Preemptive plasmapheresis and recurrence of focal segmental glomerulosclerosis in pediatric renal transplantation

Gonzalez E, Ettenger R, Rianthavorn P, Tsai E, Malekzadeh M. Preemptive plasmapheresis and recurrence of focal segmental glomerulosclerosis in pediatric renal transplantation.
Pediatr Transplantation 2011: 15: 495–501. © 2011 John Wiley & Sons A/S. Abstract: FSGS has a high recurrence rate after renal transplantation. To examine the effects of the use of preemptive and post‐transplant PP on recurrence and graft outcome, we conducted a retrospective study on 34 pediatric patients (mean age 13 ± 5 yr) with biopsy‐proven pretransplant FSGS and who underwent a renal transplantation between 1996 and 2007. Recurrence was defined as a serum albumin level of <3.0 g/L in the presence of nephrotic‐range proteinuria (>40 mg/m²/h). Total response to PP therapy was defined as the resolution of the nephrotic‐range proteinuria and partial response as persistent proteinuria despite PP but not in the nephrotic range. Fifteen patients received a LD renal transplantation and 19 patients received a DD renal transplantation. Nineteen patients received CsA and 14 patients received tacrolimus. Nineteen patients (56%) had FSGS recurrence. There was no difference in the recurrence rate between patients receiving CsA vs. tacrolimus. Among the 15 LD patients, 13 received preemptive PP (1–10 sessions) and seven patients (47%) had subsequent FSGS recurrence. Among the 19 DD patients, four received preemptive PP and 12 (63%) had FSGS recurrence. The number of preemptive PP did not affect the recurrence rate. In a group of patients with a previous graft loss secondary to recurrence, the rate of recurrence was lower than expected (40%) and two of the three patients who did not recur had three or more sessions of preemptive PP. Of the 19 patients with recurrence, 17 were treated with PP therapy and 88% of the patients fully or partially responded. Only five patients had graft loss at three yr post‐transplant: two from FSGS recurrence and three from non‐compliance. These results suggest that preemptive PP does not decrease the rate of recurrence after transplantation but might be beneficial in treating high‐risk patients with documented recurrence. Patients with FSGS recurrence post‐transplant can achieve good graft survival with both LD and DD transplantation.     

Success with plasmapheresis treatment for recurrent focal segmental glomerulosclerosis in pediatric renal transplant recipients

FSGS recurs in approximately 30% of transplanted kidneys and may lead to graft loss. We retrospectively examined the efficacy of early and intensive PP without additional IS in pediatric kidney transplant patients with recurrent FSGS at our center. Seven of 24 patients (29%) had nephrotic proteinuria and histologic evidence of FSGS recurrence within 1–5 days post‐transplantation. PP was initiated early after transplantation and initially performed daily until sustained decline in proteinuria. PP frequency was then individually tapered according to proteinuria. Recurrent FSGS in all seven patients responded to a four‐ to 32‐wk course of PP. Two of seven patients had a second recurrence of FSGS, and both recurrences remitted after an additional 3–6 wk of PP. Median observation period was 4.5 yr (0.8–16.3 yr). Complete remission of recurrent FSGS has been sustained in all seven patients, and all patients have stable graft function with recent plasma creatinine <1.5 mg/dL in six of seven patients. Most recent urine protein/creatinine is 0.13–0.61 mg/mg in six of seven patients. One patient has heavy proteinuria secondary to chronic allograft nephropathy 16 yr post‐transplant. Intensive and prolonged PP, when initiated early in the post‐operative period, is effective in treating recurrent FSGS and preventing graft loss without the use of additional immunosuppressants.     

Ofatumumab in post‐transplantation recurrence of focal segmental glomerulosclerosis in a child

FSGS is a potentially devastating form of nephrotic syndrome. Treatment of SRNS can be difficult, especially post‐transplantation. The current therapy of post‐transplant SRNS includes plasmapheresis, ACE‐I, CNI, and monoclonal antibodies (rituximab). Patients who are refractory to these interventions have limited therapeutic alternatives. We present a case of a patient with SRNS secondary to FSGS. He did not respond to immunosuppressive medications prior to transplant, progressed to ESRD, and was started on chronic hemodialysis. He received a DDKT which was complicated by post‐transplant FSGS recurrence. A course of plasmapheresis, rituximab, and CNI were administered with some response. Ofatumumab was then given to the patient. As a result, the patient achieved partial remission. Ofatumumab may be a safe and effective option for post‐transplant recurrence of FSGS.     

Long‐term effect of rituximab in maintaining remission of recurrent and plasmapheresis‐dependent nephrotic syndrome post‐renal transplantation – Case report

Grenda R, Jarmu?ek W, Pi?tosa B, Rubik J. Long‐term effect of rituximab in maintaining remission of recurrent and plasmapheresis‐dependent nephrotic syndrome post‐renal transplantation – Case report.
Pediatr Transplantation 2011: 15: E121–E125. © 2010 John Wiley & Sons A/S. Abstract: Early recurrence of nephrotic syndrome after renal transplantation is a common serious adverse event in children with severe primary FSGS, affecting long‐term outcome. There is no consensus in terms of uniform management in these cases. We describe the long‐term effect of four unadjusted doses of 375 mg/m² i.v. rituximab, given to a five and a half‐yr‐old, nephrectomized child with immediate recurrence of nephrotic syndrome post‐transplantation and dependency from repeated PF. Rituximab was introduced at three months post‐transplantation after performing 18 sessions of PF and development of established dependency of the disease from plasma exchange. Complete remission of proteinuria was achieved with four doses, and it was maintained during next eight months of follow‐up. Complete B CD₁₉ cell depletion was observed during four months after final dose, followed by severe depletion after eight months. No side effects of therapy were noted. Patient was free from PF, which was stopped while introducing rituximab, remaining non‐proteinuric on triple immunosuppression (CsA, MMF, Pred).     

Rituximab for post-transplant recurrences of FSGS

Abstract:  A 14-yr-old boy whose primary kidney disease was FSGS developed severe recurrence of proteinuria immediately after a second living-related kidney transplant. Despite pre- and post-operative PP and immunosuppressive treatment consisting of steroids, CycA, daclizumab, and MMF, daily protein excretion and serum creatinine increased. We therefore administered rituximab on the fourth day of transplantation. He received four weekly doses of rituximab (375 mg/m²/dose), which resulted in a rapid clearing of circulating CD19-positive B cells, and remission of proteinuria was achieved six wk after the first rituximab treatment. Graft function was excellent six months after transplantation with proteinuria of 8 mg/m²/h. We conclude that rituximab may be an effective treatment for post-transplant recurrence of FSGS.     

Recurrence of focal segmental glomerulosclerosis in renal allograft: An in‐depth review

Vinai M, Waber P, Seikaly MG. Recurrence of focal segmental glomerulosclerosis in renal allograft: An in‐depth review.
Pediatr Transplantation 2010: 14: 314–325. © 2010 John Wiley & Sons A/S. Abstract: Focal segmental glomerulosclerosis is a major cause of chronic kidney disease requiring transplantation in children. Recurrence rate in the renal allograft transplantation is as high as 50%. Recurrence of FSGS is associated with renal dysfunction and early graft loss. To date, there is no established therapy for recurrent FSGS after renal transplant. We have reviewed the current English literature in order to summarize current practices with emphasis on graft outcome. We conclude that despite multiple approaches to the post transplant management of recurrent FSGS, none have been shown to be consistently beneficial. Currently, pheresis combined with high dose anti‐calcineurin with or without rituximab seems to be the most promising. Further controlled studies are needed to define the optimal therapeutic regimens to treat recurrent of FSGS.     

Ofatumumab in post‐transplantation recurrence of a pediatric steroid‐resistant idiopathic nephrotic syndrome

Treatment of SRNS is a challenge. Antiproliferative agents and depleting antibodies have been reported to be effective. However, these agents are not always successful, and use of ofatumumab could provide a different treatment option. Our patient was diagnosed with a SRNS at 5 years of age. She developed ESRD, with FSGS. This was cause for a first renal transplantation. The NS relapsed, leading to loss of the graft, and a second renal transplantation was performed. Due to the recurrence of the NS, IAds were initiated and led to a complete remission. Our patient remained dependent on IAds, however, despite treatments with calcineurin inhibitors, corticosteroids, rituximab, and abatacept. Ofatumumab was introduced and led to a remission, thus allowing cessation of the IAd treatment. Another infusion of ofatumumab was administered 8 months after the last one, due to the recurrence of the NS and a renewed increase in B cells. Although it did not result in a complete remission, the proteinuria was stabilized in the absence of IAds. Ofatumumab may be an alternative treatment for post‐transplantation rituximab‐resistant SRNS, although this needs to be confirmed by further studies.     

Successful unrelated umbilical cord blood cell transplantation without conditioning for a neonate with severe combined immunodeficiency

Taga T, Itoh E, Noda Y, Kato H, Maruo Y, Takano T, Ohta S, Takeuchi Y, Kumaki S. Successful unrelated umbilical cord blood cell transplantation without conditioning for a neonate with severe combined immunodeficiency.
Pediatr Transplantation 2011: 15: E152–E155. © 2010 John Wiley & Sons A/S. Abstract: A neonate was diagnosed as having SCID from his umbilical cord blood cells immediately after birth because his older brother had died of SCID eight months earlier. One locus‐mismatched unrelated umbilical cord blood cell transplantation without conditioning was performed at the age of 30 days. The CD3‐positive cells were detected on day 14 post‐transplantation. There were no peri‐transplantation complications. Four yr after transplantation, the boy is in excellent condition and T and NK cell engraftments are complete. His peripheral B cells with a common gamma chain were not detected by flow cytometry, and he still needs IgG replacement; however, his IgM and IgA levels have gradually increased, and the dosage of IVIG per body weight has gradually decreased. We speculate that the very few B cells that proliferate from transplanted cord blood cells produce gamma globulin. Unrelated cord blood cell transplantation, even though mismatched, without conditioning would be a treatment option for neonates with severe combined immunodeficiency.     

Plasmapheresis‐resistant acute humoral rejection successfully treated with anti‐C5 antibody

Even if kidney graft survival has improved during the last decades, sensitized pediatric patients are an emerging problem. We describe a 17‐yr‐old male who lost his first graft due to chronic rejection becoming hyperimmunized (CDC PRA 99.61%). A desensitization protocol based on high‐dose IVIG, PP, and two Mabthera^® infusions was performed with minor response (CDC PRA post‐desensitization 80%). One month after his second non‐living transplant, he developed a biopsy‐proven AMR; post‐transplant immunological monitoring showed the presence of donor‐specific anti‐DQ5 antibodies (DSA, MFI 20.000). He received methylprednisolone pulses and 45 PP sessions without clinical response; eculizumab was then used to salvage a kidney undergoing severe PP‐resistant rejection. A biopsy performed after the fourth eculizumab infusion showed complete resolution of AMR. Eculizumab infusions were then continued for the first year post‐transplantation. Two yr after transplantation, graft function is stable. Anti‐C5 therapy may represent an effective therapeutic option in pediatric patients with PP‐resistant AMR.     

Recurrence of idiopathic focal segmental glomerulosclerosis after kidney transplantation: Experience of a Korean tertiary center

FSGS is the second most common cause of idiopathic NS in children. It often progresses to ESRD and commonly recurs after KT. To investigate the risk factors and the prognosis of recurrence in pediatric idiopathic FSGS in Korea, retrospective review of 43 KT in 38 children with idiopathic FSGS of last two decades was conducted. The patients presented at the median age of 5.1 yr (range 1.1–13.8 yr) and received KT 5.7 yr later (range 1.3–17.6 yr). FSGS recurred in 20 allografts immediately after transplantation, only in those who presented with NS but not in those who presented with AUA. The risk factors for recurrence were age of onset >5 yr and progression to ESRD within six yr but not sooner than 18 months. CR was achieved in 13 patients with FSGS recurrence and sustained in nine without subsequent relapse over a median of six and a half yr (0.6–20.7 yr). Pediatric idiopathic FSGS presenting with NS recurred in more than half of patients after transplantation. Interestingly, more rapid progression within less than 18 months did not predict recurrence. To identify high‐risk patients of recurrence, an international cooperative study would be necessary.     

Liver transplantation for a patient with homocystinuria

Lin N‐C, Niu D‐M, Loong C‐C, Hsia C‐Y, Tsai H‐L, Yeh Y‐C, Tsou M‐Y, Liu C‐S. Liver transplantation for a patient with homocystinuria.
Pediatr Transplantation 2012. © 2012 John Wiley & Sons A/S. Abstract: A 24‐yr‐old man was diagnosed with HCU during neonatal screening and remained on a pyridoxine, vitamin B12, folic acid, and betaine regimen with dietary methionine restriction for more than 10 yr. He had normal mental development, marfanoid appearance, myopia because of lens dislocation, and recurrent ankle subluxation during adolescence. Thereafter, he was a poor adherent to the conventional diet‐restrictive therapy, and LT was considered when he developed hypertension and multiple infarctions over the right cerebellum early in the second decade of his life despite taking aspirin as a prophylaxis from 17 yr of age. In November 2009, he received a deceased whole LT from a blood group compatible donor. Along with the success of the transplantation, he was completely disease free without dietary or nutritional control. To the best of our knowledge, this is the first case of LT intended to cure HCU, and with promising results. This case provides an insight into the role of LT for this congenital metabolic disease, for which the decision should be made by judging between the severity of the disease and the risk of the operation, as well as the life quality of the patient.     

Nephrotic syndrome after conversion to alternate day steroids in two children with a history of recurrent FSGS

FSGS is a common indication for kidney transplantation in children. However, transplantation is often complicated by recurrence of FSGS in the transplanted kidney, resulting in nephrotic syndrome and an increased risk of graft loss. Acute treatment strategies for recurrent FSGS include plasmapheresis and increased immunosuppressive therapy. There is little information on the long-term management of immunosuppression in these patients. We describe two children who were successfully treated with plasmapheresis for recurrent FSGS that occurred immediately post-transplant. Nephrotic syndrome reappeared years later when the patients were converted from daily to alternate day prednisone. In children with a history of FSGS, caution is necessary when altering the dosing schedule of prednisone.     

Outcomes of renal transplant in patients with anti‐complement factor H antibody‐associated hemolytic uremic syndrome

Atypical HUS associated with anti‐CFH autoantibodies is an uncommon illness associated with high risk of progression to end‐stage renal disease. Disease relapses after transplantation, observed in one‐third cases, often lead to graft loss. We report four patients with anti‐CFH antibody‐associated HUS who underwent renal transplantation 16–62 months from initial presentation. Two patients each received organs from deceased and living‐related donors. Anti‐CFH antibody titers were monitored during the illness and following transplantation. All patients received two doses of IV rituximab before or after transplantation; three patient each received 1–2 g/kg of IV immunoglobulin or underwent 2–5 sessions of plasma exchanges. The use of therapeutic plasma exchange, IV immunoglobulin, and rituximab in two cases enabled two‐third reduction in anti‐CFH antibody titers before transplantation. At 5‐ to 26‐month follow‐up, all patients showed satisfactory graft function without recurrence of HUS. This is the first report of patients with anti‐CFH antibody‐associated HUS who underwent living‐related renal transplantation. Clearance of anti‐CFH antibody by therapeutic plasma exchange and adjuvant immunosuppression aimed at decreasing antibody levels may enable successful transplantation and recurrence‐free survival.     

Outcomes after renal transplantation for FSGS in children

Focal segmental glomerulosclerosis (FSGS) is the primary diagnosis resulting in end-stage renal disease in approximately 12% of children receiving renal transplantation. Recurrent FSGS after transplantation is unpredictable and clear risk factors have not been identified. Post-transplantation, the incidence of acute tubular necrosis requiring dialysis is higher in children with FSGS compared with other diagnoses and may represent immediate severe recurrence. Graft survival is decreased in children with FSGS compared with other primary diagnoses, and the impact is greatest in recipients of living donor transplants. Graft loss caused by recurrent FSGS is significantly higher in living donor transplants compared with cadaveric donor transplants in children. Compared with adults, the impact of FSGS on graft survival appears to be greatest in children. White recipient race is associated with a higher risk of graft loss from recurrent FSGS. Efforts to elucidate the mechanisms of recurrent FSGS and to understand risk factors based on genetics, potential circulating cytokines and permeability factors, age and race must move forward before we can significantly impact outcomes in renal transplantation for FSGS.     

Successful living‐related renal transplantation in a patient with factor H antibody‐associated atypical hemolytic uremic syndrome

CFH‐Ab‐associated aHUS requires different diagnostic and therapeutic approaches and then the genetically defined aHUS forms. The risk of post‐transplant recurrence with graft dysfunction in CFH‐Ab aHUS is not well documented. It is suggested that recurrence can be expected if a significant CFH‐Ab load persists at the time of transplantation. A pretransplant procedure to reduce CFH‐Ab titer seems reasonable, but accurate recommendations are lacking. Whether further prophylactic interventions after transplantation are necessary has to be decided on an individual basis. We report the case of a late diagnosed CFH‐Ab HUS with initial ESRD and a successful living‐related renal transplantation over a post‐transplant period of four and a half years on the basis of a prophylactic pretransplant IVIG admission.     

Successful lung transplant in a child with cystic fibrosis and persistent Blastobotrys rhaffinosifermentans infection

Fungal respiratory infections in patients with CF are a significant concern both pre‐ and post‐lung transplantation (LTx). Fungal infection is associated with increased mortality post‐LTx, and in the past decade, the prevalence of fungal colonization in Canadian pediatric patients with CF has increased. The emergence of novel fungal pathogens is particularly challenging to the transplant community, as little is known regarding their virulence and optimal management. We present a case of a successful double‐lung transplant in a pediatric patient with CF who was infected pretransplantation with a novel yeast, Blastobotrys rhaffinosifermentans. This patient was treated successfully with aggressive antifungal therapy post‐transplantation, followed by extended fungal prophylaxis. The significance of fungal colonization and infection in children with CF pre‐ and post‐LTx is reviewed.     

Isolated abdominal nocardiosis in a pediatric renal transplant recipient

Nocardia infection after RT is uncommon. The most common modes of exposure are inhalation of dust containing nocardia or contaminated soil/water and surgical instruments. Isolated abdominal nocardiosis following RT has not been reported. We report an 11‐year‐old female who developed nocardia abscesses of the abdomen post‐RT. ESRD was secondary to FSGS and she had received multiple immunosuppressive agents prior to transplant. Induction immunosuppression consisted of thymoglobulin and maintenance was with tacrolimus, mycophenolate, and prednisone. There were construction activities in the hospital ward during her hospital stay. Due to immediate recurrence of FSGS in the allograft, she received plasma exchange, rituximab, and IVIG. Anti‐infective prophylaxis consisted of TMP‐SMX, valganciclovir, and nystatin. She developed multiple loculated fluid collections in the abdomen 6 weeks later. Histology of lesions demonstrated suppurative caseating granulomatous inflammation and the AFB culture showed Nocardia farcinica. With the reduction of immunosuppressive agents along with usage of TMP‐SMX, imipenem‐cilastatin, and linezolid, she had a partial recovery after 9 months with persistent small abscesses but remained asymptomatic clinically. There was no evidence of nocardia infection in lungs and brain. Repeat AFB culture from the lesions was negative. Allograft function remained stable throughout. She remains on oral TMP‐SMX therapy. We postulated that she could have acquired nocardia either from the contaminated air particles in the hospital from the construction activities or reactivation of nocardia from prior colonization. Nocardia infection should be suspected in immunocompromised patients with unexplained fever and abdominal pain.     

Imaging in pediatric renal transplantation

Renal transplantation is the therapy of choice in children with ESKD. Radiological investigations are required in both pre‐ and post‐transplant assessment, although there is paucity of both consensus‐based statements and evidence‐based imaging guidelines in pediatric renal transplantation. The phases of pediatric ESKD management that require imaging are pretransplantation recipient assessment and post‐transplantation surveillance for detection of potential complications. We present suggestions for imaging algorithms for both pre‐ and post‐transplant assessment in pediatric renal transplant recipients.     

Sustainability of humoral responses to varicella vaccine in pediatric transplant recipients following a pretransplantation immunization strategy

Abstract: Varicella infections pose serious challenges for organ transplant recipients. To determine the safety and immunogenicity of the OMVV and determine the maintenance of OMVV responses in transplanted subjects at varying periods of immunosuppression within the first two yr following transplantation. Eligible subjects given a two‐dose OMVV pretransplantation were monitored for AE. Antibody levels were assessed at baseline, six wk post‐OMVV, pretransplantation and up to 24 months post‐transplantation. Seroprotection was defined as ≥5 gpEU. Twenty‐one seronegative children were vaccinated. Following 42 doses, no vaccine‐related serious AE occurred. Mab_titer were 17.8 (5.7–910.2) and 183.5 EU (18.8–8116.4) at six and 12 wk, respectively (p < 0.0001). Fourteen (66.7%) participants were transplanted at a median of 16 months (1.5–56) following OMVV and had Mab_titer of 27.2 EU (9.0–236.2) just prior to transplantation. Of 11 who had post‐transplantation serology, seroprotection was sustained at three, six and 12 months post‐transplantation in 10/11, 12/12 and 8/10 subjects. In five of six subjects with two‐yr follow‐up, antibody levels remained seroprotective. No breakthrough varicella infections occurred. The receipt of OMVV prior to transplantation induced humoral responses which persisted in the early months following transplantation and up to two yr post‐transplantation and was not associated with any serious adverse consequences.     

The effect of peri‐transplant plasmapheresis in the prevention of recurrent FSGS

Many pediatric centers utilize a variety of protocols including preemptive plasmapheresis to prevent the recurrence of FSGS post‐transplant. But the effectiveness of this expensive, time‐consuming process of plasmapheresis in the prevention of FSGS recurrence is still unclear. We retrospectively reviewed all pediatric cases of FSGS in our center that received a kidney transplant and compared the transplant and patient outcomes of those transplanted after 2006 who received pretransplant plasmapheresis to those prior to 2006 who did not. Of the 57 children with FSGS, 31 and 26 were transplanted before and after 2006, respectively. The cohorts differed significantly in keeping with the center immunosuppression protocol changes, and prior to 2006, the recipients were significantly younger. All children with FSGS transplanted after 2006 underwent three and one sessions of 1.0 plasma volume/exchange plasmapheresis with fresh frozen plasma replacement prior to the transplant in living and deceased donors, respectively, in addition to five sessions of every other day post‐transplant pheresis. The incidence (27% vs 26%, P = 1.0) and time to recurrence of FSGS in the kidney allograft (P = .22) were not significantly different in patients that did and did not undergo prophylactic plasmapheresis. We need to re‐evaluate the role of preemptive plasmapheresis in the prevention of FSGS recurrence in a prospective multicenter study.