomes in individuals with IgAN who undergo kidney transplant with alemtuzumab induction therapy. Pascual and associates demonstrated that alemtuzumab was not associated with an increased rate of recurrence of glomerular disease compared with interleukin 2 receptor antagonists or antithymocyte globulin.19 Furthermore, immunodepletion is potentially protective and associated with reduced recurrence in IgAN patients, although the mechanism is still unknown.20

There has been controversy regarding the role of steroid minimization protocols in the treatment of kidney transplant recipients with IgAN. Traditionally, steroids have been the preferred treatment for patients with IgAN and an important part of the immuno­suppressive protocol after kidney transplant. Recently, steroid-free and steroid minimization protocols were developed to avoid many of the adverse effects of long-term steroid use. However, steroid minimization protocols are associated with increased rates of recurrence in IgAN transplant recipients.8,21 For example, Kukla and associates21 observed a recurrence rate of 22% in their early steroid withdrawal group compared with 5.2% in their steroid continuation group (P = .02). Similarly, Von Visger and associates demonstrated a signi­ficantly higher risk of recurrence with steroid withdrawal protocols (hazards ratio of 8.59; 95% confidence interval, 3.03-24.38; P < .001).22 In a large, retrospective review of the UNOS/OPTN database, Leeaphorn and associates showed that steroid continuation was associated with a significantly lower rate of graft loss due to recurrence.23

Given that our center only utilized a steroid minimization protocol, we were unable to compare our recurrence rate to that of a steroid continuation group within the same patient population. However, the recurrence rate in our steroid minimization population is similar to that demonstrated by Kukla and associates.21 Thus, our data suggest that alemtuzumab induction in the setting of steroid minimization has little effect on recurrence rates compared with other induction immunosuppression agents.

It is important to mention that, in 2016, after analyzing our outcome data and noting a greater than 20% rejection rate, we have since altered our protocol to include maintenance steroids for our IgAN patients, African American patients, and other high-risk groups.

The strengths of our present analysis include a relatively long follow-up period and a consistent immunosuppressive protocol. Weaknesses include a small sample size of patients with IgAN, a lack of comparison to other induction immunosuppression drugs, and a lack of comparison between a steroid minimization and a steroid continuation group. However, the literature on IgAN is partly based on single-center studies.

Conclusions

Steroid minimization in kidney transplant recipients with IgAN remains controversial. We have demon­strated that, in the setting of steroid minimization and alemtuzumab induction, graft outcomes in IgAN recipients are similar to those in recipients without IgAN. Furthermore, our recurrence rate was comparable to previous rates reported in the literature for steroid minimization protocols. However, our recurrence rate was elevated compared with other studies that utilized steroid continuation protocols. At this time, we recommend maintenance steroid therapy with the use of alemtuzumab for patients with IgAN.


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DOI : 10.6002/ect.2018.0310


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From the 1College of Medicine and Life Sciences, University of Toledo, the 2Department of Urology and Pathology, University of Toledo College of Medicine and Life Sciences, and the 3Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Kevin Becker, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
E-mail: Kevin.becker@rockets.utoledo.edu