Ectopic Relapse of Anti-neutrophil Cytoplasmic Antibody-associated Pituitary Vasculitis with No Elevation of Anti-neutrophil Cytoplasmic Antibodies after Renal Remission

The relationship between anti-neutrophil cytoplasmic antibody (ANCA) titer levels and relapse risk in patients with ANCA-associated vasculitis (AAV) following clinical remission remains controversial. We herein report a case showing ectopic relapse of AAV in the pituitary with no ANCA elevation after renal remission. Magnetic resonance imaging revealed an enlarged pituitary gland. A pituitary biopsy showed geographic necrosis with multinucleated giant cells. We diagnosed this case as relapse of AAV in the pituitary. One month after rituximab therapy, the pituitary gland volume had decreased. The intensification of therapy due to the possibility of vasculitis relapse may facilitate better control of AAV.     

Anti-Cardiolipin and Anti-Neutrophil Cytoplasmic Antibodies in Iranian Patients with Behcet's Disease

Background: The prevalence of anti-Neutrophil Cytoplasmic Antibodies (ANCAs) and anti-Cardiolipin Antibodies (anti-CL Ab) in Behcet’s Disease (BD) and also their roles in vascular involvement is controversial. Objective: To assess the prevalence of ANCAs and anti-CL Ab as well as their correlations with clinical manifestations in Iranian patients with BD. Methods: In this case/control study, the sera from 88 patients with BD and 88 healthy controls were evaluated. The levels of ANCAs and anti-CL Ab were measured using indirect ELISA method. Results: The levels of anti-CL, anti-PR3 and anti-MPO (Myeloperoxidase) IgG autoantibodies between BD patients and healthy controls were not statistically different (p=0.21, p=0.28 and p=0.74, respectively). In addition, there were no significant deferences between BD patients with and without vascular involvement in the levels of anti-CL (1.42 ± 1.24 GPLU/ml and 1.58 ± 1.18 GPLU/ml, respectively; p=0.71), anti-PR3 (0.0 ± 0.0 U/ml and 0.08 ± 0.27 U/ml, respectively; p=0.10) and anti MPO (0.48 ± 0.23 U/ml and 0.52 ± 0.22 U/ml, respectively; p=0.41) IgG autoantibodies. Nevertheless, mean titer of anti-CL IgG was higher in male patients with skin rash than those without skin rash (2.2 ± 0.88 GPLU/ml and 1.11 ± 1.22 GPLU/ml, respectively; p=0.017). Conclusion: While anti-CL, anti- PR3 and anti-MPO IgG autoantibodies do not play a major role in susceptibility to BD or pathogenesis of vascular involvement in our patients, anti-CL Ab might be involved in skin lesion development in Iranian male BD patients. However, the results should be confirmed in other studies.     

The New Histopathologic Classification of ANCA-Associated GN and Its Association with Renal Outcomes in Childhood

Background and objectives

A proposed histopathologic classification for ANCA-associated GN is predictive of long-term renal outcome in adult populations. This study sought to validate this system in a pediatric cohort.

Design, setting, participants, & measurements

This was a retrospective, single-center, cohort study of 40 children diagnosed and followed until their transition to adult care at one institution between 1987 and 2012. Renal biopsy specimens were reviewed by a pathologist blinded to patient outcome and were classified using the new histopathologic classification system of focal, crescentic, mixed, and sclerotic groups. Time to the composite outcome of CKD stages 3 and 4 (determined by eGFR with repeated creatinine measures using the Schwartz equation) or ESRD (defined as dialysis dependence or transplantation) were ascertained.

Results

The study population consisted of 40 children (70% female), followed for a median of 2.4 years. The biopsy specimens were categorized as focal in 13 patients (32.5%), crescentic in 20 (50%), mixed in two (5%), and sclerotic in five (12.5%). Mixed and crescentic were combined for analyses. Survival analysis of time to the composite renal endpoint of at least 3 months of eGFR<60 ml/min per 1.73 m² or ESRD differed significantly among the three biopsy groups log-rank P<0.001), with an adjusted hazard ratio of 3.14 (95% confidence interval, 0.68 to 14.4) in the crescentic/mixed group and 23.6 (95% confidence interval, 3.9 to 144.2) in the sclerotic category compared with the focal category. The probability of having an eGFR>60 ml/min per 1.73 m² at 2 years was 100% for the focal, 56.5% for the crescentic/mixed, and 0% for the sclerotic biopsy categories.

Conclusions

This study showed the clinical utility of this histopathologic classification system and its ability to discriminate renal outcomes among children with ANCA GN.     

Predictors of Treatment Outcomes in ANCA-Associated Vasculitis with Severe Kidney Failure

Background and objectives

In ANCA-associated GN, severe renal dysfunction portends a poor prognosis for renal recovery and patient survival. This study evaluated the prognostic factors affecting renal and patient outcomes in patients presenting with severe kidney failure to guide immunosuppressive therapy.

Design, setting, participants, & measurements

This study retrospectively evaluated clinical and histopathologic characteristics of 155 patients who underwent biopsy between October 1985 and February 2011 (median eGFR at presentation, 7.1 ml/min per 1.73 m²; 87% required hemodialysis), all treated with immunosuppressive medications. Three outcomes of interest were measured: patient survival, renal survival, and treatment response (defined as dialysis-free survival without active vasculitis by 4 months after biopsy). Competing risk, Cox, and logistic regression analyses were conducted for each outcome measure.

Results

Within 4 months after biopsy, treatment response was attained in 51% of patients, 35% remained on dialysis, and 14% died. In a competing risk analysis, estimated cumulative incidence rates of ESRD and disease-related mortality were 26% and 17% at 1 year and 32% and 28% at 5 years, respectively. Cyclophosphamide therapy and treatment response by 4 months were independently associated with patient and renal survival, adjusting for the percentage of normal glomeruli, histopathologic chronicity index score, and baseline clinical characteristics. Only 5% of patients still dialysis dependent at 4 months subsequently recovered renal function. Low chronicity index score (odds ratio [OR], 1.16; 95% confidence interval [95% CI], 1.04 to 1.30, per unit decrease) and baseline eGFR>10 ml/min per 1.73 m² (OR, 2.77; 95% CI, 1.09 to 7.01) were significantly associated with treatment response by 4 months. Among cyclophosphamide-treated patients, the likelihood of treatment response was >14% even with highest chronicity index score and eGFR<10 ml/min per 1.73 m².

Conclusions

Although low baseline renal function and severe renal scarring are associated with lower treatment response rate, no “futility” threshold could be identified. Conversely, continued immunosuppressive therapy beyond 4 months is unlikely to benefit patients who remain dialysis dependent.     

Incidence,Risk Factors for and Outcomes of Transplant-Associated Thrombotic Microangiopathy

Transplant-associated thrombotic microangiopathy (TA-TMA) is a complication of allogeneic transplantation (allo-HCT). The incidence and risk factors associated with TA-TMA are not well known. A retrospective analysis from the Center for International Blood and Marrow Transplant Research (CIBMTR) was conducted including patients receiving allo-HCT between 2008 and 2016, with the primary objective of evaluating the incidence of TA-TMA. Secondary objectives included identification of risk factors associated with TA-TMA, and the impact of TA-TMA on overall survival and the need for renal replacement therapy (RRT). Among 23,665 allo-HCT recipients, the 3-year cumulative incidence of TA-TMA was 3%. Variables independently-associated with increased incidence of TA-TMA included female sex, prior autologous transplant, primary disease (acute lymphoblastic leukaemia and severe aplastic anaemia), donor type (mismatched or unrelated donor), conditioning intensity (myeloablative), GVHD prophylaxis (sirolimus + calcineurin inhibitor), pre-transplant kidney dysfunction and acute GVHD (time-varying effect). TA-TMA was associated with higher mortality (HR = 3·1, 95% Confidence Interval [CI] = 2·8–16·3) and RRT requirement (HR = 7·1, 95% CI = 5·7–311·6). This study provides epidemiologic data on TA-TMA and its impact on transplant outcomes. Increased awareness of the risk factors will enable providers to be vigilant of this uncommon but serious transplant complication. The results will also provide benchmarking for future study designs and comparisons.     

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.     

Overlap of Thrombotic Microangiopathy and Mesangial Proliferative Glomerulonephritis Caused by Combination Therapy with Atezolizumab and Bevacizumab

Vascular endothelial growth factor inhibitors and checkpoint inhibitors are effective treatments for solid tumors. These new classes of anti-cancer agents frequently cause kidney-related side effects. Although their anti-cancer effects may be enhanced when used in combination, the severity of their kidney-related side effects is unknown. We herein report the first case of thrombotic microangiopathy and mesangial proliferative glomerulonephritis caused by combined treatment with atezolizumab and bevacizumab in a 74-year-old man with hepatocellular carcinoma. The combination therapy was discontinued and replaced with intravenous methylprednisolone followed by oral prednisolone. Subsequently, the urinary protein excretion levels declined.     

Renal Thrombotic Microangiopathy after Hematopoietic Cell Transplant: Role of GVHD in Pathogenesis

Background and objectives: Thrombotic microangiopathy (TMA) is a known complication of hematopoietic cell transplantation (HCT). The etiology and diagnosis of TMA in this patient population is often difficult because thrombocytopenia, microangiopathic hemolytic anemia, and kidney injury occur frequently in HCT recipients, and are the result of a variety of insults.Design, setting, participants & measurements: The authors reviewed renal pathology and clinical data from HCT patients to determine the prevalence of TMA and to identify correlative factors for developing TMA in the kidney. Kidney tissue was evaluated from 314 consecutive autopsies on patients who died after their first HCT (received between 1992 and 1999). Renal pathology was classified into three groups: (1) no renal thrombus (65%), (2) TMA (20%), and (3) isolated thrombosis (15%). Logistic regression models estimated the associations between each histologic category and clinical parameters: donor and recipient gender, patient age, human leukocyte antigen (HLA) matching of the donor and recipient, total body irradiation (TBI), acute graft versus host disease (GVHD), acute kidney injury, medications, and viral infections.Results: In a multivariate analysis, TMA correlated with acute GVHD grades II to IV, followed by female recipient/male donor, TBI > 1200 cGy, and adenovirus infection. Grades II to IV acute GVHD and female gender were associated with isolated renal thrombus.Conclusions: TMA in HCT recipients is associated with acute GVHD grades II to IV, recipient/donor mismatch, TBI > 1200 cGy, and adenovirus infection.Thrombotic microangiopathy (TMA) encompasses a spectrum of clinical diseases characterized by systemic or intrarenal platelet aggregation, thrombocytopenia, and microvascular fragmentation of erythrocytes, resulting in ischemic organ injury. Endothelial damage is thought to represent the inciting factor in TMA syndromes (1). Once the endothelium is damaged, loss of endothelial resistance to thrombus formation, leukocyte adhesion, and increased vascular sheer stress ensues and may augment and perpetuate the injury (2). Although abnormalities in von Willebrand factor and complement pathways have also been associated with inherited and recurrent forms of TMA (2), they have not been found in patients who developed TMA after hematopoietic cell transplant (HCT) (3).The incidence of TMA syndromes in the setting of HCT ranges between 2% and 21% (4–6). Renal biopsy specimens are difficult to obtain immediately after HCT, and therefore much of the literature on TMA has relied on clinical and laboratory features alone. However, it is difficult to establish the diagnosis of TMA in HCT patients by clinical and laboratory features alone because anemia, thrombocytopenia, and elevations in lactate dehydrogenase (LDH) and creatinine occur frequently because of delayed engraftment, infections, medications, or graft versus host disease (GVHD). Clinical manifestations of TMA range from a fulminant presentation associated with severe acute renal failure and death to a more common, indolent course resulting in the eventual development of chronic kidney disease. In many cases, elevations in serum creatinine may not occur until late in the disease process despite endothelial injury in the kidney, and therefore the diagnosis may be delayed or missed. We hypothesize that renal endothelial injury, consistent with TMA, exists in the absence of a clinical diagnosis of TMA and that this early injury may set the stage for progression to chronic kidney disease. In this study, we examined the renal pathology and clinical data from HCT patients to more accurately identify the prevalence of and risk factors for the development of TMA in the kidney.     

Infection in Patients with Suspected Thrombotic Microangiopathy Based on Clinical Presentation

Open in a separate window     

Renal involvement in ANCA associated vasculitis

Kidney is involved in upto 75–80% of various ANCA associated vasculitis (AAV) and remains the major cause of mortality and morbidity. The classic clinical presentation is that of rapidly progressive renal failure with cresenteric glomerulonephritis being its pathologic correlate. ANCA positivity has been implicated in the pathogenesis and is useful for diagnosis.The treatment of renal AAV involves the use of steroids in combination with other immunosuppressive agents like cyclophosphamide to induce remission followed by maintenance therapy with a less potent agent like azathioprine. Plasmapharesis has a definite role especially in presence of renal failure while Rituximab is emerging as a promising alternative for remission induction.     

霉酚酸酯与环磷酰胺治疗ANCA相关血管炎的临床对照研究

目的:对照比较霉酚酸酯(MMF)与间断环磷酰胺(CTX)静脉冲击疗法治疗抗中性粒细胞胞浆抗体(ANCA)相关性血管炎(AAV)的疗效、副作用和复发率。方法:35例活动性AAV患者(MPOANCA28例,PR3ANCA阳性2例),男性15例,女性20例,年龄18～71(平均49.1±12.2)岁,均有肾脏损害,SCr≤500μmol/L,肾活检为寡免疫复合物性节段坏死性肾炎伴新月体形成。35例患者分两组,其中激素联合MMF组18例(MMF组),CTX组17例(CTX组)。两组患者基础病情无差异,均以甲基强的松龙静脉冲击后口服MMF(1.5～2g/d)或间断CTX(0.75～1.0g/m2·BSA,每月1次×6次)静脉冲击治疗。缓解后采用雷公藤多甙维持治疗。血管炎活动性采用BVAS评分,慢性损伤采用VDI评分。比较两组缓解率、肾功能变化、副作用发生率及复发率。结果:①MMF组治疗时间6～24月,2例治疗6个月后失访,其余随访12～60(平均29.7±16.8)月,CTX组4例失访,其余随访12～63(平均28.5±14.6)月。②MMF组总缓解率高于CTX(94.4%vs76.9%),其中3、6、12个月缓解率分别为50%vs15.4%(P<0.05),77.8%vs61.5%和100%vs81.8%(P>0.05)。③肾功能:随访末两组各有2例进入终末期肾功能衰竭,MMF组肾功能恢复正常比例高于CTX组(44.4%vs15.4%)。12个月后MMF组VDI评分显著低于CTX组(P<0.05)。④血清ANCA变化:治疗12个月内,MMF组12例ANCA阳性的患者5例(41.7%)转阴,6例(50%)滴度下降,1例无变化。CTX组5例ANCA阳性者1例ANCA转阴(20%),2例(40%)滴度下降,2例无变化。⑤复发:MMF组2例(11.8%)复发,CTX组3例(30%)复发。⑥死亡和副作用:MMF组并发肺炎和带状疱疹各1例,其中1例死亡,2例消化道症状明显;CTX组肺炎和白细胞减少各1例,4例明显消化道症状,1例疾病复发后死于尿毒症。结论:与传统CTX疗法比较,MMF治疗AAV有更高的诱导缓解和改善肾功能的作用,复发率低。MMF抑制血清ANCA的作用强于CTX。但尚需多中心、大样本和长期随访的临床试验以评价MMF治疗AAV的疗效。     

Thrombotic Microangiopathy,Podocytopathy, and Damage to the Renal Tubules with Severe Proteinuria and Acute Renal Dysfunction Induced by Lenvatinib

Lenvatinib, a tyrosine kinase inhibitor (TKI), is a stronger inhibitor of vascular endothelial growth factor receptor, fibroblast growth factor receptors 1 to 4, and platelet-derived growth factor receptor (PDGFR) than other TKIs. We herein report a 77-year-old Japanese woman who received the minimum dose of lenvatinib for treatment of hepatocellular carcinoma. Within one month of starting treatment, she developed severe proteinuria, hypertension, and renal dysfunction. A kidney biopsy showed drug-induced thrombotic microangiopathy, podocytopathy, and polar vasculosis. We also observed damage to the renal tubules, where PDGFR is located. To our knowledge, this is the first report of lenvatinib-induced damage to the renal tubules.     

M2 Macrophage Infiltrates in the Early Stages of ANCA-Associated Pauci-Immune Necrotizing GN

Background and objectives

This study examined kidney biopsies with focal segmental glomerular fibrinoid necrosis to identify early features of pauci-immune necrotizing GN and the primary effector cells mediating initial capillary injury.

Design, setting, participants, & measurements

Seventeen consecutive kidney biopsies with focal pauci-immune necrotizing GN, obtained over a 6-year period (2007–2012), were studied. Neutrophils and CD68⁺, CD163⁺, CD3⁺, CD56⁺, and CD20⁺ cells were scored in paraffin sections counterstained with periodic acid–Schiff. Electron microscopy was performed in 15 of 17 biopsies and additional examples of pauci-immune necrotizing GN (n=25). Biopsies with thin basement membrane nephropathy (n=5) served as immunohistologic normal controls.

Results

Biopsies with pauci-immune necrotizing GN had a mean of 10 (range=3–25) normal-appearing glomeruli, a mean of 2 (range=1–5) glomeruli with segmental fibrinoid necrosis, and a mean of 2 (range=1–11) glomeruli with cellular crescents. CD68⁺ and CD163⁺ macrophages predominated at sites of fibrinoid necrosis in pauci-immune necrotizing GN, exceeding the quantity of neutrophils and T cells (mean scores [SD]=2.5 [0.7] and 2.2 [0.75] versus 0.6 [0.5] and 0.1 [0.3], respectively; P<0.001). B and natural killer cells were rare. Normal-appearing glomeruli in pauci-immune necrotizing GN had significantly more CD68⁺ and CD163⁺ macrophages than the controls (CD68⁺, 0.9 [0.3] versus 0.4 [0.3]; CD163⁺, 1 [0.4] versus 0.4 [0.3]; P<0.001). The quantity of other glomerular infiltrates did not differ from controls. The serum creatinine level at biopsy correlated with the glomerular CD68 and neutrophil scores (r=0.74 and r=0.71, respectively; P=0.001) but did not correlate with the extent of fibrinoid necrosis (r=0.36). Macrophages were localized at minute perforations and attenuations of the capillary basement membrane by electron microscopy.

Conclusions

Early pauci-immune necrotizing GN is characterized by a selective localization of CD163⁺ M2 macrophages at sites of glomerular fibrinoid necrosis and in normal-appearing glomeruli. These observations indicate that alternatively activated macrophages are positioned as potential effectors of glomerular injury in the early stages of pauci-immune necrotizing GN and may be potential targets for therapeutic intervention.     

Glomerulonephritis Associated with Infective Endocarditis Showing Serological Positivity for PR3-anti-neutrophil Cytoplasmic Antibody and Anti-glomerular Basement Membrane Antibody

We herein report a case of crescentic glomerulonephritis (GN) associated with infective endocarditis (IE). A 61-year-old-woman presented with a fever and renal dysfunction and was diagnosed with IE. The patient was positive for proteinase 3-anti-neutrophil cytoplasmic antibody (PR3-ANCA) and anti-glomerular basement membrane (GBM) antibodies. Renal biopsy findings showed crescentic GN with isolated deposition of C3c, a serum conversion product of complement C3. Given these clinical findings, the patient was diagnosed with infective endocardis (IE)-associated GN. Antibiotic therapy was continued without immunosuppressive agents. After the initiation of the antibiotics, the fever resolved, and the renal function gradually recovered. This case highlights the notion that laboratory findings should be carefully evaluated with reference to other findings.     

Management and Outcomes of Renal Disease and Acute Myocardial Infarction

Background

Contemporary trends in the management and outcomes of chronic kidney disease patients who develop an acute myocardial infarction have not been adequately described, particularly from the more generalizable perspective of a population-based investigation.

Methods

The study population consisted of 6219 residents of the Worcester, Massachusetts, metropolitan area who were hospitalized with acute myocardial infarction in 6 annual periods between 1995 and 2005. Patients were categorized as having preserved kidney function (n = 3154), mild to moderate chronic kidney disease (n = 2313), or severe chronic kidney disease (n = 752) at the time of hospital admission.

Results

Patients with chronic kidney disease were more likely to be older, to have a greater prevalence of comorbidities, and to experience significant in-hospital complications or die during hospitalization in comparison with patients with preserved kidney function. Although patients with chronic kidney disease were less likely to receive effective cardiac medications or undergo coronary interventional procedures than patients without kidney disease, we observed a marked increase in the use of effective cardiac medications and coronary interventional procedures in patients with chronic kidney disease during the period under study. In-hospital death rates declined over time among patients with chronic kidney disease, whereas these death rates remained unchanged among persons with normal kidney function.

Conclusion

The results of this study in residents of a large New England metropolitan area provide insights into changing trends in the treatment and impact of chronic kidney disease in patients hospitalized with acute myocardial infarction.