CJASN ePress. Published on March 28, 2013 as doi: 10.2215/CJN.00430113 Special Feature

American Society of Nephrology Quiz and Questionnaire 2012: Transplantation

Daniel C. Brennan* (Discussant), Richard J. Glassock† (Co-Moderator), and Anthony J. Bleyer‡ (Co-Moderator) Summary Presentation of the Nephrology Quiz and Questionnaire has become an annual tradition at the meetings of the American Society of Nephrology. It is a very popular session, as judged by consistently large attendance. Members of the audience test their knowledge and judgment on a series of case-oriented questions prepared and discussed *Renal Division, by experts. They can also compare their answers in real time, using audience response devices, to those of program Washington directors of nephrology training programs in the United States, acquired through an Internet-based questionnaire. University, St. Louis, Missouri; †David Topics presented here include fluid and electrolyte disorders, transplantation, and ESRD and dialysis. Cases Geffen School of representing each of these categories, along with single-best-answer questions, were prepared by a panel of Medicine at UCLA, experts (Drs. Palmer, Fervenza, Brennan, and Mehrotra, respectively). The correct and incorrect answers were Los Angeles, briefly discussed after the audience responses, and the results of the questionnaire were displayed. This article California; and ‡ recapitulates the session and reproduces its educational value for a larger audience—that of the readers of the Section on Nephrology, Wake Clinical Journal of the American Society of Nephrology. Have fun. Forest Medical Clin J Am Soc Nephrol 8: ccc–ccc, 2013. doi: 10.2215/CJN.00430113 School, Winston- Salem, North Carolina

Transplantation Case 1 A. Antibody-mediated rejection Correspondence: Dr.DanielC. A 51-year-old man with ESRD from IgA nephropathy B. Recurrent IgA nephropathy Brennan, Renal received a one-haplotype matched living-related trans- C. Serum sickness Division, Washington plant from his brother. The baseline panel-reactive D. Pneumocystis jiroveci infection University, 4104 antibody level was 0%, and both donor and recipient E. CMV infection Queeny Tower, One were cytomegalovirus (CMV) seropositive. Induction Barnes-Jewish Hospital Plaza, St. immunosuppression included 1 mg/kg rabbit antithy- Louis, MO 63110- mocyte globulin (r-ATG) initiated intraoperatively, Discussion of Question 1a 1010. Email: 2 mg/kg r-ATG given postoperatively on days 1 and The correct answer is C. dbrennan@dom. 2, and 500 mg methylprednisolone. The recipient’s Although antibody-mediated rejection can occur in wustl.edu maintenance immunosuppression consists of tacrolimus the absence of graft dysfunction, it is unlikely unless (trough, 7 ng/dl); enteric mycophenolic acid salt, 360 mg the transplant is high risk. It is usually diagnosed by twice daily; and prednisone, 5 mg daily. surveillance biopsy (1). This transplant was a one- He presents 25 days after transplantation with acute haplotype living-related organ in an unsensitized onset of fever, jaw pain, and bilateral hip and shoul- patient. In addition, the patient received r-ATG in- der pain. He is receiving prophylactic trimethoprim- duction, which would further reduce the risk of early sulfamethoxazole, 400/800 mg/d, and valganciclovir, rejection even in living-donor recipients (2,3). 450 mg/d. He also takes clopidogrel for a history of Whether recurrent IgA is more common after coronary artery disease, status post drug-eluting stent living-related transplants is controversial (4), but it placement. He had a history of raising, hunting, and would not be associated with the presenting symp- ingesting rabbits. toms. Use of r-ATG induction (5,6) and steroids re- The physical examination findings include a body duce the risk of recurrence (7). temperature of 36.5°C, BP of 134/84 mmHg, no graft Serum sickness is the most likely cause, even tenderness, and pain and limited range of motion of the though this is the patient’s first exposure to r-ATG. affected joints. The patient has a functioning left Cimino- In one study of transplant recipients, almost 50% of Brescia fistula. His baseline serum creatinine level is 1.5 patients had an exposure to rabbits before receiving mg/dl, with an estimated GFR of 58 ml/min per thymocyte globulin. However, even in this group, se- 1.73 m2. Laboratory data show a white blood cell count rum sickness was relatively uncommon (8). Because of 19,500 cells/mm3. The current serum creatinine level is serum sickness is uncommon, even in patients with a 1.5 mg/dl. A urinalysis shows no protein or hematuria. history of exposure to rabbits, such a history should not preclude the use of r-ATG in appropriate patients. Question 1a (see Figure 1 for Responses of Program This patient’s prior exposure to rabbits makes him Directors and Attendees) statistically more likely to get serum sickness after his Which ONE of the following is the MOST likely initial exposure to r-ATG. Pneumocystis jiroveci,for- diagnosis? merly called Pneumocystis carinii, pneumonia does www.cjasn.org Vol 8 July, 2013 Copyright © 2013 by the American Society of Nephrology 1 2 Clinical Journal of the American Society of Nephrology

Discussion of Question 1b The correct answer is B. It is highly likely that the patient has serum sickness, and this question deals with its management. The possible treatments for serum sickness include plasmapheresis and glucocorticoid therapy. The patient has a functional fistula, which can be used for pheresis by a physician trained in extracorporeal therapies, such as a nephrologist. Pheresis also serves as a diagnostic and therapeutic option. Even a single plasmapheresis session can markedly improve arthralgias (8). Glucocorti- coids are an effective treatment for serum sickness, but they take longer to work than pheresis. They may be pref- erable if pheresis cannot be performed using the arterio- venous fistula and it is necessary to place a central line for pheresis, with its attendant risks of pneumothorax, bleed- Figure 1. | Answers for case 1, question 1a. Which ONE of the fol- ing, or infection. If steroids are used, however, intravenous lowing is the MOST likely diagnosis? Correct answer: C. administration may be preferred to oral. not usually present early, and prophylactic trimethoprim- Transplantation Case 2 sulfamethoxazole nearly eliminates the risk of this condition A 64-year-old man had a previous transplant in 1998 that (9). Although the white blood cell count is elevated, this had failed in 2003 secondary to recurrent membranous fl most likely re ects reactive leukocytosis related to recovery glomerulopathy. He underwent a second transplantation of the bone marrow after transplantation and resolution of from a living-unrelated donor, with thymocyte globulin uremia. induction in 2004. The HLA match was 2A, 2B, 1DR CMV reactivation is rare with adequate prophylaxis, mismatch, the donor was CMV seropositive, and the making CMV infection unlikely (10). CMV also rarely re- recipient was CMV seronegative (D+/R2). The patient’s activates sooner than a month after transplantation, even maintenance immunosuppression regimen consisted of without prophylaxis (10,11). The elevated white blood cell tacrolimus (trough levels, 3–4 ng/ml); azathioprine, 150 count would also be unusual because leukopenia with mg/d; and prednisone, 5 mg/d. His baseline creatinine monocytosis is more characteristic of CMV infection. level was 1.2–1.5 mg/dl. Eighteen months after transplan- tation, an allograft biopsy is performed for persistent pro- Question 1b (See Figure 2) teinuria of 1.5 g/d. Pathologic examination reveals Which ONE of the following would be the MOST membranous glomerulopathy with minimal signs of allo- expedient treatment? graft rejection. Serum creatinine level is 1.3 mg/dl, total cholesterol is 154 mg/dl, triglycerides are 226 mg/dl, and A. Plasmapheresis, intravenous immunoglobulin, and rit- albumin is 3.9 mg/dl. No anti-HLA antibodies are detect- uximab initiated immediately able by single-bead assay. He has no edema. B. Plasmapheresis until symptom resolution C. High-dose intravenous trimethoprim-sulfamethoxazole Question 2a (See Figure 3) D. Conversion valganciclovir to intravenous ganciclovir Which ONE of the FOLLOWING would be the LEAST E. Oral glucocorticoid burst and taper beneficial initial treatment?

A. Performing plasmapheresis until the results of an anti- phospholipase A2 receptor (PLA2R) antibody level are received B. Alternating intravenous alkylating agents and high-dose steroids in place of the azathioprine and low-dose steroids C. Starting angiotensin-converting enzyme inhibitor D. Augmenting tacrolimus dosage E. Starting rituximab

Discussion of Question 2a The correct answer is A. The recognition that an antibody to PLA2R is associated with membranous nephropathy in up to 75% of idiopathic and recurrent membranous cases is one of the most significant findings in nephrology in recent years (12–15). However, the test is not routinely available, and there is Figure 2. | Answers for case 1, question 1b. Which ONE of the fol- insufficient evidence that the result can be used as a sur- lowing would be the MOST expedient treatment? Correct answer: B. rogate marker of disease activity. In addition, up to 50% of Clin J Am Soc Nephrol 8: ccc–ccc, July, 2013 Quiz and Questionnaire 2012, Brennan et al. 3

Steroids remain one of the most potent anti–Bcelland anti-plasma cell agents available in the immunosuppres- sive regimen. This provides the theoretical rationale for this approach. Prolonged high-dose steroids are associated with successful treatment, but high-dose steroids are not benign. Use of angiotensin-converting enzyme inhibitors/ angiotensin-receptor blockers and statin therapy is usually benign and an essential component of efforts to control the nephrotic syndrome; this is true even in a patient with a solitary kidney, such as a transplant recipient who probably has some degree of transplant renal artery stenosis. Tacrolimus has been used for treatment of idiopathic membranous nephropathy in doses similar to what the pa- tient is already receiving (17). Use of tacrolimus to treat re- current membranous nephropathy is less well defined. In the Figure 3. | Answers for case 2, question 2a. Which ONE of the face of recurrent skin cancers, augmentation of tacrolimus FOLLOWING would be the LEAST beneficial initial treatment? Cor- would not be the best option for this patient (see below), rect answer: A. but plasmapheresis would still be the least reasonable option. Rituximab has recently been demonstrated to be an effective treatment for de novo membranous nephropathy fi patients may not have an identi able antibody and may and recurrent membranous nephropathy (18–24). New still respond to therapy or remit spontaneously. Theoreti- evidence suggests that rituximab may be considered as cally, plasmapheresis would remove antibody, but it first-line treatment for idiopathic and perhaps recurrent would not stop antibody production. For this reason, A membranous nephropathy (25). is the correct answer; all other options have some potential in the management of this patient. This is a case of recurrent membranous in a patient who Further Case Description for Transplantation Case 2 is already receiving a second-line agent and who lost a The dose and frequency of rituximab administration kidney from recurrent membranous. Although the patient have been based on those used for hematologic malignan- is not overtly nephrotic, treatment seems indicated. Accord- cies. Alternative dosing may be as effective, less inconve- ing to Kidney Disease Improving Global Outcomes guide- nient, and less costly (see below). lines for the treatment of idiopathic membranous A single dose of rituximab, 500 mg (240 mg/m2), is ad- glomerulopathy, use of an alkylating agent alternating ministered. The daily protein excretion decreases to 130 mg, with high-dose steroids (the Ponticelli or modified Ponticelli 8 months after infusion. Two years after rituximab infusion, regimen) is considered as first-line treatment, with cyclo- the proteinuria increases to a peak of 1800 mg/d, and find- sporine or tacrolimus as second-line agents (16). There are no ings on renal biopsy are again consistent with recurrent guidelines for treatment of the scenario of the case-patient. membranous nephropathy. A second infusion of rituximab,

Figure 4. | Proteinuria and creatinine response in relation to rituximab dose. Proteinuria decreased dramatically and rapidly after each rit- uximab dose of 500 mg (240 mg/m2). 4 Clinical Journal of the American Society of Nephrology

Question 2b (See Figure 5) Which ONE of the following is the MOST reasonable initial approach?

A. Discontinue tacrolimus B. Discontinue azathioprine C. Discontinue steroids D. Re-treat with rituximab E. Change azathioprine to rapamycin

Discussion of Question 2b The correct answer is B. The patient’s membranous nephropathy may be triggered by his skin cancers, and calcineurin inhibitors dramatically increase the risk for skin cancer. Tacrolimus is one of the most important immunosuppressive agents, and complete Figure 5. | Answers for case 2, question 2b. Which ONE of the fol- withdrawal would risk losing the graft. Reduction could lowing is MOST reasonable initial approach? Correct answer B. be considered carefully because the patient has already stated that he would rather die than return to dialysis. 500mg(240mg/m2), leads to another remission, with daily Although most transplant physicians probably think that protein excretion decreasing to 100 mg 3 months after infu- azathioprine is one of the drugs most likely to cause skin sion. Twenty-four months later, the patient again develops cancer, a recent study showed that calcineurin inhibition proteinuria of 1800 mg/d, and a repeat biopsy shows recur- results in a 200-fold increased skin cancer risk compared rent membranous glomerulopathy. The patient receives a with the normal population and that the skin cancer risk third dose of rituximab, 500 mg (240 mg/m2), with resolu- with azathioprine is 3-fold less than that with calcineurin tion of proteinuria to 100 mg/d within 1 month of treat- inhibitors; mammalian target of rapamycin inhibitors are ment. Five and a half years after transplant, approximately associated with even lower rates of skin cancer (26). Because 30 months after the last rituximab dose, metastatic squa- the patient would rather die than go on dialysis, reduction of mous cell carcinoma of the head and neck is diagnosed azathioprine is probably the most reasonable initial ap- and the patient undergoes successful resection. Proteinuria proach. If the patient does not respond, re-treatment with increases to 1 g/d 2 years after the third infusion of rituximab rituximab should be considered because the patient lost his (Figure 4). The patient states that he would rather die than first allograft from recurrent membranous nephropathy and return to dialysis. does not want to undergo dialysis.

Figure 6. | Dose effect of rituximab on CD20 cells. Even very-low-dose rituximab (50–150 mg/m2) depletes CD20 cells for at least 6 months and is similar to a more standard dose of 350 mg/m2. Frequent dosing may not be necessary, and less frequent dosing could reduce costs and infectious risks. Modified from reference 30, with permission. Clin J Am Soc Nephrol 8: ccc–ccc, July, 2013 Quiz and Questionnaire 2012, Brennan et al. 5

Figure 7. | Dose effect of rituximab before splenectomy in ABO-incompatible kidney transplant recipients. Doses of rituximab as low as 10 mg/m2 given to recipients before kidney transplantation with simultaneous splenectomy profoundly reduce the number of CD20-positive B cells, and doses as low as 35 mg/m2 completely deplete splenic CD20-positive B cells. Modified from reference 29, with permission.

Skin cancers are associated with human papillomavirus membranous. A conversion would have to be done with infection, and a reduction of steroids may allow for close monitoring of urine protein excretion rates, renal reduced warts and skin cancer. Complete discontinuation function, and clinical adverse effects. A recent study of steroids, especially late after kidney transplantation, is showed that conversion to rapamycin significantly de- associated with deterioration of graft function and loss and creased the number of skin cancers but was associated would not be a good initial option (27). with the development of adverse effects in .60% of the This patient received relatively low-dose rituximab twice patients who converted (33). during a 4-year period. Rituximab is approved for treat- ment of chronic lymphocytic leukemia, non-Hodgkin B cell Disclosures lymphoma, rheumatoid arthritis, Wegener granulomatosis, None. and microscopic polyangiitis. The approved dose is 375– 500 mg/m2 every 2–4 weeks according to the disease state, References but the frequency of dosing outside of the U.S. Food and 1. Montgomery RA, Hardy MA, Jordan SC, Racusen LC, Ratner LE, Drug Administration indications is unknown. Although Tyan DB, Zachary AA; Antibody Working Group on the di- the reports for treatment have used 375 mg/m2 with re- agnosis, reporting, and risk assessment for antibody-mediated peat dosing, this large dose and frequency may be unnec- rejection and desensitization protocols: Consensus opinion from essary. The CD20 lymphocyte peripheral and splenic the antibody working group on the diagnosis, reporting, and risk assessment for antibody-mediated rejection and desensitization depletion is profound and prolonged at doses as low as protocols. Transplantation 78: 181–185, 2004 50 mg/kg (Figures 6 and 7) (28–30). An abstract at the 2. Gaber AO, Matas AJ, Henry ML, Brennan DC, Stevens RB, Kapur American Society of Transplantation 2012 annual meeting S, Ilsley JN, Kistler KD, Cosimi AB; Thymoglobulin Antibody reported that doses of an average of approximately 100 Immunosuppression in Living Donor Recipients Investigators: 2 Antithymocyte globulin induction in living donor renal trans- mg/m (or 200 mg per person), as was used in this case, plant recipients: Final report of the TAILOR registry. Trans- were associated with long-term remission (31). There is an plantation 94: 331–337, 2012 association between cancer and treatment of membranous 3. Hardinger KL, Schnitzler MA, Koch MJ, Labile E, Stirnemann PM, nephropathy, as well as development of progressive mul- Miller B, Enkvetchakul D, Brennan DC: Thymoglobulin in- tifocal leukoencephalopathy and post-transplant lympho- duction is safe and effective in live-donor renal transplantation: A single center experience. Transplantation 81: 1285–1289, 2006 proliferative disorder, with repeated rituximab dosing. 4. Saab G, Brennan DC: IgA nephropathy: Recurrence after trans- The patient is not overtly nephrotic, so repeat rituximab plantation. UpToDate. September 7, 2012. Available at: http:// dosing would not be the best option. www.uptodate.com/contents/iga-nephropathy-recurrence-after- Changing azathioprine to rapamycin may ameliorate the transplantation. Accessed November 20, 2012 fi 5. Berthoux F, El Deeb S, Mariat C, Diconne E, Laurent B, Thibaudin skin cancers (32). However, there is a signi cant risk of L: Antithymocyte globulin (ATG) induction therapy and disease worsening proteinuria and inducing graft dysfunction, es- recurrence in renal transplant recipients with primary IgA ne- pecially in this patient with proteinuria and recurrent phropathy. Transplantation 85: 1505–1507, 2008 6 Clinical Journal of the American Society of Nephrology

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