Clinicopathological Characteristics and Outcome of Chinese Patients with Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome: A 9-Year Retrospective StudyZhang W. · Shi H. · Ren H. · Shen P.-Y. · Pan X.-X. · Li X. · Chen Y.-X. · Xu Y.-W. · Chen X.-N. · Zhu P. · Chen N.
Department of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China Corresponding Author
Background: The pathogenesis of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is unclear and the prognosis is poor. Few studies have been published focusing on Chinese patients with TTP-HUS. We performed a retrospective study on the clinical characteristics and outcome of Chinese patients with TTP-HUS. Method: Patients with TTP-HUS, admitted to our hospital from 1998 to 2006, were retrospectively analyzed. Results: There were 26 females and 6 males in our study. Fifteen patients had systemic lupus erythematosus (SLE)-associated TTP-HUS; 2 had pregnancy-associated TTP-HUS; 1 had antiphospholipid syndrome-associated TTP-HUS; 2 had drug-associated TTP-HUS; 4 had malignant angionephrosclerosis- associated TTP-HUS; 3 had vasculitis-associated TTP-HUS, and the remaining 5 had idiopathic TTP-HUS. Twenty-six patients had acute kidney injury and 21 had nephrotic syndrome. Hypertension was found in 31 patients. For the treatment, 15 patients had plasmapheresis, 12 had continuous veno-venous hemodiafiltration and 14 had hemodialysis. Eighteen patients were treated with intravenous immunoglobulin. Corticosteroids were used in patients with idiopathic TTP-HUS. For the patients with SLE-associated TTP-HUS, corticosteroids and immunosuppressant were used. Outcome was poor: 6 patients died; 17 recovered from renal insufficiency; 5 progressed to chronic renal failure, and 4 were dependent on hemodialysis. Conclusions: Most of our patients had secondary TTP-HUS. SLE-associated TTP-HUS is the most common form of TTP-HUS. Early diagnosis and treatment can improve prognosis. An immunosuppressant together with corticosteroids could improve prognosis in some patients.
Copyright © 2009 S. Karger AG, Basel
Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, acute renal failure and central nervous system impairment [1, 2]. Though thrombocytopenia and microangiopathic hemolytic anemia are sufficient to establish a clinical diagnosis, these criteria do not distinguish TTP from HUS. Hence, the comprehensive term TTP-HUS is appropriate to diagnose patients with such symptoms . The incidence of TTP-HUS is less than 5% among all patients with acute renal failure . The pathogenesis of the disease is still unclear and the prognosis is poor. Due to improved strategies of treatment, the survival rate of patients with TTP-HUS has risen significantly. With adequate treatment, the survival rate of patients with TTP-HUS could reach 90–93% and renal survival could reach 50–60% [3,5,6,7,8,9,10].
To date, little is known about the characteristics and outcome of Chinese patients with TTP-HUS, and few studies have been published focusing on those patients. Therefore, we retrospectively analyzed the data of 32 Chinese patients with TTP-HUS in order to further study the characteristics of Chinese patients with the disease.
Patients and Methods
Thirty-two patients with TTP-HUS admitted to the Shanghai Ruijin Hospital between July 1998 and December 2006 were retrospectively analyzed in this study.
The diagnostic criteria of TTP-HUS were based on the following items [3, 11, 12]: (1) microangiopathic hemolytic anemia as indicated by the presence of schizocytosis >2% on peripheral smear, low haptoglobin values, high lactate dehydrogenase (LDH) and blood uric acid values, reticulocytosis, negative Coomb’s test, and high bilirubin values; (2) thrombocytopenia (platelet count <100×109/dl), and (3) renal involvement as indicated by hematuria, proteinuria, nephrotic syndrome, acute kidney injury (AKI), elevated serum creatinine and blood urea nitrogen levels, oliguria or anuria.
Renal pathology: Glomerular microthrombi composed of platelet aggregates and fibrin; endothelial cell swelling; stenosis of capillary lumens; microthrombi in glomerular capillaries or in renal small arteries.
The diagnostic criteria for systemic lupus erythematosus (SLE) were made according to the definitions of the American College of Rheumatology . The diagnostic criteria for antiphospholipid syndrome (APS) were defined by the International Consensus Conference (Sapporo, 1998) and Sydney criteria [14, 15]. The clinical diagnosis of idiopathic TTP-HUS was made when other known causes had been eliminated [16, 17]. The diagnostic criteria for malignant hypertension were: diastolic blood pressure >120 mm Hg with retinal (hemorrhage, papilledema), brain, kidney, or heart damage (left-ventricular heart failure, hypertensive encephalopathy).
All patients were tested for complete blood count, routine biochemical workup, coagulation studies, urine test and LDH. The estimated glomerular filtration rate (GFR) was calculated using the Cockcroft-Gault formula (CG-GFR) = (140 – age) × weight/72 × Scr (×0.85 if female) . AKI was evaluated according to the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group guidelines [19, 20].
Renal biopsy specimens were processed for light microscopy, immunofluorescence (IF) and electron microscopy. The direct IF technique using antibodies against IgA, IgG, IgM, C3, C4, C1q and fibrin was processed for the IF study.
Plasma exchange (PE), continuous veno-venous hemodiafiltration (CVVHDF)/hemodialysis (HD) or intravenous immunoglobulin was used in different forms of TTP-HUS. Adjuvant therapies such as immunosuppressants, steroids or antiplatelet agents were added according to pathogenesis of the disease.
All data were computed using SAS 6.04. Differences in quantitative parameters between groups were performed by t test (for normally distributed data) or non-parametric test (for not normally distributed data). All the measurement data are expressed as mean ± SD. A p value of <0.05 was considered statistically significant.
Thirty-two patients with TTP-HUS were retrospectively analyzed. They represented 3.24% (32/989) of all AKI patients in our hospital during that period. The duration between disease onset and diagnosis was 1–260 days. Twenty-six cases presented with AKI (5 in AKI phase I, 4 in phase II and 17 in phase III), 3 presented with chronic renal failure, and the remaining 3 presented with normal renal function. Five patients had oliguria (urine output <400 ml/24 h) and 4 patients had anuria (urine output <100 ml/24 h) with duration of 6–55 days.
For the pathogenesis of the disease: 15 patients had SLE-associated TTP-HUS; 2 had pregnancy-associated TTP-HUS; 1 had APS-associated TTP-HUS; 2 had drug-associated TTP-HUS (ticlopidine and mitomycin associated); 4 had malignant angionephrosclerosis-associated TTP-HUS; 3 had vasculitis-associated TTP-HUS (2 with MPA and 1 with allergic purpura), and the remaining 5 patients had idiopathic TTP-HUS.
In our study, only 1 patient had diarrhea at onset of disease; she was negative for Shiga toxin-producing Escherichia coli. No patient in our study presented with central nervous system involvement at diagnosis. Details of the clinical and laboratory presentation were summarized in table 1.
|Table 1. Characteristics of the patients with TTP-HUS at diagnosis|
Twenty-five (78.1%) patients had renal biopsy. In 12 patients, capillary wall thickening, endothelial cell swelling and stenosis of the capillary lumens were the major pathological lesions. Schistocytes, platelets and fibrin thrombi could also be found in the glomerular capillaries. Some patients had mesangiolysis, interstitial edema and inflammatory cell infiltration. In 10 patients, chronic lesions such as glomerular basement membrane thickening and atrophy or sclerosis of glomerular tufts were found. One patient had renal infarction and 2 presented with acute tubular necrosis. Of the 15 patients with lupus nephritis, 14 cases had type IV and 1 had type III+V. Endothelial cell swelling, schistocytes or thrombi in the capillary lumens could be found by electron microscopy.
PE was performed in patients with severe TTP-HUS (hematocrit <20%, platelets <100 × 109/ml, LDH >6,001 IU/l, Scr >442 μmol/l). Fifteen patients were treated with plasmapheresis (double filtration plasmapheresis in 13 cases and single plasmapheresis in 2 cases) 3–6 times every other day (blood flow 100–150 ml/min; 30–50 mg heparin at start of plasmapheresis followed by continuous infusion of 8–10 mg/h). Among those patients, 12 underwent CVVHDF, 14 had HD (9 had CVVHDF in the acute phase and HD afterwards), 9 had PE in combination with CVVHDF and/or HD. Eighteen cases were treated with intravenous immunoglobulin (400 mg/day); among those patients, 12 were also treated with PE. Platelet transfusion was not used. Eight patients were administered transfusion of washed red blood cells due to severe anemia. No antiplatelet agents were used in these patients except for those with APS. In patients with autoimmune disease-associated TTP-HUS (SLE-associated TTP-HUS, vasculitis-associated TTP-HUS and APS-associated TTP-HUS), corticosteroids (1 mg/kg/day) together with immunosuppressants (cyclophosphamide, mycophenolate mofetil or vincristine) were administered. Corticosteroids (10–40 mg/day) and vincristine (1–2 mg/day, 4 times total) were used in patients with idiopathic TTP-HUS. In patients with APS, low molecular weight heparins and aspirin were added. Details of treatment are summarized in table 2.
|Table 2. Outcome of patients with TTP-HUS|
The follow-up of 32 TTP-HUS patients was 46.0 ± 32.8 (range 3–112) months. Six died during follow-up: 4 had TTP-HUS secondary to severely active SLE, 1 had idiopathic TTP-HUS and 1 had mitomycin-associated TTP-HUS. The duration between disease onset and diagnosis of those 6 patients was more than 1 month. Two patients died of Gram-negative sepsis, 1 died of fungal pneumonia, and 3 refused further treatment and died due to complications of end-stage renal disease.
Seventeen patients recovered from renal insufficiency. Five patients progressed to chronic renal failure independent of dialysis, and 4 ultimately depended on HD.
The survival rate in patients with SLE-associated TTP-HUS and other forms of TTP-HUS was 73.3 and 88.2%, respectively. Renal survival in patients with SLE-associated TTP-HUS and other forms of TTP-HUS was 60.0 and 47.1%, respectively. There was no significant difference with regard to survival rate and renal survival in those patients (p > 0.05).
The purpose of our study is to analyze the clinical characteristics and outcome of Chinese patients with TTP-HUS. For this purpose, we first reviewed the literature, and compared the etiology between our patients and Caucasian patients (table 3).
|Table 3. Comparison of etiology of patients with TTP-HUS|
The current study showed that nearly half of our patients (15/32, 46.9%) had SLE-associated TTP-HUS. It was the most common form of the disease among our patients. Idiopathic TTP-HUS accounted for 15.6% (5/32) only. However, in the studies published elsewhere, idiopathic TTP-HUS was one of the most common forms of the disease which accounted for 27–40% of the patients [4, 6, 21]. Atypical HUS affected about 5–10% of all patients with TTP-HUS according to literature [22,23,24]; however, no patient was diagnosed as typical TTP-HUS in our study. The etiological differences of the disease might be related to racial differences between the Asian population and Caucasians.
We did not detect ADAMTS13 in our study, as this detection method is not available in our region, thus some of our patients with idiopathic TTP-HUS could have had an associated genetic defect of the complement system. Usually, a severe ADAMTS13 deficiency could be specific for TTP [3, 25] and patients described as having HUS did not have or rarely had an associated ADAMTS13 deficiency [26,27,28]. However, recent studies demonstrated that HUS patients with acute renal failure could also have an ADAMTS13 deficiency [3, 29]. Therefore, it was proposed that an ADAMTS13 deficiency might not be detected in all patients who are appropriately diagnosed as TTP-HUS, and it could serve as prognostic factor of the disease .
Two of our patients had pregnancy-associated TTP-HUS. During pregnancy, preeclampsia, placental abruption and increased production of blood coagulation factors could injure the endothelial cells and thus cause dysfunction of the coagulation system, which may finally lead to local diffuse intravascular clotting, glomerular microthrombi and subendothelial fibrin deposition [30, 31]. Most pregnancy-associated TTP-HUS occurs in the last trimester and at about the time of delivery . In our study, a young female patient had AKI, loin pain, gross hematuria, pulmonary embolism and congestive heart failure after delivery. The laboratory tests showed anticardiolipin antibody-IgG (+) and anti-β2-GPI antibody (+), an increased level of reticulocytes, serum LDH, schistocytosis, and a decreased level of platelets and haptoglobin. She was diagnosed as having APS-associated TTP-HUS. It was reported that 61% of TTP-HUS patients have APS , which implies the importance of screening for APS in TTP-HUS patients.
AKI is the major manifestation of renal involvement in TTP-HUS patients. Gross or microscopic hematuria and proteinuria may also be present in TTP-HUS patients with renal involvement. Some patients could present with nephrotic syndrome, hypertension, oliguria or anuria and renal insufficiency. It was reported that 80% of patients depend on HD during the acute phase . In our study, 81.3% (26/32) of the patients had AKI at the onset of disease. Nephrotic syndrome and hypertension were found in 65.6 and 96.8% of our patients, respectively. All the patients had microscopic hematuria; most of them had gross hematuria and fever at presentation.
Treatment of TTP-HUS should be administered according to the pathogenesis of the disease. PE is the gold standard therapy for idiopathic TTP-HUS which may be live-saving in genetic forms. It is also useful in treating several forms of TTP-HUS [3, 7, 10, 16,33,34,35]. In our study, after PE therapy, the level of hemoglobin, platelets, reticulocyte count and haptoglobin improved in 15 patients with severe TTP-HUS. However, renal function did not improve after PE. Six patients died during PE and CVVHDF/HD therapy. Their deaths might be attributed to the severe organ involvement and delayed treatment. It was reported that PE in combination with fresh frozen plasma (FFP) transfusion was useful in the treatment of patients with TTP-HUS [4, 5, 8]. Since FFP transfusion can supply the activating factor of ADAMST13, while PE alone can remove inhibitory factors, further study is needed to investigate the beneficial effects of FFP transfusion therapy in the treatment of severe TTP-HUS. In patients with idiopathic TTP-HUS, PE together with vincristine and steroids was reported to be useful for the prevention of relapses and shortening the duration of the idiopathic form [11, 16,35,36,37]. However, the corticosteroid doses in the treatment of TTP-HUS have not yet found consensus [11, 16]. In some studies, long-term and low doses of corticosteroids were recommended while others suggested a high dose of corticosteroids followed by a tapering schedule [4, 5, 8, 35]. As there are few studies on corticosteroids in combination with other treatments, further studies are necessary to evaluate the therapeutic effects of different doses of corticosteroids. As the etiology of TTP-HUS is heterogeneous, adopting a therapeutic strategy according to the patient’s clinical situation is important to improve prognosis. In our own experience, HD or CVVHDF is necessary to improve outcome in patients with water retention, disturbance of electrolytes, oliguria, anuria, hyperkalemia, metabolic acidosis, heart failure or pulmonary edema.
In the literature, patients with TTP-HUS could have vascular lesions and some could progress to end stage renal disease. The prognosis was poor and some depended on dialysis [38,39,40]. In our study, the mortality rate was 18.8%, which was higher than the rates reported in the literature [4, 6, 9, 11, 41]. Considering the severe clinical situation of our patients, the outcome of our patients with TTP-HUS was poorer.
Prognostic factors in TTP-HUS are not well established due to the rarity of the disease. In our study as well as some others, no clinical features at diagnosis were predictive for survival (data not shown) [9, 10, 42]. However, it was reported that advanced age, low hemoglobin level, high leukocyte count, HD, positive HIV serology, and neurological features are prognostic factors of TTP-HUS [4, 6, 11]. Since our study focused on data from Chinese patients with TTP-HUS, further study is needed to analyze the prognostic factors of TTP-HUS in other Asian populations.
In summary, TTP-HUS is a disease with a poor prognosis. SLE-associated TTP-HUS is the most common form of TTP-HUS in Chinese patients. Early recognition and adequate treatment is necessary to improve outcome.
This study was supported by a grant from the Leading Academic Discipline Project of Shanghai Health Bureau (No. 05III001) and a grant from the Shanghai Leading Academic Discipline Project (No. T0201).
Prof. Nan Chen, MD
Department of Nephrology, Shanghai Ruijin Hospital Shanghai Jiaotong University School of Medicine, Shanghai 200025 (PR China)
Tel. +86 21 6437 0045/ext. 665 233, Fax +86 21 6445 6419
Received: July 8, 2008
Accepted: November 24, 2008
Published online: May 13, 2009
Number of Print Pages : 7
Number of Figures : 0, Number of Tables : 3, Number of References : 42
Nephron Clinical Practice
Vol. 112, No. 3, Year 2009 (Cover Date: June 2009)
Journal Editor: El Nahas M. (Sheffield)
ISSN: 1660-2110 (Print), eISSN: 1660-2110 (Online)
For additional information: http://www.karger.com/NEC