Less Maintenance Immunosuppression in Lung Transplantation Following Hematopoietic Stem Cell Transplantation From the Same Living Donor

Living‐donor lobar lung transplantation (LDLLT) is one of the final options for saving patients with pulmonary complications after hematopoietic stem cell transplantation (HSCT). We retrospectively investigated 19 patients who had undergone LDLLT after HSCT in Japan. Eight patients underwent LDLLT after HSCT in which one of the donors was the same living donor as in HSCT (SD group), while 11 received LDLLT from relatives who were not the HSCT donors (non‐SD group). In the SD group, three patients underwent single LDLLT. The 5‐year survival rate was 100% and 58% in the SD and non‐SD groups, respectively. In the SD group, postoperative immunosuppression was significantly lower than in the non‐SD group. Two patients died of infection and one died of post‐transplant lymphoproliferative disease (PTLD) in the non‐SD group, while only one patient died of PTLD 7 years after LDLLT in the SD group. Hematologic malignancy relapsed in two patients in the non‐SD group. For the three single LDLLTs in the SD group, immunosuppression was carefully tapered. In our study, LDLLT involving the same donor as for HSCT appeared to have advantages related to lower immunosuppression compared to LDLLT from relatives who were not the HSCT donors.     

Kidney transplantation

Renal transplantation is well established as the treatment of choice for selected patients with end-stage renal failure. A renal transplant recipient can enjoy an improved quality of life while benefiting from a reduction in the mortality compared with long-term dialysis. However, the success of transplantation is limited by the disparity between an ever growing demand and an insufficient supply of organs. Expansion of the organ donor pool has been achieved through increased utilization of living donor kidneys, transplantation across HLA and ABO boundaries, as well as a greater acceptance and consideration of more marginal kidneys from deceased donors. While 1-year graft survival rates are significantly higher than a decade ago, the rate of chronic graft loss after the first year remains substantial. Although the surgical procedure has changed little over many years, recipients have certainly become more complex with increasing age, obesity, comorbidity and repeat transplants.     

Kidney transplantation

Renal transplantation is well established as the treatment of choice for selected patients with end-stage renal failure. A renal transplant recipient can enjoy an improved quality of life whilst benefiting from a reduction in the mortality compared with long-term dialysis. However, the success of transplantation is limited by the disparity between an ever growing demand and an insufficient supply of organs. Expansion of the organ donor pool has been achieved through increased utilization of living donor kidneys, transplantation across HLA and ABO boundaries as well as a greater acceptance and consideration of more marginal kidneys from deceased donors. Whilst one-year graft survival rates are significantly higher than a decade ago, the rate of chronic graft loss after the first year remains substantial. Although the surgical procedure has changed little over many years recipients have certainly become more complex with increasing age, obesity, co-morbidity and repeat transplants.     

Kidney transplantation

Renal transplantation is well established as the treatment of choice for selected patients with end stage renal failure. A renal transplant recipient can enjoy an improved quality of life while benefiting from a reduction in the mortality associated with long-term dialysis. However, the success of transplantation is limited by the disparity between an ever growing demand for organs and an insufficient supply of organs. Expansion of the organ donor pool has been achieved through increased utilization of living donor kidneys in paired and domino transplant schemes, transplantation across HLA and ABO boundaries, as well as a greater acceptance and consideration of extended criteria allografts. While 1-year graft survival rates are significantly higher than a decade ago, the rate of chronic graft loss after the first year remains substantial. The surgical procedure can be challenging due to operating on recipients with multiple comorbidities, an increasing incidence of obesity as well as utilizing allografts with complex vascular anatomy.     

Data-Driven Kidney Transplant Phenotyping as a Histology-Independent Framework for Biomarker Discovery

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Kidney Disease Following Hematopoietic Stem Cell Transplantation

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Data-driven Derivation and Validation of Novel Phenotypes for Acute Kidney Transplant Rejection using Semi-supervised Clustering

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A Prospective Randomized Trial of Steroid-Free Maintenance Regimens in Kidney Transplant Recipients—An Interim Analysis

We compared three maintenance immunosuppressive regimens in a rapid discontinuation of prednisone protocol. From March 1, 2001, through December 31, 2003, 239 first and second kidney transplant recipients (166 LD; 73 DD) were randomized. All recipients were treated with Thymoglobulin; all received steroids intraoperatively and for 5 days postoperatively. Randomization was to cyclosporine-mycophenolate mofetil (n = 85); high-level tacrolimus (TAC) (8-12 ng/mL)-low-level sirolimus (SRL) (3-7 ng/mL) (n = 72); or low-level TAC (3-7 ng/mL)-high-level SRL (8-12 ng/mL) (n = 82). We found no difference at 24 months between groups in patient, graft, death-censored graft, or acute rejection-free graft survival, or in kidney function. Wound complications were more common in SRL-treated recipients (p = 0.02); we found no other differences between groups in complication rates. Our data suggest that excellent patient and graft survival and low rejection rates can be obtained using a variety of maintenance protocols without prednisone.     

Familial Hypocalciuric Hypercalcemia in the Donor and Recipient of a Living Related Donor Kidney Transplant

Familial hypocalciuric hypercalcemia (FHH) is caused by heterozygous inactivation of the calcium-sensing receptor, which is notably expressed in parathyroid and kidney. FHH is characterized by asymptomatic hypercalcemia and hypophosphatemia and confers minimal, if any, morbidity. Renal transplantation in patients with FHH has not been described previously. This report describes a patient with FHH who developed end-stage renal disease from another cause and subsequently received a living related donor kidney transplant from her FHH-affected daughter. The excellent posttransplant clinical course of both recipient and donor is emphasized.     

Induction of Chimerism in Rhesus Macaques through Stem Cell Transplant and Costimulation Blockade-Based Immunosuppression

A strategy for producing high-level hematopoietic chimerism after non-myeloablative conditioning has been established in the rhesus macaque. This strategy relies on hematopoietic stem cell transplantation after induction with a non-myeloablative dose of busulfan and blockade of the IL2-receptor in the setting of mTOR inhibition with sirolimus and combined CD28/CD154 costimulation blockade. Hematopoietic stem cells derived from bone marrow and leukopheresis products both were found to be successful in inducing high-level chimerism. Mean peripheral blood peak donor chimerism was 81% with a median chimerism duration of 145 days. Additional immune modulation strategies, such as pre-transplant CD8 depletion, donor-specific transfusion, recipient thymectomy or peritransplant deoxyspergualin treatment did not improve the level or durability of chimerism. Recipient immunologic assessment suggested that chimerism occurred amidst donor-specific down-regulation of alloreactive T cells, and the reappearance of vigorous T-mediated alloreactivity accompanied rejection of the transplants. Furthermore, viral reactivation constituted a significant transplant-related toxicity and may have negatively impacted the ability to achieve indefinite survival of transplanted stem cells. Nevertheless, this chimerism-induction regimen induced amongst the longest-lived stem cell chimerism reported to date for non-human primates and thus represents a platform upon which to evaluate emerging tolerance-induction strategies.     

Cost-Effectiveness of Extending Medicare Coverage of Immunosuppressive Medications to the Life of a Kidney Transplant

Unless they maintain Medicare status through disability or age, kidney transplant recipients lose their Medicare coverage of immunosuppression 3 years after transplantation. A significant transplant survival advantage has previously been demonstrated by the extension of Medicare immunosuppressive medication coverage from 1 year to 3 years, which occurred between 1993 and 1995. The United States Renal Data System (USRDS) was analyzed for recipients of kidney transplants from 1995 to 1999. Using a Markov model, we estimated survival and costs of the current system of 3-year coverage compared with lifetime immunosuppression coverage. Results were calculated from the perspectives of society and Medicare. Extension of immunosuppression coverage produced an expected improvement from 38.6% to 47.6% in graft survival and from 55.4% to 61.8% in patient survival. The annualized expected savings to society from lifetime coverage was $136 million assuming current rates of transplantation. Medicare would break-even compared with current coverage if the fraction of patients using extended coverage was <32%. The extension would be cost-effective to Medicare if this fraction was <91%. Extended Medicare immunosuppression coverage to the life of a kidney transplant should result in better transplant and economic outcomes, and should be considered by policy makers.     

Living Donor Kidney and Autologous Stem Cell Transplantation for Primary Systemic Amyloidosis (AL) with Predominant Renal Involvement

Primary systemic amyloidosis (AL) is characterized by multiorgan deposition of monoclonal immunoglobulin light chain. Renal involvement is common and impaired kidney function is associated with reduced median survival. Autologous stem cell transplantation (SCT) for AL achieves superior response rates compared to chemotherapy alone but patients with end-stage renal disease (ESRD) may be excluded from consideration. A treatment approach consisting of living donor kidney transplantation (LDKTx) followed by autologous SCT was developed for AL with ESRD. Eight patients underwent LDKTx with immediate graft function. Two suffered unanticipated complications post-KTx and died 10 and 3 months later. Two cases of subclinical acute cellular rejection (ACR) and one case of clinical ACR occurred--all reversible with corticosteroid. Six patients had successful stem cell harvests performed and five of these underwent SCT with satisfactory trilineage engraftment. Renal function remained stable following SCT in four and was reduced in one due to infectious and bleeding complications. One patient, who has thus far elected not to undergo SCT, has proteinuria and histologic evidence of recurrent renal amyloidosis. This experience supports the feasibility of sequential living donor KTx and autologous SCT for carefully selected patients with ESRD due to AL.     

Antibody-Mediated Microcirculation Injury Is the Major Cause of Late Kidney Transplant Failure

We studied the phenotype of late kidney graft failure in a prospective study of unselected kidney transplant biopsies taken for clinical indications. We analyzed histopathology, HLA antibodies and death-censored graft survival in 234 consecutive biopsies from 173 patients, taken 6 days to 31 years posttransplant. Patients with late biopsies (>1 year) frequently displayed donor-specific HLA antibody (particularly class II) and microcirculation changes, including glomerulitis, glomerulopathy, capillaritis, capillary multilayering and C4d staining. Grafts biopsied early rarely failed (1/68), whereas grafts biopsied late often progressed to failure (27/105) within 3 years. T-cell-mediated rejection and its lesions were not associated with an increased risk of failure after biopsy. In multivariable analysis, graft failure correlated with microcirculation inflammation and scarring, but C4d staining was not significant. When microcirculation changes and HLA antibody were used to define antibody-mediated rejection, 17/27 (63%) of late kidney failures after biopsy were attributable to antibody-mediated rejection, but many were C4d negative and missed by current diagnostic criteria. Glomerulonephritis accounted for 6/27 late losses, whereas T-cell-mediated rejection, drug toxicity and unexplained scarring were uncommon. The major cause of late kidney transplant failure is antibody-mediated microcirculation injury, but detection of this phenotype requires new diagnostic criteria.     

Alemtuzumab Induction and Sirolimus Plus Mycophenolate Mofetil Maintenance for CNI and Steroid-Free Kidney Transplant Immunosuppression

We performed a pilot study in which 22 kidney recipients (14 LD: 8 DCD) were given alemtuzumab induction (30 mg day 0 and 1), steroids (500 mg mp day 0 and 1, none thereafter), mycophenolate mofetil (MMF) maintenance (500 mg b.i.d) and sirolimus (concentration controlled 8-12 ng/mL). With a mean follow-up of 15.9 months, patient survival is (21/22) 96% and graft survival (19/22) 87%. Acute rejections occurred in (8) 36.3% (two humoral). Of 19 surviving grafts, 18 (95%) remain steroid and 15 (79%) CNI-free. At 1 year, mean creatinine was 1.43 mg/dL. Overall infection rates were low, but 2 patients developed severe acute respiratory distress syndrome (ARDS) at month 3 and 7, respectively, resulting in mortality in one and a graft loss in the other. No cancer or PTLD was observed. Leukopenia was common and MMF dose was reduced or eliminated in 6/22 (27%) patients. The reported higher than expected rate of acute rejection, leukopenia and possible pulmonary toxicity suggests excessive morbidity. Modifications such as an initial period of CNI use should be considered.     

CD4+ CD25bright+ Regulatory T Cells Can Mediate Donor Nonreactivity in Long-Term Immunosuppressed Kidney Allograft Patients

CD4+ CD25bright+ FoxP3+ T cells are potent regulators of T-cell reactivity, but their possible involvement in donor-specific nonresponsiveness after clinical kidney transplantation remains to be elucidated. We assessed the proliferative donor-reactivity in 33 kidney allograft recipients who were maintained on a combination of proliferation inhibitors (mycophenolate mofetil (MMF) or Azathioprine (Aza)) and prednisone, long (> 5 years) after transplantation. Of the 33 patients, 8 still exhibited donor-reactivity, whereas 25 were classified as donor nonreactive patients. Within these 25 donor nonreactive patients, we assessed the involvement of CD4+ CD25bright+ regulatory T cells both by depleting them from the responder population as well as by reconstituting them to the CD25(-/dim) effector population. The absence of proliferation in these 25 patients, was abolished in 7 (28%) recipients upon depletion of the CD4+ CD25bright+ T cells. Reconstitution of these cells suppressed the donor-reactivity in a dose-dependent manner. Adding-back CD4+ CD25bright+ T cells inhibited the anti-third party response in all recipients, indicating that functional CD4+ CD25bright+ T cells circulate despite more then 5 years of immunosuppressive treatment. Altogether, we conclude that in long-term immunosuppressed kidney allograft patients functional regulatory CD4+ CD25bright+ T cells circulate but that these cells mediate donor non reactivity only in a subset of patients.     

Association between Primary Graft Dysfunction among Lung,Kidney and Heart Recipients from the Same Multiorgan Donor

Even organs from an ideal donor will occasionally develop primary graft dysfunction (PGD) causing a significant morbidity and mortality after transplantation. It is likely that this situation represents subtle undetectable levels of ongoing donor organ dysfunction. The aim of this study is to investigate the association of PGD between lung, kidney and heart recipients from the one donor. From 202 multiorgan donors, contributed 231 consecutive lung transplants at the Alfred Hospital, 378 kidney and 114 heart transplants were subsequently performed at multiple centers across Australia and New Zealand. Eight hundred seventy‐five organs were used for 723 transplants. The incidence of PGD after lung, kidney and heart transplants was 20% (47/231), 24% (92/378) and 20% (23/114), respectively. In paired single organ recipients, PGD in one of the pair was a significant risk factor for the development of PGD in the other [lung: odds ratio = 5.63 (1.72–18.43), p = 0.004; kidney: odds ratio = 3.19 (1.90–5.35), p < 0.0001]. In multivariate analysis, same donor heart PGD [3.37 (1.19–9.50), p = 0.02] was an independent risk factor for lung PGD and same donor lung PGD was significant risk factor for kidney PGD [1.94 (1.01–3.73), p = 0.04], if the PGD status of the paired kidney was not known. There was a significant association for the development of PGD across different organs transplanted from the same donor.     

Deceased Donor Kidney Transplantation from Donors with Acute Renal Failure due to Rhabdomyolysis

With the current shortage of solid organs for transplant, the transplant community continues to look for ways to increase the number of organ donors, including extending the criteria for donation. In rhabdomyolysis, the byproducts of skeletal muscle breakdown leak into the circulation resulting in acute renal failure in up to 30% of patients. In nonbrain dead patients, this condition is reversible and most patients recover full renal function. Seven potential donors had rhabdomyolysis with acute renal failure as evidenced by the presence of urine hemoglobin, plasma creatinine kinase levels of greater than five times the normal and elevated creatinine. One donor required dialysis. At our institution, 10 kidneys were transplanted from the seven donors. Two grafts had immediate function, five grafts experienced slow graft function and three grafts had delayed graft function requiring hemodialysis. At a mean of 8.7 months posttransplant (2.4–25.2 months), all patients have good graft function, are off dialysis and have a mean creatinine of 1.3 (0.7–1.8). In conclusion, our experience suggests that rhabdomyolysis with acute renal failure should not be a contraindication for donation, although recipients may experience slow or delayed graft function.