Michelle A. Josephson

KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary

The 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on the monitoring, management, and treatment of kidney transplant recipients is intended to assist the practitioner caring for adults and children after kidney transplantation. The guideline development process followed an evidence-based approach, and management recommendations are based on systematic reviews of relevant treatment trials. Critical appraisal of the quality of the evidence and the strength of recommendations followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. The guideline makes recommendations for immunosuppression and graft monitoring, as well as prevention and treatment of infection, cardiovascular disease, malignancy, and other complications that are common in kidney transplant recipients, including hematological and bone disorders. Limitations of the evidence, especially the lack of definitive clinical outcome trials, are discussed and suggestions are provided for future research. This summary includes a brief description of methodology and the complete guideline recommendations but does not include the rationale and references for each recommendation, which are published elsewhere.

Reproduction and Transplantation: Report on the AST Consensus Conference on Reproductive Issues and Transplantation

Vincent T. Armenti, MD, PhD, Professor of Surgery, Temple University School of Medicine, Abdominal Transplant Program, Philadelphia, Pennsylvania

Treatment of renal allograft polyoma BK virus infection with leflunomide.

Background. Polyoma BK virus produces an aggressively destructive nephropathy in approximately 3% to 8% of renal allografts, is associated with graft loss within one year in 35% to 67% of those infected and there is no therapy of proven efficacy. Leflunomide is an immune suppressive drug with anti viral activity in vitro and in animals. Methods. We treated twenty-six patients with biopsy proven NK virus nephropathy (BKN) with either leflunomide alone (n=17) or leflunomide plus a course of cidofovir (n=9) and followed them for six to forty months. Leflunomide was dosed to a targeted blood level of active metabolite, A77 1726, of 50 &mgr;g/ml to 100 &mgr;g/ml (150 &mgr;M to 300 &mgr;M). Response to treatment was gauged by serial determinations of viral load in blood and urine (PCR), serum creatinine, and repeat allograft biopsy. Results. In the 22 patients consistently sustaining the targeted blood levels of active drug, blood and urine viral load levels uniformly decreased over time (P<.001). Mean serum creatinine levels stabilized over the first six months of treatment, and with 12 months or more of follow-up in 16 patients the mean serum creatinine has not changed significantly from base line. Four patients who did not consistently have blood levels of active drug (A77 1726) above 40 &mgr;g/ml did not clear the virus until these levels were attained or cidofovir was added. Conclusions. Leflunomide inhibits Polyoma virus replication in vitro and closely monitored leflunomide therapy with specifically targeted blood levels appears to be a safe and effective treatment for Polyoma BK nephropathy.

Treatment of Refractory BK Virus‐Associated Nephropathy With Cidofovir

BK virus‐associated nephropathy (BKVN) has become recognized as an important cause of allograft dysfunction in renal transplant recipients and despite reduction in immunosuppression, 30–40% of recipients ultimately progress to allograft loss. Cidofovir is an antiviral agent that demonstrates in vitro activity against murine polyomavirus and has been proposed for treatment of BKVN in renal allograft recipients. We describe the clinical course, renal function, serial renal histology and urine and blood viral load measurements in two consecutive patients with refractory BKVN who were treated with low‐dose cidofovir (0.25 mg/kg IV). In each case, renal dysfunction and BK viral load progressed despite reduced immunosuppression, and persistent BK virus infection was documented in serial renal allograft biopsy specimens. Administration of low‐dose cidofovir was associated with clearance of BK virus DNA from blood and allograft, and stabilization of renal function in both patients, without significant toxicity. These preliminary data suggest that low‐dose cidofovir may be tolerated, even among renal transplant recipients with significant renal dysfunction due to BKVN. Prospective, controlled trials are warranted to further define the optimal dose, toxicity and potential role of cidofovir in renal transplant recipients with BK virus nephropathy.

A report of the Lisbon Conference on the care of the kidney transplant recipient

An International Conference on the Care of the Kidney Transplant Recipient was convened in Lisbon, Portugal from February 2– 4, 2006 under the auspices of the National Kidney Foundation and Kidney Disease: Improving Global Outcomes (KDIGO), and in cooperation with The Transplantation Society. Conference participants included over 100 experts and leaders in kidney transplantation, representing more than 40 countries from around the world, including participants from Africa, Asia, Australia, Europe, North American, and South America (Appendix). The goal of the conference was to develop recommendations to improve the outcomes of kidney transplant recipients worldwide with regard to the following basic medical issues: cardiovascular disease (Work Group I), cancer and infection (Work Group II), and anemia, bone disease, reproductive issues, growth and development (Work Group III). Work Groups I, II, and III addressed the preand posttransplant care of kidney transplant recipients by the following components: timelines of preand posttransplantation, immunosuppression, level of kidney allograft function, and burden of disease (prior history of dialysis or preemptive transplant and how that history affects outcome). A graft maintenance section (Work Group IV) addressed: 1) recipient (and donor) selection; 2) surgical aspects and immediate posttransplant care of recipients including consideration of minimal surgical infrastructure; 3) immunosuppression including an assessment of the incremental expected value of more complex and expensive regimens in comparison to simpler and less expensive regimens, generics, midand long-term immunosuppression; 4) living donor versus deceased donor transplantation; and 5) midand long-term posttransplant care and monitoring of allograft function. In addition, conference participants were asked to examine the issue of applicability of the recently published Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines for chronic kidney disease (CKD) in kidney allograft recipients (1). Specifically, Work Group V addressed the role of estimated glomerular filtration rate (eGFR) in monitoring kidney function after transplantation, as well as the stratification for intervention according to eGFR values.

Pregnancy after Kidney Transplantation

Reproductive success is a common, expected outcome for male and female recipients of solid-organ transplants. Men can father children, and women can become pregnant and carry the fetus to delivery. There are, however, important maternal and fetal complications that need to be considered to provide optimal care to the mother and her infant. Although pregnancy is common after the transplantation of all solid organs, guidelines for optimal counseling and clinical management are limited. This review discusses information to help the physician counsel the kidney transplant recipient about risks of pregnancy for the mother and the fetus and provides information to help guide treatment of the pregnant transplant recipient.

Implications of Immunohistochemical Detection of C4d along Peritubular Capillaries in Late Acute Renal Allograft Rejection

Background. Immunohistochemical detection of the C4d complement product along peritubular capillaries (PC) may indicate humoral rejection of renal allografts. We examined the frequency of PC C4d expression in renal-allograft biopsies with acute rejection (AR) arising more than 6 months after transplantation and the impact of this finding. Methods. C4d was detected by immunoperoxidase in 2-micron paraffin sections of consecutive biopsies obtained over a 3-year period. The extent was classified as diffuse (≥50% PC C4d+), focal (<50% C4d+), and negative (C4d−). Clinical data were obtained by retrospective chart review. Fifty-five AR episodes with Banff 97 types 1A (n=13), 1B (n=26), 2A (n=11), 2B (n=3), and 3 (n=2) met inclusion criteria. Results. PC C4d expression was diffuse in 23 (42%), focal in 9 (16%), and negative in 23 (42%) biopsies. AR episodes with focal and diffuse C4d expression had higher proportionate elevation of serum creatinine at biopsy and 4 weeks after diagnosis (P≤0.05). Biopsies with diffuse PC C4d had interstitial hemorrhage (56.5%) and plasmacytic infiltrates (52%) more frequently than C4d− biopsies (22% and 16%), P=0.02, but had no other distinctive histologic features. Graft loss was greater in diffuse (65%) compared with focal C4d+ (33%) and C4d− (33%) groups 1 year after diagnosis, P=0.03. Other clinical and pathologic parameters did not differ significantly, including treatment received for AR. Conclusion. Evidence of acute cellular with occult humoral rejection is identified in more than 40% of late AR episodes. Late acute humoral rejection may be associated with interstitial hemorrhage and plasma cells and contributes significantly to graft loss.

BK Virus Infection is Associated with Hematuria and Renal Impairment in Recipients of Allogeneic Hematopoetic Stem Cell Transplants

BK virus (BKV) is an important pathogen and cause of nephropathy in renal transplant recipients, but its significance following hematopoetic stem cell transplantation (HSCT) is less well described. We measured blood and urine BKV in 124 allogeneic HSCT patients (67 had undergone prior HSCT [surveillance cohort]; 57 were monitored from transplant day 0 [prospective cohort]). BK viruria was manifest in 64.8% of the patients; 16.9% developed viremia. In the prospective cohort, the median time from transplantation to BK viremia development (128 days) was longer than for viruria (24 days; P < .0001). Among clinical factors (sex, disease, transplant type, alemtuzumab use, cytomegalovirus [CMV] viremia, graft-versus-host disease [GVHD], donor HLA C7 allele), only CMV viremia was more common in patients with BKV infection (P < or = .04). There was a direct relationship between blood and urine BKV levels and the occurrence, and degree, of hematuria (P < or = .03). Finally, BKV infection was analyzed along with other clinical factors in relation to the development of post-HSCT renal impairment. On multivariate analysis, only BK viremia (P=.000002) and alternative-donor transplantation (P=.002) were independent predictors of development of post-HSCT renal impairment, with BK viremia associated with a median 1.62mg/dL rise in creatinine from the pretransplant baseline. Among 8 patients in the surveillance cohort with BK viremia, 2 developed biopsy-proven BKV nephropathy requiring hemodialysis. Investigation of whether prophylaxis against, or treatment of, BKV in the post-HSCT setting mitigates the associated morbidities, especially kidney injury, warrants prospective evaluation.

Successful retransplantation after renal allograft loss to polyoma virus interstitial nephritis.

Background. Although polyoma virus infection is being increasingly recognized as a cause of renal allograft dysfunction and failure, the risk of polyoma recurrence in a subsequent transplant is unknown. We present the first reported case of successful retransplantation after polyoma virus-induced renal allograft loss. Case report. A 40-year-old Caucasian woman received a cadaveric kidney transplant. Baseline immunosuppression included corticosteroids, mycophenolate mofetil, and tacrolimus. Her post-transplant clinical course was complicated by an early acute rejection episode on posttransplant day (PTD) 6, that warranted treatment with OKT3. A biopsy performed on PTD 154 to evaluate a rise in creatinine revealed polyoma virus interstitial nephritis. Despite reduction in immunosuppression, the renal function progressively worsened and dialysis was initiated by PTD 160, followed by transplant nephrectomy on PTD 184. Four months later, she received a living related kidney from her sister. Immunosuppression was initiated with prednisone, azathioprine, and tacrolimus. She had immediate graft function with a decrease in serum creatinine from 12.8 to 1.1 mg/dl. Three and one-half years after her second renal transplant, her allograft functions well, with a serum creatinine of 1 mg/dl. Both quantitative and qualitative assays of blood and urine (by PCR) remain negative for BK virus, indicating the absence of virus reactivation. Conclusion. Judicious retransplantation should be considered as a therapeutic option in the management of polyoma virus induced graft failure. Previous graft loss secondary to polyoma virus infection is not a contraindication to retransplantation.

Pancreas transplantation for diabetes mellitus

Vascularized pancreas transplantation has assumed an increasing role in the treatment of diabetes mellitus. Through 1993, over 5500 pancreas transplants have been performed worldwide, with over 80% being combined pancreas-kidney transplants. Overall one-year patient survival exceeds 90% and graft survival (complete insulin independence) exceeds 70%. Although successful pancreas transplantation achieves euglycemia and complete insulin independence, this occurs at the expense of hyperinsulinemia and chronic immunosuppression. The net result of these changes on diabetic complications in the long term remains to be determined. In the short term, improvement in the quality of life and possible prevention of further morbidity associated with diabetes makes pancreas transplantation an important therapeutic option, particularly when combined with a kidney transplant, in appropriately selected diabetic patients.