Case Series: Hemolytic Uremic SyndromedAnother Cause of Transplant Dysfunction M.N.A. Ali, A.B. Syed, and S.C. Bhandari ABSTRACT Background. Renal transplantation is the optimal treatment for suitable patients with end-stage renal disease (ESRD). However, acute graft dysfunction occurs in 5%e35% of patients. This is commonly due to acute rejection, drug toxicity, ureteric obstruction, or infection. Atypical hemolytic uremic syndrome (aHUS), either recurrent or de novo, is uncommon after transplantation. Cases. We highlight three cases of acute transplant dysfunction in which transplant biopsy revealed HUS without associated clinical or hematologic clues to the etiology. Two cases had recurrent HUS and 1 had de novo HUS secondary to tacrolimus therapy. Screenings for ADAMTS-13 and gene mutations of complement regulatory proteins were negative. Thrombocytopenia and red blood cell fragments on blood film appeared some days later. Treatment. Treatment comprised a combination of plasma exchange with fresh-frozen plasma and switching immunosuppressive therapy, which led to the recovery of the above hematologic features but salvaged graft function in only 1 case. Conclusions. Classical hematologic findings of HUS appeared late in these cases. HUS should be considered in cases of allograft dysfunction where there is no obvious cause, and biopsy should be performed. This enables early initiation of therapy to gain rapid recovery of hematologic parameters and potentially of transplant function.
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ENAL TRANSPLANTATION is the optimal treatment for patients with end-stage renal disease (ESRD).1,2 Evolving immunosuppressive therapy has resulted in a significant reduction in acute transplant rejection episodes and improved short- and long-term graft survival. However, acute graft dysfunction still occurs in 5% of cases, and most clinicians follow a standard algorithm for acute and chronic renal allograft dysfunction encompassing: Acute cellular rejection. Antibody-mediated rejection. Ureteric obstruction. Drug toxicity. Infection. Viral infections: cytomegalovirus (CMV), BK nephropathy. Vascular compromise. Recurrent disease.
We present 3 cases of acute transplant dysfunction in which early transplant biopsy revealed hemolytic uremic syndrome (HUS) despite a lack of clinical or classic hematologic changes (Table 1).
CASE 1
A 28-year-old woman with ESRD due to reflux nephropathy had commenced dialysis at the age of 16 years in 1996. In
From the Department of Renal Medicine, Hull and East Yorkshire Hospitals, NHS Trust, and Hull and York Medical School, Hull, East Yorkshire, United Kingdom. Address reprint requests to Prof Sunil Bhandari, Department of Renal Medicine, Hull Royal Infirmary, HU3 2JZ, Leeds, Yorkshire LS8 2TB, United Kingdom. E-mail: [email protected]
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.07.060
ª 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
3284
Transplantation Proceedings, 45, 3284e3288 (2013)
HEMOLYTIC UREMIC SYNDROME
3285 Table 1. Synopsis of the Cases Case 1
Maintenance immunosuppression Early symptoms Initial signs Late signs/laboratory investigations
Platelet count Regulatory complements/ADAMTS13 Biopsy
Case 2
Case 3
Tacrolimus, mycophenolate, prednisolone Diarrhea Persistent neutropenia
Tacrolimus, mycophenolate
Cyclosporine, steroids
None Acute graft dysfunction
Acute graft dysfunction, anemia, mildly elevated LDH, no red cell fragments Normal
Anemia, red cell fragments until very late, mildly elevated LDH
None Acute graft dysfunction, urine infections Anemia, red cell fragments until very late, elevated LDH
Negative TMA, aHUS secondary to tacrolimus
Thrombocytopenia very late at the time of the biopsy Negative 1st biopsy: unremarkable; 2nd biopsy: recurrence of aHUS
Thrombocytopenia very late Negative 1st biopsy: no acute rejection; 2nd biopsy: ATN, chronic tubulo-interstitial changes; 3rd biopsy: TMA
Abbreviations: aHUS, atypical hemolytic uremic syndrome; ATN, acute tubular necrosis; LDH, lactate dehydrogenase; TMA, thrombotic microangiopathy.
1997 she received a deceased brain-dead-donor renal transplant which failed in 2001 owing to chronic allograft nephropathy. In 2005 she received a second transplant from her father (mismatch 1:1:1). This failed owing to a combination of extensive interstitial fibrosis and tubular atrophy resulting from severe vascular rejection and chronic ureteric obstruction. In 2009 she received a third allograft from her mother (mismatch 1:1:1) and was maintained on tacrolimus (calcineurin inhibitor [CNI]), mycophenolate, and prednisolone. Her blood count showed persistent neutropenia possibly due to mycophenolate, but CMV polymerase chain reaction was negative and platelets were normal. She was reviewed by the hematologist and underwent a bone marrow biopsy, which showed reactive changes only.
After 9 months, the patient developed diarrhoea; platelet count was normal, and there was no evidence of fragmented red cells. Stool analysis for E coli 0157, E coli 0104:H4, and other pathogens were negative. Serum creatinine rose from a baseline of 130 mmol/L to 200 mmol/L. Transplant biopsy showed blood vessels suggestive of thrombotic microangiopathy (TMA) and the possibility of de novo atypical HUS (aHUS; Figure 1). Tacrolimus trough levels remained within a therapeutic range throughout. Her platelet count remained normal, but she developed fragments and lactate dehydrogenase (LDH) levels rose to 881 IU/L (normal range, 100e400 IU/L). Tacrolimus was substituted with cyclosporine (Table 2). Plasma exchange therapy (PEx) with the use of freshfrozen plasma (FFP) was commenced. After an initial improvement in graft function, further deterioration led to a second transplant biopsy, which showed moderate scarring, persistent TMA, and polyoma virus with positive SV-40 staining. Leflonamide and ciprofloxacin were introduced for BK virus, and immunosuppressive therapy was reduced. A third biopsy showed resolution of TMA and BK nephropathy, but progressive chronic scarring led to loss of the allograft over a subsequent 9-month period.
CASE 2
Fig 1. Collapsed capillary loops, small amounts of a hyaline material, and several arteriolar vessels, demonstrating fibrinoid necrosis.
A 36-year-old man initially presented in April 2008 with acute kidney injury (AKI) and presumed aHUS for which he was treated with PEx. However, he progressed to ESRD and peritoneal dialysis. He received a living-related transplant from his mother (mismatch 1:1:0) in April 2010. His maintenance immunosuppression included tacrolimus and mycophenolate only. Despite good primary graft function, there was a slow rise in creatinine from 120 mmol/L to 175 mmol/L. Investigations for obstruction, infection, and
3286
ALI, SYED, AND BHANDARI Table 2. Case 1 Blood Investigations
Date
Tacrolimus (N: 0e3 mo: 9e14 ng/L) Cr (>3 mo: 4e9 ng/L) (N: 60e110 mmol/L) Hb (g/dL)
Mar 19 Mar 24 Apr 1 Apr 15 Apr 28 May 4 May 10 May 12 May 5 May 17 May 20
N N
N N N
185 217 165 200 191 241 227 238 254
8.9 8.0 7.7 7.7 8 7.7 8 7.7 7.5 7.0
PLT
N N N N N N N N N (194) 160
Blood film
LDH Biopsy (N: 100e400 IU/L)
Bilirubin
N
No red cell fragments Neutropenia No red cell fragments No red cell fragments
N 849 Mildly elevated
Toxic neutrophils, low WCC Red cell fragments
881
Elevated
Biopsy
The blood investigations demonstrate the rise in creatinine and fall in hemoglobin along with blood film showing microangiopathic hemolytic anemia picture very late, days before the biopsy, which in turn showed evidence of thrombotic changes and cellular rejection. Abbreviations: Cr, creatinine; Hb, hemoglobin; LDH, lactate dehydrogenase; N, normal; PLT, platelets; TMA, thrombotic microangiopathy.
transplant artery stenosis were negative and first biopsy was unremarkable. The serum creatinine continued to rise to 243 mmol/L. The second biopsy was consistent with aHUS (possibly recurrence of primary disease). Platelets were initially normal before falling to 113 109/L and there were no red cell fragments initially. LDH subsequently rose to 870 IU/L. Tacrolimus was switched to cyclosporine, and PEx with FFP was commenced. The patient subsequently developed a drop in hemoglobin, thrombocytopenia, and fragmented red blood cells on blood film. Tests for mutations of the complement regulators and ADAMTS-13 analysis were negative. After 10 sessions of PEx, the platelet count improved with resolution of red cell fragments but little improvement of allograft function. Further transplant biopsy was in keeping with chronic HUS. The patient received 5 further courses of PEx, and cyclosporine dose was reduced. Transplant function improved to a serum creatinine of 275 mmol/L from a peak of 402 mmol/L. He remained stable for a period of time before self-withdrawal of immunosuppressive therapy owing to depression and reverting to dialysis therapy. CASE 3
An 18-year-old girl had Dþ HUS secondary to E coli 0157 diagnosed at the age of 2 years which led to ESRD. She had received peritoneal dialysis and later hemodialysis. A livingrelated renal transplant from her father (mismatch 1:1:1) was carried out in February 2010. Her renal function deteriorated immediately after transplantation. Transplant biopsy showed chronic damage with no acute rejection. Serum creatinine remained persistently elevated, and a further transplant biopsy showed moderate chronic tubulointerstitial and cortical damage in association with nephrocalcinosis, which was thought to be the result of acute tubular necrosis in the immediate post-transplantation period (Fig 1). There were no features of acute cellular rejection.
The patient remained anemic, requiring intravenous iron and erythropoietin, and her serum creatinine was 200 mmol/L. She was subsequently admitted with an E coli (non-0157) and Klebsiella urine infection, which was treated successfully with antibiotics. Following this episode of illness there was a marked deterioration in renal function, necessitating a further biopsy of the transplanted kidney. This revealed changes suggesting recurrence of HUS. The patient subsequently developed thrombocytopenia and fragmented red cells. Cyclosporine was switched to tacrolimus, and the dose of steroids was increased. The patient underwent PEx with FFP. Transplant function stabilized with a serum creatinine of 210 mmol/L, and platelets normalized. Screening for E coli 0157 remained negative, and atypical screenings for complement regulator proteins and ADAMTS-13 were negative. She remains well. DISCUSSION
HUS is a TMA, characterized by a triad of mechanical nonimmune hemolytic anemia (negative Coombs test and fragmented red blood cells), thrombocytopenia, and renal failure. It is associated with features of intravascular haemolysis such as high LDH and low/undetectable serum haptaglobulin.3 HUS is classified into 2 forms: typical and atypical. Typical HUS is more common in children. It is mostly associated with Shiga toxineproducing E coli serotype 0157:H7, which causes diarrhea, and more recently E coli 0104:H4 from the German bean sprout outbreak (which had a high mortality). Generally the former has a good prognosis, with observed mortality and ESRD of 5%.4 Atypical HUS is uncommon and accounts for 5%e10% of all HUS cases.5 It is predominantly seen in adults and may be due to a number of triggers. It is further classified into primary and secondary aHUS (Table 3). In case 1, BK nephropathy was a possible trigger, whereas in case 3 urinary tract infections may have acted as the trigger. Case 2,
HEMOLYTIC UREMIC SYNDROME Table 3. Causes of Atypical Hemolytic Uremic Syndrome (aHUS) Primary: Mutations in complement Complement factor H (CFH) regulatory proteins Complement factor B Complement factor I Membrane cofactor protein Complement factor C3 Thrombomodulin Autoantibody Anti-CFH antibody Infections Streptococcus pneumoniae Human immunodeficiency virus H1N1 influenza A Cancer Disseminated malignancy Cancer chemotherapy and ionizing Mitomycin, bleomycin, radiation gemcitabine, cisplatin Bone marrow transplantation Drugs Calcineurin inhibitors Mammalian target of rapamycin inhibitors Quinine Ticlopedine Pregnancy and HELLP (hemolysis, elevated liver enzymes, low platelet count) Autoimmune disease Systemic lupus erythematosus Antiphospholipid syndrome Scleroderma
we think, was a recurrence of primary disease, but again no triggers were identified. Primary aHUS was initially presumed to be idiopathic; however, recent advances have indicated that 70% of aHUS cases are due to mutations in complement-regulatory proteins and autoantibodies,6e10 which can occur sporadically or familial. These mutations, either singly or in combination, play a central role in uncontrolled complement system activation and endothelial cell injury leading to TMA. Recurrence in renal allograft patients who survived Shiga toxineassociated HUS with ESRD is rare (
R
ENAL TRANSPLANTATION is the optimal treatment for patients with end-stage renal disease (ESRD).1,2 Evolving immunosuppressive therapy has resulted in a significant reduction in acute transplant rejection episodes and improved short- and long-term graft survival. However, acute graft dysfunction still occurs in 5% of cases, and most clinicians follow a standard algorithm for acute and chronic renal allograft dysfunction encompassing: Acute cellular rejection. Antibody-mediated rejection. Ureteric obstruction. Drug toxicity. Infection. Viral infections: cytomegalovirus (CMV), BK nephropathy. Vascular compromise. Recurrent disease.
We present 3 cases of acute transplant dysfunction in which early transplant biopsy revealed hemolytic uremic syndrome (HUS) despite a lack of clinical or classic hematologic changes (Table 1).
CASE 1
A 28-year-old woman with ESRD due to reflux nephropathy had commenced dialysis at the age of 16 years in 1996. In
From the Department of Renal Medicine, Hull and East Yorkshire Hospitals, NHS Trust, and Hull and York Medical School, Hull, East Yorkshire, United Kingdom. Address reprint requests to Prof Sunil Bhandari, Department of Renal Medicine, Hull Royal Infirmary, HU3 2JZ, Leeds, Yorkshire LS8 2TB, United Kingdom. E-mail: [email protected]
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.07.060
ª 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
3284
Transplantation Proceedings, 45, 3284e3288 (2013)
HEMOLYTIC UREMIC SYNDROME
3285 Table 1. Synopsis of the Cases Case 1
Maintenance immunosuppression Early symptoms Initial signs Late signs/laboratory investigations
Platelet count Regulatory complements/ADAMTS13 Biopsy
Case 2
Case 3
Tacrolimus, mycophenolate, prednisolone Diarrhea Persistent neutropenia
Tacrolimus, mycophenolate
Cyclosporine, steroids
None Acute graft dysfunction
Acute graft dysfunction, anemia, mildly elevated LDH, no red cell fragments Normal
Anemia, red cell fragments until very late, mildly elevated LDH
None Acute graft dysfunction, urine infections Anemia, red cell fragments until very late, elevated LDH
Negative TMA, aHUS secondary to tacrolimus
Thrombocytopenia very late at the time of the biopsy Negative 1st biopsy: unremarkable; 2nd biopsy: recurrence of aHUS
Thrombocytopenia very late Negative 1st biopsy: no acute rejection; 2nd biopsy: ATN, chronic tubulo-interstitial changes; 3rd biopsy: TMA
Abbreviations: aHUS, atypical hemolytic uremic syndrome; ATN, acute tubular necrosis; LDH, lactate dehydrogenase; TMA, thrombotic microangiopathy.
1997 she received a deceased brain-dead-donor renal transplant which failed in 2001 owing to chronic allograft nephropathy. In 2005 she received a second transplant from her father (mismatch 1:1:1). This failed owing to a combination of extensive interstitial fibrosis and tubular atrophy resulting from severe vascular rejection and chronic ureteric obstruction. In 2009 she received a third allograft from her mother (mismatch 1:1:1) and was maintained on tacrolimus (calcineurin inhibitor [CNI]), mycophenolate, and prednisolone. Her blood count showed persistent neutropenia possibly due to mycophenolate, but CMV polymerase chain reaction was negative and platelets were normal. She was reviewed by the hematologist and underwent a bone marrow biopsy, which showed reactive changes only.
After 9 months, the patient developed diarrhoea; platelet count was normal, and there was no evidence of fragmented red cells. Stool analysis for E coli 0157, E coli 0104:H4, and other pathogens were negative. Serum creatinine rose from a baseline of 130 mmol/L to 200 mmol/L. Transplant biopsy showed blood vessels suggestive of thrombotic microangiopathy (TMA) and the possibility of de novo atypical HUS (aHUS; Figure 1). Tacrolimus trough levels remained within a therapeutic range throughout. Her platelet count remained normal, but she developed fragments and lactate dehydrogenase (LDH) levels rose to 881 IU/L (normal range, 100e400 IU/L). Tacrolimus was substituted with cyclosporine (Table 2). Plasma exchange therapy (PEx) with the use of freshfrozen plasma (FFP) was commenced. After an initial improvement in graft function, further deterioration led to a second transplant biopsy, which showed moderate scarring, persistent TMA, and polyoma virus with positive SV-40 staining. Leflonamide and ciprofloxacin were introduced for BK virus, and immunosuppressive therapy was reduced. A third biopsy showed resolution of TMA and BK nephropathy, but progressive chronic scarring led to loss of the allograft over a subsequent 9-month period.
CASE 2
Fig 1. Collapsed capillary loops, small amounts of a hyaline material, and several arteriolar vessels, demonstrating fibrinoid necrosis.
A 36-year-old man initially presented in April 2008 with acute kidney injury (AKI) and presumed aHUS for which he was treated with PEx. However, he progressed to ESRD and peritoneal dialysis. He received a living-related transplant from his mother (mismatch 1:1:0) in April 2010. His maintenance immunosuppression included tacrolimus and mycophenolate only. Despite good primary graft function, there was a slow rise in creatinine from 120 mmol/L to 175 mmol/L. Investigations for obstruction, infection, and
3286
ALI, SYED, AND BHANDARI Table 2. Case 1 Blood Investigations
Date
Tacrolimus (N: 0e3 mo: 9e14 ng/L) Cr (>3 mo: 4e9 ng/L) (N: 60e110 mmol/L) Hb (g/dL)
Mar 19 Mar 24 Apr 1 Apr 15 Apr 28 May 4 May 10 May 12 May 5 May 17 May 20
N N
N N N
185 217 165 200 191 241 227 238 254
8.9 8.0 7.7 7.7 8 7.7 8 7.7 7.5 7.0
PLT
N N N N N N N N N (194) 160
Blood film
LDH Biopsy (N: 100e400 IU/L)
Bilirubin
N
No red cell fragments Neutropenia No red cell fragments No red cell fragments
N 849 Mildly elevated
Toxic neutrophils, low WCC Red cell fragments
881
Elevated
Biopsy
The blood investigations demonstrate the rise in creatinine and fall in hemoglobin along with blood film showing microangiopathic hemolytic anemia picture very late, days before the biopsy, which in turn showed evidence of thrombotic changes and cellular rejection. Abbreviations: Cr, creatinine; Hb, hemoglobin; LDH, lactate dehydrogenase; N, normal; PLT, platelets; TMA, thrombotic microangiopathy.
transplant artery stenosis were negative and first biopsy was unremarkable. The serum creatinine continued to rise to 243 mmol/L. The second biopsy was consistent with aHUS (possibly recurrence of primary disease). Platelets were initially normal before falling to 113 109/L and there were no red cell fragments initially. LDH subsequently rose to 870 IU/L. Tacrolimus was switched to cyclosporine, and PEx with FFP was commenced. The patient subsequently developed a drop in hemoglobin, thrombocytopenia, and fragmented red blood cells on blood film. Tests for mutations of the complement regulators and ADAMTS-13 analysis were negative. After 10 sessions of PEx, the platelet count improved with resolution of red cell fragments but little improvement of allograft function. Further transplant biopsy was in keeping with chronic HUS. The patient received 5 further courses of PEx, and cyclosporine dose was reduced. Transplant function improved to a serum creatinine of 275 mmol/L from a peak of 402 mmol/L. He remained stable for a period of time before self-withdrawal of immunosuppressive therapy owing to depression and reverting to dialysis therapy. CASE 3
An 18-year-old girl had Dþ HUS secondary to E coli 0157 diagnosed at the age of 2 years which led to ESRD. She had received peritoneal dialysis and later hemodialysis. A livingrelated renal transplant from her father (mismatch 1:1:1) was carried out in February 2010. Her renal function deteriorated immediately after transplantation. Transplant biopsy showed chronic damage with no acute rejection. Serum creatinine remained persistently elevated, and a further transplant biopsy showed moderate chronic tubulointerstitial and cortical damage in association with nephrocalcinosis, which was thought to be the result of acute tubular necrosis in the immediate post-transplantation period (Fig 1). There were no features of acute cellular rejection.
The patient remained anemic, requiring intravenous iron and erythropoietin, and her serum creatinine was 200 mmol/L. She was subsequently admitted with an E coli (non-0157) and Klebsiella urine infection, which was treated successfully with antibiotics. Following this episode of illness there was a marked deterioration in renal function, necessitating a further biopsy of the transplanted kidney. This revealed changes suggesting recurrence of HUS. The patient subsequently developed thrombocytopenia and fragmented red cells. Cyclosporine was switched to tacrolimus, and the dose of steroids was increased. The patient underwent PEx with FFP. Transplant function stabilized with a serum creatinine of 210 mmol/L, and platelets normalized. Screening for E coli 0157 remained negative, and atypical screenings for complement regulator proteins and ADAMTS-13 were negative. She remains well. DISCUSSION
HUS is a TMA, characterized by a triad of mechanical nonimmune hemolytic anemia (negative Coombs test and fragmented red blood cells), thrombocytopenia, and renal failure. It is associated with features of intravascular haemolysis such as high LDH and low/undetectable serum haptaglobulin.3 HUS is classified into 2 forms: typical and atypical. Typical HUS is more common in children. It is mostly associated with Shiga toxineproducing E coli serotype 0157:H7, which causes diarrhea, and more recently E coli 0104:H4 from the German bean sprout outbreak (which had a high mortality). Generally the former has a good prognosis, with observed mortality and ESRD of 5%.4 Atypical HUS is uncommon and accounts for 5%e10% of all HUS cases.5 It is predominantly seen in adults and may be due to a number of triggers. It is further classified into primary and secondary aHUS (Table 3). In case 1, BK nephropathy was a possible trigger, whereas in case 3 urinary tract infections may have acted as the trigger. Case 2,
HEMOLYTIC UREMIC SYNDROME Table 3. Causes of Atypical Hemolytic Uremic Syndrome (aHUS) Primary: Mutations in complement Complement factor H (CFH) regulatory proteins Complement factor B Complement factor I Membrane cofactor protein Complement factor C3 Thrombomodulin Autoantibody Anti-CFH antibody Infections Streptococcus pneumoniae Human immunodeficiency virus H1N1 influenza A Cancer Disseminated malignancy Cancer chemotherapy and ionizing Mitomycin, bleomycin, radiation gemcitabine, cisplatin Bone marrow transplantation Drugs Calcineurin inhibitors Mammalian target of rapamycin inhibitors Quinine Ticlopedine Pregnancy and HELLP (hemolysis, elevated liver enzymes, low platelet count) Autoimmune disease Systemic lupus erythematosus Antiphospholipid syndrome Scleroderma
we think, was a recurrence of primary disease, but again no triggers were identified. Primary aHUS was initially presumed to be idiopathic; however, recent advances have indicated that 70% of aHUS cases are due to mutations in complement-regulatory proteins and autoantibodies,6e10 which can occur sporadically or familial. These mutations, either singly or in combination, play a central role in uncontrolled complement system activation and endothelial cell injury leading to TMA. Recurrence in renal allograft patients who survived Shiga toxineassociated HUS with ESRD is rare (
