The use of apheresis in immune renal disorders

Abstract: Rapidly progressive glomerulonephritis (RPGN) is often associated with the presence of auto‐antibodies. Included in this group are the glomerulonephritides associated with anti‐GBM antibody (Goodpasture's syndrome), IgA mesangial deposition (the renal component of Henoch‐Schönlein purpura), lupus erythematosus, cryoglobulinemia and the antineutrophil cytoplasmic antibody (ANCA)‐associated pauci‐immune group. In each of these cases, apheresis may provide a therapeutically useful option. Apheresis has also been found useful in certain types of antibody‐mediated transplant rejection and in lowering the levels of preformed cytotoxic antibodies which may preclude transplantation. Finally, there are renal diseases in which the immune component is less clearly involved with pathogenesis but for which apheresis may offer a clear benefit, such as in the renal failure associated with ‘cast nephropathy’ (multiple myeloma) or the recurrence of FSGS (focal segmental glomerulosclerosis) in transplanted kidneys. It is the purpose of this paper to review the evidence supporting the use of apheresis in immune‐related diseases.     

Microscopic polyangiitis in a patient with rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic disorder that primary involves joints, although renal disease has also been associated it is not common that rapidly progressive glomerulonephritis (RPGN) appears. We report the case of a patient with nodular and aggressive RA who had an acut renal failure secondary to ANCA positive RPGN due to a Microscopic polyangiitis who was not responsive to steroids and cyclophosphamide therapy.     

急进性肾炎Ⅲ型与原发性小血管炎

为了解急进性肾炎（ＲＰＧＮ）Ⅲ型患者的病理、临床以及发病机制的特点。对我院肾内科近３年来收治的本病患者的临床病理资料进行了回顾性研究。结果发现：８例ＲＰＧＮⅢ型患者中５例抗中性粒细胞胞浆抗体（ＡＮＣＡ）阳性，主要为核周型。与ＲＰＧＮⅢ型ＡＮＣＡ阴性组患者相比，ＡＮＣＡ阳性组发病年龄较晚，多数患者有发热、关节痛等肾外表现，血清Ｃ反应蛋白阳性、γ球蛋白升高、大多数血沉更快（＞１００ｍｍ／１ｈ）。病理检查可见肾小球局灶节段性纤维素样坏死，多数患者经积极治疗后肾功能明显好转，并脱离透析，预后较好。支持多数ＲＰＧＮⅢ型是以肾脏受累为主要表现的小血管炎的观点。     

Cytapheresis for the Treatment of Myeloperoxidase Antineutrophil Cytoplasmic Antibody‐Associated Vasculitis: Report of Five Cases

Abstract: To minimize the adverse effects of high‐dose administration of steroids and cyclophosphamide in patients with myeloperoxidase (MPO) antineutrophil cytoplasmic antibody (ANCA), granulocytapheresis (GCAP) or leukocytapheresis (LCAP) was performed to reduce inflammation. Four patients with rapidly progressive glomerulonephritis (RPGN) and one patient with pulmonary hemorrhage due to MPO‐ANCA‐associated vasculitis were treated by cytapheresis. The prednisolone (PSL) dose was 0.28 ± 0.15 mg/kg/day (mean ± SD) (range 0.18–0.50 g/kg/day). In the 4 RPGN patients, the peak serum creatinine level was 3.7 ± 1.9 mg/dl (range 1.7 to 5.6 mg/dl). GCAP was performed in 3 RPGN patients and in 1 pulmonary hemorrhage patient. LCAP was performed in 1 RPGN patient. In the 4 RPGN patients, renal function improved after combined therapy with cytapheresis and corticosteroids. In the pulmonary hemorrhage patient, evidence of pulmonary hemorrhage on chest computed tomography scanning diminished after combined therapy with cytapheresis and corticosteroids. Cytapheresis, when combined with a low‐dose or intermediate‐dose PSL regimen, is effective in the treatment of ANCA‐associated vasculitis.     

Apheresis for Renal Disease

Abstract: Many primary renal diseases are associated with either antibody deposition within the glomerulus or an antibody associated autoimmunity, as may be seen with certain vasculitidies. Examples of these diseases include Goodpasture's syndrome, cryoglobulinemia, antineutrophil cytoplasmic antibody positive syndromes, and other forms of rapidly progressive glomerulonephritis. Immunoglobulins also may be nephrotoxic to the tubules such as is the case with myeloma related light chains. Given the rapid removal of immunoglobulins by therapeutic plasma exchange, this modality has been considered an appealing management option in the treatment of these renal diseases. Although not classically considered as autoimmune diseases, thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are related syndromes which often involve the kidneys. Although previously unexplained, it has been long appreciated that therapeutic plasma exchange (PE) can be a useful treatment for these microangiopathic hemolytic anemias, but the most recent insights into their pathogenesis suggest that PE may be beneficial by replacing a missing enzyme or removing pathogenic autoantibodies.     

Rapid-detection GBM-ANCA ELISA. An emergency tool for the early diagnosis of type I and II rapidly progressive glomerulonephritis

Rapidly progressive glomerulonephritides (RPGN) are forms of necrotizing glomerulonephritis associated with anti-glomerular basement membrane (anti-GBM) and anti-neutrophil cytoplasmic antibodies (ANCA) against the antigens proteinase-3 (anti-PR3) and myeloperoxidase (anti-MPO). RPGN have a course of rapid progression to renal failure. We compared the results from the semiquantitative ELISAs for anti-GMB antibodies, PR3-ANCA and MPO-ANCA and the indirect immunofluorescence technique (IIF) against a new rapid assay (30 minutes) for the same antibodies in patients with clinically suspected RPGN. The semiquantitative ELISAs for anti-GBM antibodies and PR3-ANCA and MPO-ANCA have a proven diagnostic significance in patients with RPGN I and III. There were no significant differences between the ANCA-GBM screening test and the results from the semiquantitative ELISAs (p > 0.05). We did not find significant differences between the results for PR3-ANCA and MPO-ANCA from the ANCA-GBM screening test with C-ANCA and P-ANCA IIF values (p > 0.05). We also corroborated that the ANCA-GBM screening test is a diagnostic tool for RPGN I and III as useful as the semiquantitative ELISAs and the IFF technique. The ANCA-GBM ELISA screening test is a tool as useful as the semiquantitative ELISA against anti-GBM antibodies for diagnosis of RPGN I. The comparison of the screening ELISA with the IIF technique and the semiquantitative ELISAs against PR3-ANCA and MPO-ANCA showed similar utility for diagnosis of RPGN III. The advantages of the new screening assay are that three antibodies are tested at the same time, yielding results in only 30 minutes.     

Improvements in treatment strategies for patients with antineutrophil cytoplasmic antibody-associated rapidly progressive glomerulonephritis

The course of rapidly progressive glomerulonephritis (RPGN) caused by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is often life-threatening, especially in the elderly when pulmonary involvement and/or severely impaired renal function are present. Corticosteroids and cyclophosphamide are the first-line treatment, but ironically infection, not vascular events such as hemorrhage, caused by the vasculitis itself, is the most common cause of death of RPGN patients. Several new treatment strategies, such as leukocytapheresis (LCAP) and intravenous immunoglobulin (IVIg), have become available during the past decade and these treatments have made it possible to treat high-risk RPGN patients without inducing serious immunosuppressive states. In the present paper we review recent clinical trials of LCAP and IVIg therapy in patients with pauci-immune/ANCA-associated RPGN, and show improved clinical outcomes after using these new treatment strategies in our institution.     

Therapeutic Plasma Exchange in the Intensive Care Setting

Abstract: The potential to treat life‐threatening conditions with therapeutic plasma exchange (TPE) is limited to a few situations. In severe pulmonary hemorrhage as a complication of several immune disorders (e.g., antiglomerular basement membrane antibody disease, Wegener's granulomatosus, lupus erythematosus), TPE should only be considered after conventional measures (mostly pulses of methylprednisolone) have been applied. Idiopathic familial and nonfamilial thrombotic thrombocytopenic purpura as well as the subset of the hemolytic uremic syndrome not associated with diarrhea are clear indications for TPE using fresh frozen plasma as replacement fluid. Patients with myasthenic crisis will also benefit from TPE and will improve within 1 day. Acute pancreatitis as a complication of the chylomicronemia syndrome has a poor prognosis and should be treated with TPE without any delay. In the case of drug overdose or intoxication, the efficiency of TPE to remove the offending drug is usually overestimated. In this situation, TPE is useful only when the plasma protein binding of the substance is high (>80%) and the volume of distribution is low (<0.2 L/kg body weight). TPE is not without risks and hazards (e.g., vascular access, bleeding, allergy), which should also be considered when discussing this extracorporeal therapy in otherwise refractory clinical conditions.     

Role of plasmapheresis performed in hemodialysis units for the treatment of anti-neutrophilic cytoplasmic antibody-associated systemic vasculitides

Anti‐neutrophilic cytoplasmic antibody (ANCA) positivity is seen in some systemic necrotizing vasculitides. Wegener's granulomatosis and microscopic polyangiitis are among the ANCA‐associated systemic vasculitides (AASV) and mortality is very high when renal failure occurs together with alveolar hemorrhage. The role of plasmapheresis in the treatment of these diseases has been studied retrospectively. Twelve patients with AASV who had plasmapheresis together with immunosuppressive medications have been involved. Primary diseases, immunosuppressive protocols, the number of plasmapheresis sessions, the amount of plasma that has been exchanged, urea and creatinine levels before and after treatment, pulmonary findings, the need for hemodialysis, and the outcome of patients were recorded. The mean age of patients was 52.9 ± 18.2 years. Wegener's granulomatosis was diagnosed in seven (58.3%) and microscopic polyangiitis in five (41.7%) patients. All patients had pulse cyclophosphamide and methylprednisolone followed by maintenance doses and plasmapheresis. Seven patients had hemodialysis at the beginning, and hemodialysis needed to be continued in three patients. Partial and complete remission was seen in 6 (50%) and 3 (25%) patients, respectively, and pulmonary findings regressed in all patients. End‐stage renal disease develops generally in AASV due to rapidly progressive glomerulonephritis causing severe irreversible glomerular damage. The mortality rate rises to 50% in cases of renal failure with diffuse alveolar hemorrhage; therefore, pulse immunosuppressive treatment with plasmapheresis may be life‐saving, as shown in our study.     

Rasch-progrediente Glomerulonephritis

Rapid progressive glomerulonephritis (RPGN) is defined as a clinical syndrome based on the change of renal function over time. Early recognition and immediate immunosuppressive intervention improve renal and general outcomes. Kidney biopsy and autoantibody serology are necessary to determine the precise diagnosis of the disease leading to RPGN. The classification of RPGN is based on immunohistology, anti-neutrophil cytoplasmic antibodies (ANCA) and anti-glomerular basement membrane antibodies (anti-GBM). Results of randomised controlled trials are put into the perspective of adapting therapy to clinical findings.     

MPO-ANCA associated crescentic glomerulonephritis with numerous immune complexes: case report

ABSTRACT: BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis (CGN) is a major cause of rapidly progressive glomerulonephritis (RPGN). ANCAassociated CGN is generally classified into pauci-immune RPGN, in which there are few or no immune complexes. Case Presentation A 78-year-old man presented with RPGN after a 7-year course of chronic proteinuria and hematuria with stable renal function. A blood examination showed a high titer of myeloperoxidase (MPO)-ANCA. A renal biopsy showed crescentic glomerulonephritis with abundant subepithelial, intramenbranous and subendothelial deposits by electron microscopy, leading to the diagnosis of ANCA-associated CGN superimposed on type 3 membranoproliferative glomerulonephritis (MPGN). CONCLUSIONS: This case is unique in that type 3 MPGN and MPO-ANCA-associated CGN coexisted, and no similar case has been reported to date. Because ANCA-associated CGN has a predilection for elderly individuals and primary type 3 MPGN is rarely seen in this age group, coincidental existence appears less likely. This case may confer valuable information regarding the link between immune complex and ANCA-associated CGN.     

Maladie de Wegener à c-ANCA de type anti-MPO révélée par une uvéite

Wegener's granulomatosis (WG) is a rare systemic necrotizing granulomatous vasculitis affecting small- to medium-sized vessels, associated with antineutrophil cytoplasm antibodies (ANCA), mainly anti-proteinase 3. Rarely, ANCA may be directed against myeloperoxidase. We report a 58-year-old woman who developed an uveitis as the presenting manifestation of Wegener's granulomatosis who highlight the usefulness of internist and ophthalmologist collaboration.     

Clinicoepidemiological manifestations of RPGN and ANCA-associated vasculitides: an 11-year retrospective hospital-based study in Japan

Antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitides are major causes of rapidly progressive glomerulonephritis (RPGN). Although recent papers suggest differences in clinicoepidemiological manifestations of ANCA-associated vasculitis between Japan [microscopic polyangiitis (MPA) ? Wegener’s granulomatosis (WG)] and Europe (WG ?MPA), little is known about the prevalence and serological pattern. We retrospectively analyzed 27 RPGN patients who were admitted in our hospital over the past 11 years and who could be basically followed for more than 1 year, concerning the incidence of ANCA-related vasculitis, the presence of (MPO)/proteinase 3 (PR3)-ANCA and their clinical outcomes. As there were no PR3-ANCA single positive and/or WG patients, all patients were serologically divided into four groups; Groups I: MPO-ANCA single-positive patients (N = 11), II: MPO-ANCA and PR3-ANCA double-positive patients (N = 3), III: antiglomerular basement membrane antibody (anti-GBM Ab)-positive patients (N = 6), and IV: all negative patients (N = 7). Patients in Groups II/III showed more severe manifestation at admission. However, in Group I, only 36.3% patients avoided death and/or dialysis-dependent end-stage renal disease. Most patients in Group IV were women (85.7%), and 50% of these patients was diagnosed as having rheumatic diseases. Every patient in Groups I?III was treated with oral corticosteroid and/or methylprednisolone pulse therapy. Most patients treated with immunosuppressants showed severe prognosis because of frequent recurrences of vasculitis and infectious episodes after repeated and prolonged treatments with immunosuppressants. Present analysis further confirms the epidemiological and serological differences in ANCA-related RPGN between Japan and Europe, and reinforced the fact that ANCA-associated vasculitis is the most serious causal disease for RPGN.     

Two cases of necrotizing crescentic glomerulonephritis with skin lesions

Two cases of rapidly progressive glomerulonephritis (RPGN) with skin vasculitis-associated anti-neutrophil cytoplasmic antibody (ANCA) are examined. Both cases showed purpura on the lower legs on admission and subsequently revealed renal or pulmonary vasculitis. One case responded positively to oral prednisolone alone, but the other case showed high ANCA titer and renal—pulmonary vasculitis. We discuss the diversity of clinical symptoms and the titer of antibody-associated vasculitis.     

Glomerulonephritis Caused by Bartonella spp. Infective Endocarditis: The Difficulty and Importance of Differentiation from Anti-neutrophil Cytoplasmic Antibody-related Rapidly Progressive Glomerulonephritis

A 65-year-old man with valvular disorder presented to his physician because of widespread purpura in both lower extremities. Blood tests showed elevated serum creatinine levels and proteinase 3-anti-neutrophil cytoplasmic antibody (ANCA) with hematuria, suggesting ANCA-related rapidly progressive glomerulonephritis (RPGN). Although multiple blood cultures were negative, transthoracic echocardiography revealed warts in the valves, and a renal biopsy also showed findings of glomerular infiltration by mononuclear leukocytes and C3 deposition in the glomeruli, suggesting infection-related glomerulonephritis. Later, Bartonella antibody turned positive. Antimicrobial treatment improved the purpura and renal function without any recurrence. ANCA-positive RPGN requires the exclusion of infective endocarditis, especially that induced by Bartonella spp.     

Anti-neutrophil cytoplasmic antibodies (ANCA) in myelodysplasia and other haematological disorders

Background: Anti-neutrophil cytoplasmic antibodies (ANCA) are typically associated with small vessel vasculitides. They are also found in situations where other autoantibodies are common, sometimes after infections and possibly in individuals who have received multiple blood transfusions. Aims: The aim of this study was to determine the incidence of ANCA in a variety of haematological disorders, where these predisposing factors may be at work. Methods: Sera from patients with myelodysplasia (n= 26), acute myeloid leukaemia (AML) (n= 3), and myeloproliferative (n= 25) or lymphoproliferative syndromes (n= 16) were screened for ANCA using a crude neutrophil cytoplasmic extract ELISA and indirect immunofluorescent examination of normal peripheral blood neutrophils. Positive results were confirmed by ELISAs for anti-proteinase 3, anti-myeloperoxidase or anti-elastase antibodies. Results: ANCA were demonstrated in two patients with myelodysplasia, both with chronic myelomonocytic leukaemia and greater than 5% blasts in the bone marrow. Both of these individuals were infected at the time that ANCA were demonstrated and other autoantibodies were present. One of these individuals had never had evidence of any vasculitis; the other probably developed myelodysplasia after treatment with cyclophosphamide for Wegener's granulomatosis. ANCA were demonstrated in one individual with AML secondary to myelodysplasia. ANCA were also found in a patient with lymphoma in whom autoantibodies against red cells and platelets were already noted. ANCA were demonstrated in one further individual with lymphomatoid granulomatosis, a condition that resembles Wegener's granulomatosis clinically and histologically, but which is treated as a lymphoma. No ANCA were present in any of the patients with myeloproliferative syndromes. Discussion: ANCA probably occur secondary to immune dysregulation in myelodysplasia and the lymphoproliferative conditions and they are not necessarily associated with the presence of a vasculitis.     

Risk factors for long-term survival and renal function in 64 patients with rapidly progressive glomerulonephritis (RPGN)

The long-term outcome in rapidly progressive glomerulonephritis (RPGN) is a subject of increasing clinical attention. We performed a retrospective study of 64 patients, who were treated between 1972 and 1990 for biopsy-confirmed RPGN (median observation time 3.3 years). The incidence of RPGN displayed a linear increase with age, and 41 percent of the patients were older than 60 years (26/64). Fifty-one of the 64 patients (80%) were treated with immunosuppressives (steroid pulses, cyclophosphamide, azathioprine, prednisolone, plasma exchange). Of the 13 patients not receiving immunosuppresion, 12 were diagnosed as cases of “idiopathic” RPGN. Anti-neutrophil cytoplasmatic antibodies (ANCA) were tested for in 6 of the 64 patients, of whom 2 with systemic immune disease were cANCA positive. In the Kaplan-Meier analysis, the overall 5-year patient survival rate with the 95 percent confidence interval [95% CI] was 70 percent [47%–93%] and did not differ for immunosuppressed and nonspecifically treated patients. Kaplan-Meier probability of life-sustaining renal function was significantly better in 51 immunosuppressed patients (p=0.03) compared to 13 nonspecifically treated patients, and the efficacy of immunosuppression in patients older than 60 years was comparable to that in younger patients. After 5-years, the proportion of patients with maintained renal function was only 27 percent [0%–57%] in the immunousppressed patients. From the multivariate Cox model, it was evident that immunosuppression had no independent beneficial effect on renal function, whereas the 20 patients with initial oliguria (<500 ml/d) had a significantly increased relative risk of 2.0 of losing renal function [1.1–3.6] compared to those without oliguria. In the Cox model, success of immunosuppression was independent of age, but the relative risk of death was at 5.3 significantly higher in patients over 60 years of age [2.0–13.9] compared to those younger than 60 years. Within the observation period, 24 patients died, 10 due to complications of immunosuppression (4 infections, 6 malignancies). We conclude that intensive immunosuppression should be given to all patients with RPGN irrespective of patient's age, but long-term efficacy is limited, complication rate is high, and initial oliguria is the most significant risk factor for loss of renal function.     

肾脏病抗中性粒细胞胞浆抗体检测的临床意义

本文通过分析２６例抗中性粒细胞胞浆抗体（ＡＮＣＡ）阳性肾脏病例的临床病理特点，探讨了ＡＮＣＡ在肾脏病中的临床意义。结果显示，ＡＮＣＡ阳性不仅可见于结节性多动脉炎（４例）、紫癜性肾炎（８例），还可见于Ⅲ型新月体肾炎（２例）及ＩｇＡ肾病（１２例）．ＡＮＣＡ阳性的肾脏病例具有某些共同的临床病理特征，提示可能具有相同的发病机理。ＡＮＣＡ阳性的ＩｇＡ肾病及Ⅲ型新月体肾炎可能是特殊类型的血管炎。     

Atypical, cytoplasmic and perinuclear anti-neutrophil cytoplasmic antibodies in patients with inflammatory bowel disease

Atypical, cytoplasmic and perinuclear anti-neutrophil cytoplasmic antibodies (x-, c- and pANCA, respectively) are associated with a variety of inflammatory diseases, including inflammatory bowel disease (IBD). Anti-neutrophil cytoplasmic antibodies are more common in patients with ulcerative colitis (UC) than in patients with Crohn's disease (CD). Most publications only refer to p- and cANCA in relation to IBD. We have prospectively evaluated the reactivity of sera from 58 patients with IBD and 10 healthy controls against human neutrophils with emphasis on the distinction of the ANCA types. The sera were incubated with ethanol- and formaldehyde-fixed granulocytes to differentiate between c-, p- and xANCA. The results showed that 10 of 24 patients with UC were positive for ANCA, whereas only one of 34 patients with CD was ANCA positive. These results correspond to a sensitivity of 42%, a specificity of 97%, a negative predictive value of 91% and a positive predictive value of 75% in UC. Of the 11 ANCA-positive sera, two showed a cytoplasmic staining pattern, three showed a perinuclear and six an atypical staining pattern. The disease activity was not correlated to either the ANCA titre or to the presence of ANCA in the serum. In conclusion, ANCA are of limited value in differentiating between UC and CD. Because the majority of ANCA in patients with IBD are xANCA, these ANCA should be explored by not only incubating on ethanol-fixed granulocytes, but also on formaldehyde-fixed granulocytes.     

A RADIOIMMUNOASSAY FOR THE DETECTION OF CIRCULATING ANTI-GLOMERULAR BASEMENT MEMBRANE ANTIBODIES

A fluid phase radioimmunoassay (RIA) has been established for the detection of circulating anti-glomerular basement membrane (GBM) antibodies. Antibodies were detected by binding with a collagenase solubilised, immunochemically purified, radiolabeled extract of human particulate GBM. Sera from 108 patients with a variety of histological types of glomerulonephritis (GN) were assessed for the presence of antibodies. Likely positive sera were those from patients with clinical features of rapidly progressive glomerulonephritis (RPGN) with crescentic or diffusely proliferative GN and linear staining of their GBM's with IgG. Thirty one of 35 sera from such patients were positive in the RIA. Sera from 14 patients with RPGN but with granular IgG deposition (i.e. immune complex related GN) were all negative for anti-GBM antibodies as were sera from 59 patients with a variety of non-crescentic non RPGN without linear IgG. Comparison of the RIA with conventional indirect immunofluorescence (IIF) showed that the RIA had a higher detection rate of antibodies in likely positive sera (19/21 RIA: 16/21 IIF) lower false positive detection rate with sera from patients without GN (0/26 RIA: 2/26 IIF) and was three to four times more sensitive in serial dilution studies.