A case of relapse of C-ANCA-associated glomerulonephritis in post-transplant patients

We experienced a case of relapse of proteinase 3-specific antineutrophil cytoplasmic autoantibody (C-ANCA)-associated rapid progressive glomerulonephritis (RPGN) in a patient after renal transplantation. A 19-yr-old man, who underwent a living donor kidney transplantation, presented a rapid renal function deterioration along with a sign of infection. Initially he was treated as acute rejection, but renal function did not improve. Renal biopsy revealed crescentic glomerulonephritis, and C-ANCA titer was 12 EU/mL, resulting in the diagnosis of C-ANCA-associated RPGN. He was treated with three consecutive methylprednisolone pulses twice in addition to the basal immunosuppressive medications (cyclosporine A and mizoribine), then his renal function improved to normal. Bearing the possibility of recurrence of glomerulonephritis in mind, we re-evaluated the nature and disease course of renal failure of original kidney. He experienced a rapid deterioration of renal function in 1992, and eventually CAPD was started in 1992. His serum in 1992 revealed high titer of C-ANCA (24 EU/mL), and renal biopsy performed in 1992 showed a crescentic glomerulonephritis. Taken together, we diagnosed this event as a relapse of C-ANCA-associated GN. Lessons from our experience are: 1) steroid pulse and high-dose corticosteroid therapy may be useful for the treatment of relapse of C-ANCA-associated GN patients after renal transplantation; 2) the possibility of a relapse of C-ANCA-associated GN following renal transplantation has to be kept in mind, especially when infection precedes the deterioration of allograft kidney function.     

Post-transplant de novo malignancies in renal transplant recipients: the past and present

Post-transplant de novo malignancies are reviewed in three time periods: (i) the azathioprine (AZA) era from 1962 to 1980-1981, (ii) the cyclosporine (CYA) era (1980 to present) in which the calcineurin inhibitors, CYA and tacrolimus (TAC), were the mainstay of recipient immunosuppression, and (iii) the TOR inhibitor era starting in the year 2000. Both transplant registry and transplant center reports on malignancies occurring in the AZA era are reviewed. Reports from transplant centers and from the Cincinnati Transplant Tumor Registry (CTTR) in both the early CYA era (1980s) and the 1900-2000 CYA era are reported. Cancer incidence associated with AZA versus CYA, CYA versus TAC, and AZA versus mycophenolate mofetil (MMF) is compared in both transplant center and registry reports including new, unreported Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) data from 1998 to 2003. The malignancy incidence associated with lymphocyte-depleting antibody and corticosteroid immunosuppression is discussed. Reduced malignancy incidence recently reported with TOR inhibitors is compared with that of conventional immunosuppression. Important nondrug factors influencing the incidence of post-transplant malignancies from seven single and three registry reports are detailed. The substantial role that de novo malignancies play in post-transplant mortality is discussed. Finally, management recommendations for recipients who develop de novo post-transplant malignancies are briefly presented.     

Long-term renal injury in ANCA-associated vasculitis: an analysis of 31 patients with follow-up biopsies.

BACKGROUND: We reported previously that in renal disease in relation to antineutrophil cytoplasm auto-antibodies (ANCA)-associated vasculitis, renal outcome correlates better with the percentage of normal glomeruli than with separate active lesions. This may imply that glomeruli, once affected by necrotizing and crescentic lesions, are irreversibly damaged. We quantified and evaluated the course of renal lesions in the present study. METHODS: We retrospectively analysed 31 patients with renal disease in relation to ANCA-associated vasculitis, all treated with immunosuppressive drugs. In all patients, a renal biopsy was performed at diagnosis. A follow-up biopsy was performed in all patients on the indication of a suspected renal relapse, after a mean interval of 31 months. RESULTS: The mean percentage of normal glomeruli in the renal biopsy did not change over time (29% in the initial and 30% in the follow-up biopsy). The mean percentage of glomeruli with crescents, however, significantly decreased from 57 to 30% (P<0.001). The percentage of glomerulosclerosis significantly increased from 12 to 39% (P<0.001). The data were independent of diagnosis, gender, age, time interval between the biopsies, and treatment. CONCLUSIONS: This is the first study to quantify glomerular changes between two time points in patients with renal vasculitis. Our results suggest that, on average, no new glomeruli are recruited into the active disease process. The sum of the percentage of crescentic and sclerotic glomeruli in the initial biopsies is larger than the percentage of sclerotic glomeruli in the follow-up biopsies. Thus, therapy seems not only to prevent normal glomeruli from being recruited into the active disease process for a certain time, but seems also to allow part of the active lesions to revert into a normal phenotype, although another part of the active lesions will be transformed to a chronic phenotype.     

Glomerular immune deposits are associated with increased proteinuria in patients with ANCA-associated crescentic nephritis.

BACKGROUND: In small vessel vasculitis and its renal-limited form, idiopathic crescentic glomerulonephritis, renal damage is characterized by pauci-immune necrotizing crescentic glomerulonephritis (CGN) without histological evidence of immunoglobulin (Ig) deposition. In some patients, however, significant amounts of immune deposits may be detected. Therefore, we evaluated the clinical significance of these immune deposits in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated pauci-immune CGN. METHODS: Renal biopsies of 45 consecutive patients with new onset of Wegener's granulomatosis, microscopic polyangiitis and idiopathic CGN were retrospectively evaluated by light microscopy, immunohistochemistry and electron microscopy and the findings compared with renal function and outcome. RESULTS: Typical pauci-immune CGN was found in 37 patients (group I). In eight patients (18%; group II), however, histopathological examination revealed substantial deposition of Ig in the mesangium and/or along the glomerular basement membrane. Five of these eight patients were cANCA positive; two initially had pANCA and developed a cANCA pattern and one was pANCA positive. There were no differences between groups in age, gender, renal function or extra-renal organ involvement at the time of biopsy. However, patients in group II had significantly more proteinuria (5.4+/-3.1 vs 1.3+/-1.0 g/24 h; P=0.016). We also observed a trend for a worse outcome with respect to renal function and mortality in group II patients; however, the differences did not reach significance. CONCLUSIONS: Our results confirm that in ANCA-associated CGN a substantial percentage of patients have evidence of Ig deposition in renal biopsies. In this subgroup, Ig deposition was associated with a significantly greater degree of proteinuria. Further investigations are necessary to define the full clinical impact of immune-complex deposition on the clinical course of renal disease in pauci-immune CGN.     

Two cases of severe de novo colitis in kidney transplant recipients after conversion to prolonged‐release tacrolimus

Diarrhea is a frequent complication in patients after solid organ transplantation. We describe two cases of severe new onset colitis in kidney transplant recipients that developed shortly after the introduction of the therapy with prolonged‐release formulation of tacrolimus replacing standard twice daily formulation of tacrolimus in one case and cyclosporine A in the second case. Both patients developed severe, intermittent bloody diarrhea with abdominal pain, weight loss, dehydration and worsening graft function that required immediate hospitalization. The symptoms did not diminish after dose reduction or withdrawal of mycophenolic acid derivatives. After excluding bacterial, viral, fungal, and parasite infections, colonoscopy with colonic biopsy was performed in both patients, which revealed features typical of colitis. Both patients received mesalazine until the symptoms stopped. In one of the patients, standard formulation of tacrolimus was immediately reintroduced. The second patient was given everolimus in an acute phase of diarrhea. Although the two cases presented in this report cannot fully support a causal relationship between the prolonged‐release tacrolimus and colitis, they should increase awareness among transplant physicians and prompt more close monitoring of such potential side effects as a part of the pharmacovigilance plan for a new formulation of the well‐established immunosuppressive drug.     

A case of de novo glomerulonephritis with electron-dense deposits following renal transplantation

Abstract:  We present here a case of de novo glomerulonephritis (GN) two yr after kidney transplantation. The patient was a 13-yr-old girl who had renal insufficiency because of bilateral hypoplastic kidneys. She received a renal allograft from her father at the age of 11 yr. Immunosuppressive treatment was started with tacrolimus, mizoribine (MZB), basiliximab, and methylprednisolone (mPSL). There were no findings of GN at the one-h biopsy (first biopsy). Two yr after transplantation, she showed proteinuria, hematuria and increased serum creatinine level with no apparent trigger. The biopsy specimen (fourth) showed mesangial proliferative GN with electron-dense deposits in a variety of regions and borderline changes indicating acute rejection. She was treated with mPSL pulse therapy, deoxyspergualin, replacement of MZB with mycophenolate mofetil, an increase of the mPSL dose, and candesartan. Her serum creatinine and urinary protein excretion levels improved after the treatment. One month later, she developed deterioration in her renal function again. Renal biopsy findings (fifth) were almost the same as the lesions observed in the fourth allograft biopsy. After she recovered from these episodes, she appeared to improve in clinical findings of GN. Protocol biopsies at three yr and five months after transplantation (sixth) showed no evidence of acute rejection, but we still observed the features of de novo GN. We could not resolve the underlying causes by reference to the clinical history and serological findings. We speculate that some kind of immunological reactions might be associated with the pathophysiology.     

Relapse rate and outcome of ANCA-associated small vessel vasculitis after transplantation.

BACKGROUND: Anti-neutrophil cytoplasm antibody-associated systemic vasculitis (AASV) is a rare disease and frequently leads to end-stage renal disease (ESRD). Potentially fatal disease activity can develop after the onset of ESRD or in transplanted patients despite the immunosuppressive effects of uraemia and rejection prophylaxis, respectively, leading to concern that such patients may have greater morbidity and mortality. METHODS: To assess the outcome of patients with AASV following kidney transplantation, a retrospective analysis was performed of nine patients with AASV at our unit who received renal transplants between 1987 and 2000. The renal survival of the patients was compared with a control population who received kidney transplants over the same period for causes other than AASV and diabetes mellitus. RESULTS: Nine patients with the diagnosis of AASV (five patients with Wegener's granulomatosis and four with microscopic polyangiitis) received eight cadaveric grafts and one live-related graft after a mean of 44 months from the start of dialysis. These patients had a mean age of 49.2 years at time of transplantation and they were followed up for a mean of 62 months post-transplantation. Two patients with Wegener's granulomatosis suffered a vasculitic relapse affecting the upper respiratory tract at 40 and 50 months post-transplantation, corresponding to a relapse rate of 0.04 per patient per year. The renal transplant function of vasculitis patients compared with 18 non-diabetic control patients who were transplanted at the same time was better in the vasculitis patients at some time points (P=0.054 at 6 months). CONCLUSIONS: There is a substantial relapse rate in the AASV population, especially affecting the upper respiratory tract and with increasing duration of follow-up. Nonetheless, renal transplantation is a good option for the treatment of vasculitis patients and their outcome compares favourably with that of other non-diabetic patients following transplantation.     

DQ molecules are the principal stimulators of de novo donor‐specific antibodies in nonsensitized pediatric recipients receiving a first kidney transplant

Data on the different HLA‐antibody (Ab) categories in pediatric kidney recipients developing de novo donor‐specific Abs (DSA) after transplantation are scarce. We retrospectively evaluated 82 consecutive nonsensitized pediatric recipients of a first kidney graft for de novo HLA Ab occurrence and antigen specificity. At a median follow‐up of 6 years, 29% of patients developed de novo DSA, while 45% had de novo non‐DSA. DSA appeared at 25‐month median time post‐transplant and were mostly directed toward HLA‐DQ antigens. Considering each HLA antigen, the estimated rate of DQ DSA (7.55 per 100 person‐years) was much higher than the rates observed for non‐DQ DSA. The HLA‐DQ Ab recognized determinants of the DQβ chain in 70% of cases, α chain in 25% of cases, and both chains in one patient. Non‐DSA peaked earlier than DSA, and were largely directed against HLA class I specificities that belonged to HLA‐A‐ and HLA‐B‐related cross‐reacting epitope groups (CREG) in 56% of cases. Our results indicate a need for evaluating HLA‐DQ compatibilities in kidney allocation, in order to minimize post‐transplant development of de novo DSA, known to be responsible for antibody‐mediated rejection and graft loss.     

De novo gastrointestinal tumours after renal transplantation: role of CMV and EBV viruses

The development of new and more effective immunosuppressive agents has provided long-term survival for transplant recipients, thereby increasing the risk of de novo malignancy in chronic immunocompromised hosts. While de novo post-transplant lymphoproliferative diseases and skin cancer has been shown to have an increased incidence in long-term surviving solid organ transplant recipients, the association with gastrointestinal (GI) cancer is controversial. Over 12 yr, 20 patients (5%) out of 395 renal transplant recipients developed 23 de novo tumours; 11 skin cancer and 12 non-skin cancer. Four patients (1%) developed de novo tumours of the GI tract (three colon, and one gastric cancer). Immediately after tumour's diagnosis, immunosuppressive therapy was reduced; all patients were shifted from cyclosporine to Rapamicine within 30 d. The tumour was surgically resected with curative intent in three cases, while one patient had only palliative surgery because of metastatic disease. The post-operative courses was uneventful. All patients maintained normal graft function. However, three out of four patients (75%) died of progression of the neoplasm, within a median time from the diagnosis of 12 months. Further, we investigated a possible correlations between de novo GI cancer and HCV, HBV status, infections, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation, episodes of rejection, and blood transfusions. All cases with GI de novo cancers reported in this paper developed CMV and EBV reactivation within three months after transplantation. Thereafter we suggest a closer follow-up for de novo GI cancer in renal transplants with early CMV and EBV reactivation in order to avoid delayed diagnosis.     

De novo malignancies following liver transplantation: a case-control study with long-term follow-up

BACKGROUND: Long-term survival data on de novo malignancy are limited following orthotopic liver transplantation (OLT) when compared with controls without malignancies. METHODS: Over a 12 yr period at our institution, 50 of 1043 patients (4.8%) who underwent OLT were identified to have 53 de novo malignancies. The clinical characteristics and survival of these patients were retrospectively reviewed and compared with a control cohort of 50 OLT recipients without malignancy matched with the incidence cases by age, year of OLT, sex, and type of liver disease. RESULTS: Chronic hepatitis C, alcohol and primary sclerosing cholangitis were the three leading causes of liver disease. Skin cancer was the most common malignancy (32%), followed by gastrointestinal (21%), including five small bowel tumors, and hematologic malignancies (17%). The cases and controls were not significantly different in the immunosuppressive regimen (p = 0.42) or the number of rejection episodes (p = 0.92). The five- and 10-year Kaplan-Meier survival rates for the cases were 77% and 34%, respectively, vs. 84% and 70%, respectively, for the controls (p = 0.02 by log-rank test). Patients with skin cancers had survival similar to the controls, but significantly better than non-skin cancers (p = 0.0001). The prognosis for patients with gastrointestinal tumors was poor, with a median survival of 8.5 months after the diagnosis. CONCLUSION: In this single institutional study, de novo malignancies after OLT were uncommon. Patients with non-skin cancer after OLT had diminished long-term survival compared with the controls. Our results differ from other reports in the high incidence of gastrointestinal malignancies with attendant poor prognosis.     

De novo membranous nephropathy and antibody‐mediated rejection in transplanted kidney

Honda K, Horita S, Toki D, Taneda S, Nitta K, Hattori M, Tanabe K, Teraoka S, Oda H, Yamaguchi Y. De novo membranous nephropathy and antibody‐mediated rejection in transplanted kidney.
Clin Transplant 2011: 25: 191–200. © 2010 John Wiley & Sons A/S. Abstract: Background: The etiology of de novo membranous nephropathy (MN) after kidney transplantation is still uncertain. Immunological response to various allograft antigens is speculated to be a candidate for the etiology. Methods: Seventeen patients with post‐transplant de novo MN were studied clinically and pathologically in comparison with control post‐transplant patients without MN. Double immunofluorescent staining was performed to identify the presence of donor‐specific human leukocyte antigen (HLA) combined with IgG in the deposits on glomerular capillary walls. Results: De novo MN occurs in relatively late period after transplantation (102.1 ± 68.3 months), presenting various degree of proteinuria. Histological findings associated with antibody‐mediated rejection (AMR), such as peritubular capillaritis and C4d deposition in peritubular capillary, were more frequently observed in the patients with de novo MN than the non‐MN control patients. Donor‐specific antibody (DSA) was detected in five patients at the time of biopsy. In one case of de novo MN with DSA, a donor‐derived HLA was identified in the subepithelial deposits on the glomerular capillary walls combined with IgG deposition. Conclusions: DSA and AMR might play some roles for the pathogenesis in some patients with de novo MN after kidney transplantation.     

Polycystic liver and kidney disease: post-transplant kidney function in patients receiving pre-emptive kidney transplantation.

The aim of the study is to evaluate the changes in kidney function after pre-emptive kidney transplantation in patients with polycystic liver and kidney disease (PLKD) and to establish whether pre-emptive kidney transplantation is warranted. Between 1998 and 2006, five patients with severe anatomical changes in both native kidneys but only mild alteration of the clearance function received combined liver and kidney transplantation. Preoperatively, Technetium-99m mercaptoacetyltriglycine (Tc99m MAG3) scintigraphy was used to evaluate separately the function of each native kidney. This examination was repeated six months after transplantation, additionally measuring the function of the transplanted kidney. Pretransplant creatinine levels were 77-115 mumol/l and Tc99m MAG3 clearance was 141-163 ml/min/1.73 sqm (74 +/- 8% of minimum-for-age values). Six months after transplant, creatinine values were not significantly different. Minimum-for-age clearance decreased by 12.5 +/- 11.5% in four patients, and increased by 26% in one patient. In four patients, the transplanted and the native kidneys assumed each about one third of total tracer clearance. In one patient, the transplanted kidney assumed 92% of the clearance function. Kidney function decreases despite pre-emptive kidney transplantation. Native kidneys are not functionally excluded and the clearance seems to be divided between native and transplanted organs. Kidney transplantation in nonuremic PLKD patients does not improve the overall kidney function and should be performed only in exceptional cases.     

De novo AL Amyloidosis in the Kidney Allograft

We report four cases of de novo amyloidosis occurring after 16, 18, 28 and 31 years following kidney transplantation. These patients presented with proteinuria and progressive allograft dysfunction. Kidney biopsy showed AL amyloidosis in all compartments of the allograft kidney. Serum immunofixation studies revealed monoclonal lambda light chains in all four cases. Bone marrow examination showed 10% plasma cells in one case, 5–10% in two cases and less than 5% in one case. Two patients died unexpectedly within 3 months and 1 year of the diagnosis of allograft AL amyloidosis. Of the remaining two, one underwent autologous stem cell transplant that resulted in complete hematologic remission. However, the patient relapsed within 2 years and also developed progressive kidney allograft failure. The patient received a second autologous stem cell transplant with complete hematologic response, followed by a second kidney transplant, which showed no evidence of amyloid at 1‐year posttransplant. The remaining case was treated with prednisone and bortezomib, which has stabilized kidney function in the short term. In conclusion, this study shows that AL amyloidosis is an uncommon but important cause of late onset proteinuria in the kidney allograft that results in kidney allograft failure.     

Breast cancer arisingde novo in recipients of kidney allograft

Immunosuppressive therapy is not only an etiologic factor ofde novo malignant disease but it also accelerates progression of the already developed malignant disease in immunosuppressed recipients. Two cases ofde novo breast cancer arising in kidney transplant recipients are reported herein. A 25 year-old woman, transplanted one haploidentical kidney transplant 4 years and 9 months ago, developed a left breast tumor. Within one month the tumor had rapidly enlarged from 3.5 cm to 8 cm in diameter by the time she underwent a radical mastectomy. Nine axillary lymph nodes were positive for metastasis. Although her graft function had been poor due to chronic rejection, she was treated with standard immunosuppressive therapy, but not adjuvant therapy. Since local recurrent disease appeared two months postoperatively, the immunosuppressive therapy was ceased and⁶⁰Co therapy started. Recurrent disease progressed rapidly, however, and she died 7 months after her operation. A 27 year-old woman, having allograft from an identical sibling, noted a right breast tumor, 8 years and 7 months later. Again the tumor had grown rapidly from 1.8 cm to 3 cm in diameter within one month. She underwent a standard radical mastectomy. One axillary lymph nodes was positive for metastasis. She has been treated with standard immunosuppressive therapy and adjuvant endocrinochemotherapy. Presently, she is alive with a well functioning graft and no disease.     

肾移植术后并发自体泌尿系统恶性肿瘤22例的临床分析

目的 分析肾移植受者并发自体泌尿系统恶性肿瘤的临床特征.方法 回顾性分析单中心1945例肾移植受者的临床资料,其中发生自体泌尿系统恶性肿瘤22例(发生率为1.13％),占所有恶性肿瘤的56.4 ％(22/39).22例中肾乳头状腺癌、肾乳头状细胞癌、肾血管肉瘤各1例;肾盂移行细胞癌1例,肾盂输尿管移行细胞癌6例,输尿管移行细胞癌7例,肾盂输尿管膀胱移行细胞癌1例;膀胱恶性肿瘤4例(包括膀胱移行细胞癌3例、膀胱交界恶性肿瘤1例).22例中,以肉眼血尿为主要症状者17例,2例反复出现镜下血尿,只有3例无明显临床症状.患者的发病年龄为(54.3±12.3)岁,诊断肿瘤的中位时间为移植术后53个月.10例采用环孢素A+硫唑嘌呤+泼尼松预防排斥反应,12例采用环孢素A+吗替麦考酚酯+泼尼松.所有患者均接受手术治疗,其中3例肾脏恶性肿瘤患者接受了根治性肾切除手术,15例肾孟、输尿管肿瘤患者接受患侧肾、输尿管切除并膀胱袖状切除,4例膀胱恶性肿瘤患者中,3例接受经尿道膀胱肿瘤电切术,1例行膀胱部分切除术.结果 随访2～97个月,死亡9例,死亡时间为肿瘤手术后6～97个月,死亡原因为骨转移1例,肺转移1例,脑转移2例,肝转移2例,全身广泛转移3例.随访截止时存活13例,存活时间最长者为单纯膀胱肿瘤患者,存活92个月,存活超过4年者4例,存活超过1年者5例.结论 自体泌尿系统恶性肿瘤是肾移植术后的一个重要并发症;无痛性肉眼血尿是最常见的症状;根治性手术切除是最主要的治 疗手段.     

Recurrent primary disease and de novo nephritis following renal transplantation

Recurrent or de novo diseases account for only 5% of graft failure in children, but have much to teach us about mechanisms. In children, almost the only metabolic disease with recurrence is type I hyperoxaluria, in which the poor long-term results of isolated renal transplantation make combined liver and renal transplantation, or even prophylactic liver transplantation before renal failure the preferable alternatives. While many forms of nephritis may show histological recurrence in allografts, it is notable that in many patients this is accompanied by no clinical manifestations or only mild disease: this is particularly so in mesangiocapillary glomerulonephritis (MCGN) type II, IgA-associated nephropathy and Henoch-Schönlein purpura. However focal segmental glomerulosclerosis and MCGN type I recur with sufficient frequency and severity to deter the use of living donors unless there is no alternative. The same is true of haemolytic-uraemic syndromes. As many as 10% of paediatric grafts may show de novo membranous nephropathy, but in the majority this is mild or not clinically evident. In contrast, the rare anti-glomerular basement membrane nephritis affecting some patients with Alport's syndrome usually results in graft failure, but occurs in only a minority of recipients with the syndrome. For all types of disease in allografts, risk factors for recurrence are poorly worked out, and attempts at treatment generally ineffective.