Hemolytic uremic syndrome in solid-organ transplant recipients

Post-transplant hemolytic uremic syndrome characterized by microangiopathic hemolysis, thrombocytopenia, and renal failure is an infrequent but potentially serious complication in organ transplant recipients. Hemolytic uremic syndrome developed in 2% (2/100) of our consecutive liver transplants. We report our patients and review a total of 91 cases of hemolytic uremic syndrome in adult solid organ transplant recipients reported in the literature. Ninety percent were observed in renal transplant recipients, 8% in liver, and 1% each in lung and heart transplant recipients. Eighty percent and 96% of cases occurred within 90 days and 1 year, respectively, post-transplantation. In renal transplant recipients, 23% of cases were due to post-transplant recurrence of hemolytic uremic syndrome. In 50% of renal transplant recipients and in all norenal solid-organ transplant recipients, hemolytic uremic syndrome was attributed to cyclosporin or tacrolimus therapy. Notably, infections were not a significant precipitating factor for post-transplant hemolytic uremic syndrome. Graft loss attributable to hemolytic uremic syndrome occurred in 43% of renal transplant recipients while renal transplantation and hemodialysis were required in the lung and heart transplant recipients due to hemolytic uremic syndrome induced renal failure. The overall mortality was 13% (12/91). Physicians caring for transplant recipients need to be aware of this potentially severe graft and life-threatening disorder since prompt recognition and removal of identifiable risk factors is critical in the management of post-transplant hemolytic uremic syndrome.     

Hemolytic anemia after renal transplantation: analysis of case reports

Hemolysis after renal transplantation in some cases is clearly related to hemolytic-uremic syndrome (HUS) and usually attributed to cyclosporine (CsA) treatment. Acute hemolysis in other recipients is related to anti-erythrocyte autoantibodies. In most cases these patients have received ABO-compatible, although ABO-nonidentical, organs, mostly from O blood group donors. We report three cases of autoimmune hemolytic anemia after renal transplantation. Two patients (patients: 1 and 2; ABO-compatible, but nonidentical kidneys) suffered acute hemolysis in the third week after transplantation. One patient (patient 3: ABO-identical kidney) suffered a chronic, subclinical course of disease beginning 5 months after transplantation. The clinical picture of this disease was completely different from HUS. The existence of severe anemia (patients 1 and 2), hyperbilirubinemia (particularly high in patient 3), increased serum lactic dehydrogenase levels, and decreased serum haptoglobin in the presence of good graft function suggested an hemolytic anemia. In all patients the direct antiglobulin test was positive. The acute or chronic symptoms of hemolysis disappeared, at 2 and 5 weeks, respectively, after conversion from CsA to tacrolimus. Hemolysis in these patients probably relates to alloantibodies derived from passenger B lymphocytes transplanted with the organs. Because hemolysis has been most frequently related to CsA therapy, it is suggested that B lymphocytes proliferated and produced antibodies because CsA effects to inhibit T-cell function generally spares B-cell activity. It is proposed that a subtype of B cells, which are resistant to CsA, produces anti-A and/or anti-B antibodies. Treatment with tacrolimus appears to be successful, probably due to its alternate, and likely more effective, manner of B-cell suppression.     

Silent renal microangiography after mitomycin C therapy

Mitomycin C (MMC) is an alkylating agent which has been associated with microangiopathic hemolytic anemia and acute renal failure, with an overall incidence between 2 and 10%. This complication can develop several months after the initiation of chemotherapy. Isolated renal impairment without overt microangiopathic hemolytic anemia, although reported, is less frequently documented. We describe a 63-year-old man who developed progressive renal failure without any evidence of hemolysis or thrombopenia 10 months after beginning chemotherapy with MMC and Ftorafur. A renal biopsy displayed features of microangiopathy. The patient required the institution of chronic hemodialysis. In conclusion, it is important to be aware of this indolent but severe renal complication in patients treated with MMC. Urinary parameters and renal function should be monitored over a long period for an early diagnosis.     

Calcium Oxalate Deposition in Renal Allografts: Morphologic Spectrum and Clinical Implications

Many aspects of calcium oxalate (CaOx) deposition in renal transplant biopsies are not known. Review of all renal transplant biopsies performed in a 7-year period showed that CaOx deposition could be classified into three groups. Group I: Seven biopsies within a month post-transplant displayed rare CaOx foci against a background of acute tubular necrosis or acute cell-mediated rejection. At follow-up, five grafts functioned well and two failed due to chronic allograft nephropathy. CaOx in this context was an incidental finding secondary to a sudden excretion of an end-stage renal disease-induced increased body burden of CaOx. Group II: Two biopsies performed 2 and 10 months post-transplant showed rare CaOx foci against a background of chronic allograft nephropathy, leading to graft loss. CaOx in this context reflected nonspecific parenchymal deposition due to chronic renal failure regardless of causes. Group III: One biopsy with recurrent PH1 characterized by marked CaOx deposition associated with severe tubulointerstitial injury and graft loss 6 months post-transplant. There were two previously reported cases in which CaOx deposition in the renal allografts was due the antihypertensive drug naftidrofuryl oxalate or increased intestinal absorption of CaOx. CaOx deposition in renal allografts can be classified in different categories with distinctive morphologic features and clinical implications.     

A surgical case for severe hemolytic anemia after mitral valve repair.

We report a rare case of severe hemolytic anemia accompanied by moderate renal insufficiency after mitral valve repair. Although the degree of the residual mitral regurgitation was less than 1+ during the first three weeks after the operation, the maximum lactate dehydrogenase (LDH) was up to 7,430 U/l and the minimum hemoglobin was 4.9 g/dl. The mitral valve replacement successfully resolved the hemolysis, but the renal function did not completely recover.     

Severe Coombs'-negative autoimmune hemolytic anemia in a kidney transplant patient.

BACKGROUND/AIM: Few cases are found in the literature regarding autoimmune hemolytic anemia which is Coombs' test positive in kidney transplant patients, although hemolytic uremic syndrome due to cyclosporin and FK506 has been well described. In the following, we describe a case of severe life-threatening Coombs' test negative autoimmune hemolytic anemia after kidney transplantation. METHODS: Soon after undergoing renal transplantation, the patient presented with hemolytic anemia. Kidney biopsy, routine Coombs' test, gel filtration and flow-cytometric assay were undertaken. RESULTS: Kidney biopsy ruled out hemolytic uremic syndrome; although Coombs' test and gel filtration assay were negative, flow cytometry revealed circulating antierythrocytic autoantibodies. CONCLUSIONS: Our findings indicate that flow cytometry may be an efficient method in the diagnosis of hemolysis of unknown origin in transplant patients. We further hypothesize that the underlying mechanism of autoimmune hemolytic anemia is related to the passenger B lymphocytes in the graft.     

Red cell antigens and renal transplantation

Donor-specific transfusion was performed with and without cyclosporine between haplomismatched relatives prior to living-donor renal transplantation. Red cell antigen mismatching was not taken as a contraindication to DST. Of 80 patients included in the trial; eleven were ABO-mismatched, 15 were Rh(D)-mismatched, and a further 11 were transfused in the presence of atypical red cell antibodies (anti-D, -C, -Fya, -Kell -N, -H/I -I, -P1, -Wra). Patients were randomized to receive cyclosporine (10 mg/kg) daily during DST or not (control group). The presence of atypical red cell antibodies, with the exception of Rh anti-D, did not appear to influence DST or renal transplantation. DST did not act as a primary stimulus to Rh anti-D production but stimulated preexisting anti D levels. ABO mismatching did not appear to influence DST or subsequent renal transplantation except in one group A [corrected] patient who received group O [corrected] blood and cyclosporine. This patient developed a severe, but self-limiting, autoimmune hemolytic anemia due to auto-anti A antibodies. A similar group A patient in the control group developed an auto-antibody with no clinical sequelae. The influence of cyclosporine on the development of this auto-antibody is uncertain. We conclude that, with the exception of preexisting anti-D antibodies, minor red cell antigen disparities should not preclude pretransplant conditioning with donor-specific transfusions.     

A rare case of acute kidney injury associated with autoimmune hemolytic anemia and thrombocytopenia after long-term usage of oxaliplatin

Oxaliplatin is effective in advanced colorectal cancer and is known to have relatively few side effects, such as hemolysis and renal toxicity. We report a case of acute kidney injury (AKI) after treatment with a combination of oxaliplatin, folinic acid and 5-fluorouracil or capecitabine. The patient developed acute renal failure, hemolytic anemia and thrombocytopenia after the 34th course of chemotherapy including oxaliplatin. A positive direct antiglobulin test and detection of immunoglobulin G and complement C3b and C3d on erythrocytes suggested the diagnosis of immune-related severe intravascular hemolytic anemia. She was successfully treated and recovered using plasma exchange, corticosteroids and hemodialysis therapy. Only seven other cases of AKI associated with oxaliplatin use have been reported to date. As in this case, acute hemolysis due to autoimmune mechanisms and subsequent AKI occurred suddenly after frequent use of oxaliplatin in four of those cases. We should be aware that oxaliplatin may cause sudden life-threatening hemolysis by drug-induced antibodies and subsequent AKI, even though oxaliplatin is frequently administered without side effects. This represents the first case report of AKI-related hemolysis due to oxaliplatin in Japan.     

Use of low dose tacrolimus, mycophenolate mofetil and maintenance IL-2 receptor blockade in an islet transplant recipient

Abstract:  The utilization of dual maintenance therapy with tacrolimus and sirolimus (the Edmonton protocol) has been widely adopted as standard immunosuppression for islet cell transplantation. This immunosuppression regimen has numerous toxicities including renal dysfunction, anemia, and recurrent aphthous ulcers. We present a case of a 63-yr-old Caucasian female who received an isolated islet transplant. Over the first six months post-transplant, the patient developed severe anemia, intractable aphthous ulcers, and renal dysfunction. Islet transplant function was excellent and the patient is insulin-independent since the end of the second month post-transplant. However, because of the above toxicities, a decision was made to change her immunosuppression regimen eight months post-transplant to low dose tacrolimus, mycophenolate mofetil, and a monthly maintenance infusion of daclizumab. Since then, her aphthous ulcers have disappeared, renal function has improved, and islet cell function remains stable.     

Repeat surgery for hemolysis 6 years after replacement of the ascending aorta for acute aortic dissection

A 71-year-old woman underwent replacement of the ascending aorta for Type A aortic dissection. After 6 years, she suddenly developed severe hemolytic anemia, and a second operation for replacement of the ascending aorta was performed. Her hemolysis was thought to occur as follows: the proximal ascending aorta of the graft might have gradually expanded until it compressed the graft. The severe hemolysis was thought to be attributable to disturbance of blood flow by a jet of blood at the site of constriction or the reversed inner felt. Such a case as this is very unusual in that the second operation for hemolytic anemia occurred 6 years after the first surgery.     

Membranous nephritis in infantile systemic lupus erythematosus associated with chromosomal abnormalities.

A white female infant who developed a sudden onset of gross hematuria and proteinuria at 3 months of age was referred for evaluation of nephrotic syndrome at 6 months. Laboratory investigations revealed severe Coomb's negative hemolytic anemia, leukopenia, thrombocytopenia, hypocomplementemia and elevated anti-nuclear antibody titer and DNA antibodies. Renal biopsy showed a membranous type of morphology. She was also found to have chromosome abnormalities. She had an eventual favorable response to steroid therapy. Systemic lupus erythematosus (SLE) is rarely seen in young infants and the renal expression of the disease found in our case has never been reported.     

Outcome of renal transplantation in fibrillary glomerulonephritis

Fibrillary glomerulonephritis (FGN) is a rare but progressive glomerular disease usually with end-stage renal disease (ESRD) developing within months or few years following the diagnosis. Little is known about the outcome of renal transplantation in patients with ESRD due to FGN. We report four patients with FGN who received renal allografts. Two patients developed recurrent FGN in their grafts. One patient was diagnosed to have recurrent FGN 9 years post-transplant, and lost his graft 4 years thereafter. Another patient had recurrent disease 2 years post-transplant but has stable graft function after 7 years. One patient died with normal renal allograft function 7 years following transplantation. The fourth patient has chronic transplant nephropathy 34 months post-transplant without evidence of recurrent FGN. A literature review revealed 10 additional patients who received 11 renal allografts due to ESRD caused by FGN. Four of these 10 patients had biopsy-proven recurrence (one patient in two subsequent grafts), but this caused graft loss only in 2 patients 56 months and 7 years post-transplant, respectively. The earliest recurrence was diagnosed 2 years post-transplant. We conclude that although the recurrence rate of FGN in renal transplants is high (around 50%), the recurrent disease has a relatively benign course and prolonged graft survival is possible.     

Hemolytic uremic syndrome associated with glomerular disease

Secondary hemolytic uremic syndrome (HUS) is uncommon. When it occurs, it is usually in association with pregnancy, malignancy, severe hypertension, drugs, or collagen vascular diseases. It has rarely been reported in patients with glomerular disease. Two such patients with secondary HUS are described. A 17-month-old girl with hematuria and the nephrotic syndrome, negative antistreptolycin O (ASO) titer, and low serum levels of C3 and C4 developed oliguria, progressive azotemia, thrombocytopenia, and microangiopathic hemolytic anemia. A kidney biopsy showed fibrin in glomerular capillaries and cresentic membranoproliferative glomerulonephritis. A 22-year-old man with a 16-year history of relapsing minimal change nephrotic syndrome had been in remission for 5 years when he experienced nephrotic syndrome relapse and developed thrombocytopenia, microangiopathic hemolytic anemia, and renal failure. A kidney biopsy revealed foot process fusion and obstruction of glomerular capillaries with fibrin and platelets. These cases illustrate that HUS can occur in association with other glomerular diseases and should be considered when thrombocytopenia and hemolytic anemia occur in a nephritic or nephrotic patient.     

Rifampicin-associated acute renal failure: pathophysiologic, immunologic, and clinical features

A 71-year-old woman was treated for a relapsing pulmonary tuberculosis with reinstitution of rifampicin after a medication-free interval of 2 years. After ingestion of the second dose, she developed severe hemolytic anemia and acute renal failure (ARF) necessitating dialysis. We demonstrated the presence in the patient's serum of rifampicin-dependent immunoglobulin G (IgG) and IgM antibodies, which caused red blood cell lysis through interaction with the I antigen on the erythrocyte surface. A review of the literature yielded 48 cases of rifampicin-associated renal failure. A subgroup of 37 patients could be distinguished, which, analogous to our case, suddenly developed ARF and frequently also developed hemolytic anemia and/or thrombocytopenia during intermittent or interrupted treatment. Regarding the pathogenesis of the ARF, renal biopsy consistently revealed tubular lesions. Although intravascular hemolysis with hemoglobinuria may play a role, it is not uniformly present. Our demonstration of an antibody with anti-I specificity provides a possible explanation. The I antigen is also expressed on tubular epithelium and may, therefore, be the target structure through which rifampicin-antibody complexes lead to tubular cell destruction. The other cases of rifampicin-associated ARF were unrelated to this subgroup: two cases of rapidly progressive glomerulonephritis, five cases of acute interstitial nephritis, and four cases of light chain proteinuria were recorded.     

Severe hemolytic anemia due to passenger lymphocytes after living-related bowel transplant

BACKGROUND: Hemolytic anemia following solid organ transplant may be caused by 'passenger' lymphocytes producing antibodies against erythrocytes. This phenomenon has never been described after intestinal transplant. MATERIALS AND METHODS: We report a case of severe, immune-mediated hemolysis due to symptomatic passenger lymphocyte syndrome (PLS) in a 4-yr-old recipient of living donor small bowel transplant. The Coombs'-positive hemolysis was caused by anti-A,B antibodies derived from donor lymphocytes in an ABO-compatible donor-recipient pair (O into A). RESULTS: This complication was successfully and efficiently treated by the novel combined use of group O RBC transfusion, plasmapheresis and rituximab (anti-CD20). CONCLUSIONS: A severe hemolytic anemia due to PLS can occur in bowel transplantation. This complication should be considered when performing ABO-incompatible bowel transplant with a blood group O donor and an A or B recipient. Treatment with plasmapheresis, blood group O transfusion and rituximab has proved successful in our case.     

Repair of paravalvular leak after a third mitral valve replacement

This study reports on a 57-year-old woman who underwent a 3rd mitral valve replacement and presented with complaints of fatigue. Laboratory examination revealed severe hemolytic anemia, and trans-esophageal echocardiography revealed a paravalvular leak (PVL) around the prosthetic valve at the posterior trigone in the mitral position. PVL was regarded as the cause of hemolytic anemia. At surgery, a small tissue defect was detected around the calcified posterior trigone of the mitral annulus with no evidence of infective endocarditis. The mitral PVL was successfully repaired with suture closure of the annular defect. The postoperative course was uneventful: postoperative echocardiography revealed no evidence of PVL, and the hemolytic anemia subsided.     

FK506-associated thrombotic microangiopathy: report of two cases and review of the literature

BACKGROUND: FK506 is a recently developed immunosuppressant that has been useful in improving the survival of transplanted organs. Among the numerous adverse side effects of FK506, thrombotic microangiopathy (TMA) stands out as an infrequent but severe complication. METHODS: We report two cases of FK506-associated TMA and review the 19 previous reported cases. RESULTS: From these 21 cases, the reported incidence of FK506-associated TMA is between 1% and 4.7%. It is more frequent in females, and the mean age at presentation is 47 years. Eighty-one percent of the cases occurred in patients with kidney allografts, and the remaining patients had liver, heart, or bone marrow transplants. Clinically, TMA was diagnosed at an average interval of 9.3 months from the time of transplantation. Patients may be asymptomatic or may present with the full-blown picture of hemolytic uremic syndrome. All patients had an elevated serum creatinine level but did not always show signs of hemolysis. Trough levels of FK506 were not predictive for the development of TMA, but generally a reduction of drug dose correlated with kidney function improvement and disappearance of the hemolytic picture. The renal allograft biopsy provided a conclusive diagnosis in all 17 cases in which this procedure was performed. Treatment, which mainly consisted of reduction or discontinuation of FK506, anticoagulation, and/or plasmapheresis with fresh-frozen plasma exchange, resolved TMA in most patients (57%). However, in one of these patients (5%), the graft was subsequently lost due to causes unrelated to TMA, such as acute or chronic rejection. Despite treatment, one patient (5%) lost the graft due to acute rejection and persistent TMA, and three other patients (14%) who had bone marrow, heart, and liver transplants, died of multiple organ failure, probably unrelated to TMA. In the remaining four patients (19%), response to treatment was not reported. CONCLUSIONS: TMA must be considered in organ transplant patients treated with FK506 whenever kidney function deteriorates, even in the absence of microangiopathic hemolytic anemia. Although TMA usually responds to treatment, it may, in rare cases, lead to loss of kidney function or even the patient's death.     

Bullous pemphigoid after liver transplantation for liver failure.

Coomb's positive autoimmune hemolytic anemia with giant cell hepatitis (GCH) is a rare cause of liver failure and is usually associated with poor prognosis. A child with liver kidney microsomal (LKM) antibody positivity underwent successful liver transplantation for liver failure secondary to GCH with Coomb's positive hemolytic anemia. Autoimmune neutropenia developed ten months after transplant. Four months later, pemphigoid skin lesions developed. The diagnosis of bullous pemphigoid (BP) was made on the basis of skin biopsy, direct and indirect immunofluorescence test results. Treatment was with immunosuppressants - prednisone and azathioprine/rapamycin, with addition of dapsone when lesions persisted. This child is unique in that his liver function and hemolytic anemia appeared to normalize after liver transplant, but neutropenia and BP both thought to be autoimmune in etiology, developed more than a year post-transplant.     

Renal failure due to scleroderma with thrombotic microangiopathy developing in a woman treated with carboplatin for ovarian cancer

Acute renal failure in association with microangiopathic hemolytic anemia and the pathological finding of thrombotic microangiopathy may occur in a number of conditions including hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and systemic sclerosis. Distinguishing between these conditions on clinical grounds may be difficult, and further investigations, including serological tests, are normally helpful. We present a patient who was treated with 5 doses of monthly carboplatin chemotherapy for stage IIb ovarian carcinoma and who subsequently developed acute renal failure and microangiopathic hemolysis together with some cutaneous features of systemic sclerosis. Initial serological tests, including anti-nuclear antibody titers measured using rat hepatocytes, were normal, and renal biopsy showed features of microangiopathic hemolysis, fibrinoid change, patchy tubular atrophy, and concentric intimal proliferation. A clinical diagnosis of diarrhea-negative hemolytic uremic syndrome was made and she was treated with plasma exchange and fresh frozen plasma infusion. However, she remained dialysis-dependent. Several weeks later she died following a cardiac arrest. Post-mortem examination revealed medial hypertrophy, concentric intimal proliferation, and thrombi within the small arteries of the kidneys and lungs. Subsequent results from tests taken at the time of her presentation with acute renal failure revealed a normal von Willebrand factor qualitative distribution, and a positive anti-nuclear antibody titer (using a human cell line) in association with positive autoantibodies to RNA polymerase types I, II, and III. Taken together, the clinical, laboratory, and post-mortem findings were suggestive of a diagnosis of systemic sclerosis. We discuss the differential diagnoses, and the associations between these and malignancy and chemotherapy. Finally, we consider the serological tests used for the diagnosis of systemic sclerosis that were, in this case, initially misleading.     

Aortic valve replacement for a patient with glucose-6-phosphate dehydrogenase deficiency and autoimmune hemolytic anemia

Autoimmune hemolytic anemia and deficiency of glucose-6-phosphate deyhdrogenase (G6PD) result in severe hemolysis with different mechanisms. In patients with both pathologies, the effects of cardiopulmonary bypass on red blood cells and thrombocytes demand special care before and after open heart surgery. We evaluated the preoperative management and postoperative care of a patient with severe aortic insufficiency associated with G6PD deficiency and autoimmune hemolytic anemia who underwent aortic valve replacement.