Nephrotic syndrome in patients after successful myeloablative allogeneic hematopoietic stem cell transplantation: clinical findings obtained from four transplanted patients

We experienced four patients who suffered from nephrotic syndrome after a successful allogeneic hematopoietic stem cell transplantation (HSCT). These cases were seen in the nineteen-year period from September, 1986 to June, 2005. Our data showed that the incidence of nephrotic syndrome was 0.51% (3 out of 585 HSCT patients) in our hospital. Pathological findings of their renal biopsy specimens revealed that 3 patients had membranous nephropathy and that one patient had minimal change disease. Three patients were positive for anti nuclear antibody. Administration of prednisolone or cyclosporine improved the nephrotic syndrome, leading all patients to a complete or almost complete remission. The nephrotic syndrome occurred at 17 to 25 months after HSCT and accompanied the relapse of chronic graft-versus-host disease (GVHD), possibly due to the termination or a decrease of immunosuppressant administration in all patients. This suggests that immunological abnormality associated with chronic GVHD may be partly involved.     

Membranous glomerulopathy associated with graft-versus-host disease following allogeneic stem cell transplantation. Report of 2 cases and review of the literature.

We report two cases of nephrotic syndrome presenting 18 and 20 months after allogeneic stem cell transplantation (alloSCT) with chronic myelogenous leukemia. Both patients had acute and chronic graft-versus-host disease (GVHD) and renal biopsy findings of membranous glomerulopathy (MG). A review of the literature revealed 10 additional cases of immune-complex-mediated glomerular disease following alloSCT, 8 of which were diagnostic of MG. All patients showed evidence of acute or chronic GVHD. Patients typically presented with preserved renal function (mean creatinine 1.2 mg/dl) and full nephrotic syndrome including heavy proteinuria (mean 9.2 g/24 h), edema, hypoalbuminemia (mean 2.1 g/dl) and hypercholesterolemia (mean 472 mg/dl). Most patients showed stabilization of renal function and significant decreases in proteinuria when treated with steroids and/or cyclosporine. The close temporal association as well as evidence from murine models of GVHD support a pathogenetic association between GVHD and the development of MG.     

Avascular osteonecrosis after allogeneic hematopoietic stem-cell transplantation: diagnosis and gender matter

BACKGROUND: Avascular osteonecrosis (AVN) is a serious complication of allogeneic stem-cell transplantation (SCT). Acute and chronic graft-versus-host disease and its treatment with steroids are identified as main risk factors. In a single-center, prospective cohort study of patients undergoing allogeneic SCT for chronic myeloid leukemia (CML), acute myeloid leukemia, myelodysplastic syndrome, and acute lymphatic leukemia, we determined the incidence of hip AVN necessitating total arthroplasty (severe adverse event) and performed risk factor analysis. METHODS: A total of 255 patients were followed for an observation period of at least 4 years. Thirteen potential risk factors including age, recipient and donor gender, underlying disease and disease stage, conditioning therapy, human leukocyte antigen match, acute or chronic graft-versus-host disease, and immunosuppressive medication were tested in univariate and multifactorial nominal logistic and Cox proportional hazard analyses. RESULTS: Severe adverse events occurred in eight patients (4-year cumulative incidence rate 6.1%). Univariate and multifactorial analysis revealed a diagnosis other than CML and steroid intake as main risk factors (chi model 31.6, P=0.0005; chi diagnosis 11, P=0.001; chi steroid 6.8, P=0.009). The demonstrably strong influence of diagnosis was steroid independent (steroid intake in CML comparable to non-CML). We repeated the analysis in 103 patients without CML (70 with acute myeloid leukemia, 13 with myelodysplastic syndrome, and 20 with acute lymphatic leukemia), excluding 152 patients with CML. Univariate and multifactorial analyses revealed female gender (of both recipient and donor) as risk factors for AVN in addition to steroids. Relative AVN risk for female compared with male donor transplantation was 8.7 (P=0.01); relative AVN risk for female compared with male recipient transplantation was 4.3 (P=0.047). CONCLUSIONS: Diagnosis and gender are steroid-independent risk factors for severe hip AVN after allogeneic SCT.     

Membranoproliferative glomerulonephritis following allogeneic hematopoietic stem cell transplantation

Nephrotic syndrome after allogeneic hematopoietic stem cell transplantation has been increasingly described as a manifestation of chronic graft-versus-host disease (GVHD); however, GVHD-associated membranoproliferative glomerulonephritis is extremely rare. A 44-year-old man developed nephrotic syndrome 24 months after HSCT for acute lymphoblastic leukemia. The renal biopsy showed type I membranoproliferative glomerulonephritis. Salivary gland biopsy demonstrated mild lymphocytic infiltration, indicating chronic GVHD. Improvement of the proteinuria and recovery of renal function were achieved within 11 months of treatment with oral prednisolone and azathioprine.     

Membranous nephropathy with graft-versus-host disease in a bone marrow transplant recipient.

A 43-year-old man developed the nephrotic syndrome 26 months after allogeneic bone-marrow transplantation for chronic myeloid leukemia. This occurred during an exacerbation of graft-versus-host disease (GVHD) and both problems remitted after therapy with cyclosporine and prednisolone. Renal biopsy showed ultrastructural and immunofluorescence evidence of membranous nephropathy. Anti-nuclear antibodies (but not antiglomerular or anti-renal tubular epithelial antibodies) were detected in his serum. Experimental GVHD in mice has been associated with immune complex glomerulonephritis and the presence of IgG autoantibodies which has been attributed to abnormal T (donor)/B (recipient) cell co-operation. This association can be extrapolated to the human GVHD where autoantibody formation is better described than immune complex glomerulonephritis.     

Similar outcome after unrelated allogeneic peripheral blood stem cell transplantation compared with bone marrow in children and adolescents

This study compares children and adolescents with hematological malignancies undergoing allogeneic stem cell transplantation (ASCT) with unrelated donors receiving either bone marrow (BM, n=39) or peripheral blood stem cells (PBSCs, n=35). Age and other characteristics were comparable in the two groups. All patients were given conventional conditioning and antithymocyte globulin (ATG). Graft-versus-host disease prophylaxis consisted of cyclosporine plus methotrexate or prednisolone. After PBSC, engraftment of neutrophils and platelets were more rapid. The incidences of acute and chronic graft-versus-host disease were similar in the two groups. In the two groups, other outcome variables, such as transplant-related mortality, overall survival, and relapse-free survival, were the same. Patients given BM tended to have more relapses (P=0.1) and patients given PBSC tended to have more incidences of infectious death. Four cases of EBV-lymphomas were found among patients receiving PBSC, whereas no case was seen in patients given BM (P=0.1). We found no differences in transplant-related mortality and survival in children and adolescents receiving BM or PBSC from unrelated donors. More rapid engraftment and a trend for less relapses in patients given PBSC grafts was noted.     

Complications rénales au décours de la greffe de cellules souches hématopoïétiques

Hematopoietic stem cell transplantation is a widely used therapeutic modality for many, mainly malignant, diseases. Toxicities of this procedure include acute and chronic renal dysfunction. Acute renal failure, generally reversible is due to acute tubular necrosis (tumor lysis syndrome, marrow-infusion toxicity, sepsis, nephrotoxins), hepatic veno-occlusive disease or acute graft-versus-host disease. Chronic renal failure is often multifactorial, caused by conditioning-associated endothelial cell toxicity (bone marrow transplant nephropathy) and calcineurin inhibitors toxicity. Renal pathologic findings are somewhat similar to thrombotic microangiopathy, with sometimes systemic disease. Rare cases of nephrotic syndrome have been described after hematopoietic stem cell transplantation, mainly membranous nephropathy, associated with graft-versus-host disease. Therapeutic options for renal dysfunction after hematopoietic stem cell transplantation are limited but kidney transplantation is possible in case of end-stage renal disease.     

A boy with membranous nephropathy after allogeneic bone marrow transplantation

A 6-year-old boy developed bronchiolitis obliterans organizing pneumonia and nephrotic syndrome 5 months after allogeneic bone marrow transplantation from an unrelated donor for acute lymphoblastic leukemia. His renal biopsy showed membranous nephropathy. He was treated with prednisolone and cyclosporine A. Proteinuria disappeared 3 months after the onset of nephrotic syndrome. To our knowledge, this patient is the youngest case with nephrotic syndrome due to membranous nephropathy after hematopoietic stem cell transplantation.     

Nephrotic syndrome after allogeneic peripheral blood stem cell transplantation

Nephrotic syndrome has been rarely reported after hematopoietic stem cell transplantation. We report a patient who developed nephrotic syndrome after allogeneic peripheral blood stem cell transplantation for acute myelogenous leukemia. Renal biopsy was performed and immunofluorescence and light microscopy were compatible with minimal change disease. The patient was treated with cyclophosphamide and prednisolone. Complete remission was achieved after three months. Previous reported cases are discussed.     

Nephrotic syndrome resulting from focal segmental glomerulosclerosis in a peripheral blood stem cell transplant patient

We describe the case of a male patient who was diagnosed with acute monoblastic leukemia and received a peripheral stem cell transplantation (PSCT) with peripheral blood hematopoietic progenitors. Because he was in clinical remission with no evidence of chronic graft-versus-host disease (GVHD), immunosuppression was withdrawn, and he developed nephrotic syndrome (NS) months later. A kidney biopsy showed focal segmental glomerulosclerosis (FSGS) as part of the GVHD. Soon after the reintroduction of previous immunosuppressive therapy, we observed a complete remission of the NS.     

Hematopoietic stem cell transplantation for beta-thalassemia major: experience in south of Iran

INTRODUCTION: Allogeneic stem cell transplantation as a curative treatment for thalassemia major was established in Shiraz in 1993. In this article we describe our results of 10 years experience with allogeneic bone marrow transplantation for thalassemia major. METHODS: From June 1993 to January 2003, 112 cases of beta-thalassemia major underwent allogeneic marrow transplantation from HLA-identical or one antigen-mismatched related donors. Conditioning chemotherapy included busulfan (14 to 15 mg/kg), cyclophosphamide (200 mg/kg), and antithymocyte globulin (ATG; 40 mg/kg). Prophylaxis for graft-versus-host disease consisted of cyclosporine, prednisolone, and methotrexate. RESULTS: One hundred twelve patients with a diagnosis of beta-thalassemia major underwent allogeneic marrow transplantation during this period. The mean age of the patients was 9.5 years with the range of 2 to 20 years. The distribution of cases according to the Lucarelli classification were: 27 cases class I, 38 cases class II, and 47 cases class III. Eighty-seven of 112 patients (77.6%) with diagnosis of beta-thalassemia major are living with full engraftment at a median follow-up of 6 years (range 2 to 119 months). CONCLUSION: Allogeneic bone marrow transplantation has changed the outcome of disease dramatically. According to our results stem cell transplantation is the treatment of choice for class I and II (Lucarelli risk groups). Also, we recommend transplantation as a curative method for treatment of class III beta-thalassemic patients.     

Favorable long-term outcome of nephrotic syndrome after allogeneic hematopoietic stem cell transplantation

BACKGROUND: The development of nephrotic syndrome (NS) after allogeneic hematopoietic stem cell transplantation (HS-CT) is a rare complication with few long-term outcome data. PATIENTS: Clinical course and long-term outcome of three adult patients and one child with NS after HSCT (total number of transplants n = 533) are presented. RESULTS: The median age at onset of NS was 35 years (range 15 - 56), occurring at a median of 17 months (range 11 - 21) after HSCT. Discontinuation of cyclosporine A (CSA) prior to onset of NS was a consistent feature and occurred a median of 6 months (range 2 - 10 months) prior to the development of NS. The histopathological lesion was membranous nephropathy (n = 3) and membranoproliferative glomerulonephritis Type 1 (n = 1). History of acute or concomitant clinically apparent chronic graft versus host disease (GVHD) was present in all cases except the pediatric patient who had abundant DR-activated cytotoxic T cells without evidence of viral reactivation. Long-term immunosuppression for 11 - 36 months with steroids (n = 1), combined steroids and CSA (n = 2) or CSA alone in steroid-refractory NS (n = 1) resulted in sustained remission of the NS in all patients (12 months - 8 years off immunosuppression). CONCLUSION: NS after HSCT seems to be etiologically related to subclinical or overt chronic GVHD, which flares up after discontinuation of CSA. However, resumption of immunosuppression can reverse NS as well as GVHD and induce favorable sustained long-term remission.     

造血干细胞移植后植入综合征研究进展

植入综合征是造血干细胞移植后中性粒细胞恢复初期发生的一种临床综合征,其临床上可以表现为发热、皮疹和毛细血管渗漏综合征,进而发展为肺实质浸润及体质量增加,甚至出现多器官功能衰竭。因其与急性移植物抗宿主病的表现接近,在其诊断及鉴别诊断方面有一定困难。本文就植入综合征发生情况、危险因素及其发病机制、诊断标准、治疗以及预后等方面进行综述。     

骨髓移植术后膜性肾病临床和病理表现

目的：探讨异基因骨髓移植后表现在肾脏的慢性移植物抗宿主病(cGVHD)的临床及病理表现。方法：通过1例ABO血型相合、HLA相合的异基因骨髓移植患cGVHD的临床和病理资料并结合献复习，对其临床和病理形态学的多态性以及治疗的关系进行综合分析。结果：cGVHD的肾脏累及罕见，临床表现为蛋白尿、肾痛综合征，同时有皮肤、肝脏、口、眼等损害。病理形态学主要为膜性肾病：肾小球毛细血管袢增厚；免疫病理示IgG沿毛细血管袢颗粒状沉积；超微病理示肾小球上皮下电子致密物沉积。结论：异基因骨髓移植后的蛋白尿、肾病综合征可能为自身免疫性疾病，是移植物对宿主产生的一种排斥反应。肾穿刺活检对该病的诊断有重要的作用，加强免疫抑制剂治疗可减少其发生。     

Cyclosporine-associated hyperkalemia: report of four allogeneic blood stem-cell transplant cases

BACKGROUND: Nephrotoxicity is a well-known effect of cyclosporine (CsA) that causes a reduction in glomerular filtration rate through vasoconstriction of the afferent glomerular arterioles and may result in acute renal failure. Isolated CsA-induced hyperkalemia occurring through different mechanisms is also common. However, there are only a few "case reports" addressing this phenomenon in allogeneic bone marrow transplantation patients. In this report, we propose mechanisms and methods of managing CsA-associated hyperkalemia in allogeneic transplantation. METHODS: We report on four allogeneic blood stem- cell transplant cases and a review of the literature. RESULTS: Four adult leukemia patients underwent allogeneic peripheral blood stem cell transplantation and received CsA as a part of their graft-versus-host disease prophylaxis. The patients developed hyperkalemia, despite adequate kidney function. CsA seemed to be the only pharmaceutical agent to which this electrolyte abnormality could be attributed. Renal tubule dysfunction and secondary hypoaldosteronism seemed to be the reasons for CsA-associated hyperkalemia. CONCLUSION: This report of four cases demonstrates that CsA should be considered among the possible causes of hyperkalemia in bone marrow transplantation. There may be a need for urgent intervention depending on the severity of hyperkalemia. Monitoring of blood CsA level and dose adjustment are important for the prevention of this complication.     

Liver chimerism after allogeneic blood stem cell transplantation

Blood stem cells can mature into elements of many different lineages. We investigated the presence and nature of donor-derived (chimeric) cells within the liver after allogeneic stem cell transplantation. METHODS: Liver biopsy autopsy specimens were examined from nine female patients who had undergone allogeneic bone marrow (n = 6) or peripheral stem cell (n = 3) transplantation from a male donor. To identify the male origin of cells within the liver, in-situ hybridization for Y-chromosomes was performed in conjunction with CD45 staining to identify leucocytes. RESULTS: Hematopoietic stem cell engraftment was confirmed in all nine recipients. Histologic examination of the liver tissue sections revealed 5.6-fold more Y-chromosome-positive than CD45-positive staining cells (P < .02), indicative of considerable nonleucocytic chimerism. This was particularly observed in patients who had developed graft-versus-host disease. CONCLUSIONS: Donor-derived cells can be found in liver tissue specimens after allogeneic stem cell transplantation. A considerable fraction of chimeric (donor-derived) cells appeared to be of nonlymphohematopoietic origin. This finding supports the theory of blood stem cells developing into liver cells of mesenchymal origin.     

A renal allograft recipient with late recurrence of focal and segmental glomerulosclerosis after switching from cyclosporine to tacrolimus

BACKGROUND: Focal and segmental glomerulosclerosis (FSGS) is one of the most frequent and severe primary glomerulonephritis that recurs in transplanted kidneys. Although cyclosporine seems to have no effect on the frequency of FSGS recurrence, there is evidence that cyclosporine reduces proteinuria and prolongs graft survival in patients with recurrent glomerulonephritis after renal transplantation. The effect of tacrolimus on nephrotic syndrome after renal transplantation is controversial. METHODS: We describe the case of a 30-year-old man with steroid-resistant nephrotic syndrome due to FSGS who developed nephrotic syndrome 5 years after renal transplantation due to recurrent disease when he was switched from cyclosporine to tacrolimus. RESULTS: He was given pulses of methylprednisolone and returned to cyclosporine. His proteinuria decreased, but he rapidly developed chronic renal failure. CONCLUSIONS: This observation strongly suggests that tacrolimus should be given with considerable care in renal transplant recipients with FSGS.     

Membranous glomerulonephritis after haematopoietic cell transplantation for multiple myeloma.

Renal involvement during graft-versus-host disease following haematopoietic cell transplantation for multiple myeloma has never been described. We report a case of a recipient who developed nephrotic syndrome and membranous glomerulonephritis 22 months after the graft and 6 months after cyclosporine withdrawal. Symptoms resolved when immunosuppressive therapy was reinstituted.     

Bile duct apoptosis and cholestasis resembling acute graft-versus-host disease after autologous hematopoietic cell transplantation

BACKGROUND: Acute graft-versus-host disease (GVHD) of the liver is a frequent complication of allogeneic hematopoietic cell transplantation. This report describes hepatic GVHD following autologous transplantation. METHODS: We reviewed 116 consecutive autologous transplant recipients. A diagnosis of GVHD was based on histology (segmental to subtotal destruction of bile ductal epithelial cells with apoptosis and lymphocytic infiltrates), clinical criteria (elevated serum alkaline phosphatase), a response to immunosuppressive therapy, and finding no other cause for cholestatic liver disease. RESULTS: Two patients developed cholestatic liver disease (alkaline phosphatase levels over five times the normal upper limit) and had liver biopsies showing apoptotic and dysmorphic ductular epithelial cells typical of GVHD. Three additional patients developed cholestasis and intestinal symptoms but had gastric biopsies only, showing apoptotic crypt epithelial cells and crypt cell drop-out typical of GVHD. CONCLUSION: Two recipients of autologous hematopoietic cells developed histologic abnormalities of small bile ducts and cholestatic liver disease resembling GVHD of the liver after allogeneic transplant. The mechanisms of bile duct damage in this setting may involve immune dysregulation related to reconstitution of immunity with peripheral blood stem cells.