The pathogenesis and diagnosis of acute kidney injury in multiple myeloma

Renal failure remains a principal cause of morbidity for patients with multiple myeloma. Once reversible factors such as hypercalcemia have been corrected, the most common cause of severe renal failure in these patients is a tubulointerstitial pathology that results from the very high circulating concentrations of monoclonal immunoglobulin free light chains. These endogenous proteins can result in isolated proximal tubule cell cytotoxicity, tubulointerstitial nephritis and cast nephropathy (myeloma kidney). Less frequently, high levels of free light chains can lead to immunoglobulin light chain amyloidosis and light chain deposition disease, although these conditions are usually associated with insidious progression of renal failure rather than acute kidney injury. Unless there is rapid intervention, progressive and irreversible damage occurs, particularly interstitial fibrosis and tubular atrophy. Despite advances in our understanding of the pathogenesis of these processes there has been a gap in translating these achievements into improved patient outcomes. The International Kidney and Monoclonal Gammopathy Research Group was formed to address this need. In this Review, we discuss the mechanisms of disease and diagnostic approaches to patients with acute kidney injury complicating multiple myeloma.     

Lymphoid subsets and prognostic factors in multiple myeloma

In a uniform series of 170 untreated myeloma patients (MM) we investigated the distribution of T cell subsets in peripheral blood (PB) and their relationship with the most relevant disease characteristics, including survival. CD4 cells were significantly decreased both in percentage and absolute numbers (P less than 0.0001). On the other hand, the CD8 cells only showed a slight increase in relative numbers. Upon correlating the abnormalities in the distribution of T cells with other clinical and biological disease characteristics the most remarkable correlation was with survival. A low number of CD4 cells (less than 700 x 10(6)/l) was associated with both an advanced clinical stage and a shorter survival (20 v. 43 months, P = 0.01). Moreover, a significant correlation also exists between the decrease in CD4 cells and both high beta 2-microglobulin (beta 2M) levels and anaemia. On the other hand, no relationship was found with the type of M-component nor with the plasma cell phenotype. Finally multivariate analysis showed that the number of CD4 cells add independent prognostic information to other well-established tests for the assessment of disease outcome in patients with multiple myeloma.     

Ten-year survival and prognostic factors in multiple myeloma

Summary. Among 1119 Japanese patients with symptomatic multiple myeloma diagnosed between 1965 and 1981, 38 (3.4%) survived more than 10 years. Younger age, low tumour mass (absence of severe anaemia, hypercalcaemia, renal failure, and multiple bone lesions), low plasma cell percentage in bone marrow, mature and intermediate myeloma according to Greipp's criteria, and a positive response to subsequent treatment, were related to long-term survival according to univariate analysis. Multivariate logistic regression analysis indicated younger age and low tumour mass as pretreatment characteristics to be related to long-term survival. Prognostic factors proposed applicable to myeloma were also related to 10-year survival.     

Severe acute pancreatitis： Pathogenetic aspects and prognostic factors

Approximately 20% of patients with acute pancreatitis develop a severe disease associated with complications and high risk of mortality. The purpose of this study is to review pathogenesis and prognostic factors of severe acute pancreatitis （SAP）. An extensive medline search was undertaken with focusing on pathogenesis, complications and prognostic evaluation of SAP. Cytokines and other inflammatory markers play a major role in the pathogenesis and course of SAP and can be used as prognostic markers in its early phase. Other markers such as simple prognostic scores have been found to be as e~ective as multifactorial scoring systems （MFSS） at 48 h with the advantage of simplicity, efficacy, low cost, accuracy and early prediction of SAP. Recently, several laboratory markers including hematocrit, blood urea nitrogen （BUN）, creatinine, matrix metalloproteinase-9 （MMP-9） and serum amyloid A （SAA） have been used as early predictors of severity within the first 24 h. The last few years have witnessed a tremendous progress in understanding the pathogenesis and predicting the outcome of SAP. In this review we classified the prognostic markers into predictors of severity, pancreatic necrosis （PN）, infected PN （IPN） and mortality.     

Syndecan-1 in multiple myeloma: relationship to conventional prognostic factors

Syndecan-1 (CD138) mediates myeloma cell adhesion, and loss of syndecan-1 from the cell surface may contribute to myeloma cell proliferation and dissemination and influence the prognosis in patients with multiple myeloma (MM). In order to test this hypothesis, we have evaluated syndecan-1 expression on the surface of malignant plasma cells and soluble forms of syndecan-1 in the serum of 25 newly diagnosed MM patients by flow cytometry and immunosorbent assay. Soluble syndecan-1 levels were significantly higher in MM as compared to controls (P<0.001). Cellular and soluble syndecan-1 was significantly inversely correlated (r=-0.89, P<0.001). The soluble syndecan-1 was significantly higher in non- responders to chemotherapy when compared to responders (P<0.01), and in non- survivors as compared to survivors (P<0.001). In contrast, cellular syndecan-1 expression was significantly lower in non- responders when compared to responders (P<0.01), and in non- survivors as compared to survivors (P<0.05). The levels of soluble syndecan-1 increased from stage I through stage II to stage III, whereas cellular syndecan-1 expression were decreased from high levels in stage III down to a low in stage I, with a statistically significant difference (P<0.01, P<0.05, respectively). There was a significant positive correlation between soluble syndecan-1 and plasma cell count (r=0.079, P<0.001), beta2 microglobulin (r=0.85, P<0.001), serum creatinine (r=0.84, P<0.001), C-reactive protein (r=0.082, P<0.001), alkaline phosphatase (r=0.58, P<0.05) and serum calcium (r=0.77, P<0.01) and a negative correlation with hemoglobin level (r=-0.78, P<0.01), platelets count (r=-0.82, P<0.01) and Albumin level (r=-0.64, P<0.01). Cox regression analysis using soluble syndecan-1 at mean-2SD of the controls could correctly classify patient outcome in 84.0%. The addition of beta2 microglobulin to soluble syndecan-1 increased the predictability of the patients' outcome to 96.7%. We conclude that soluble syndecan-1 levels are negatively correlated to the cellular form and that high levels of soluble syndecan-1 and lower expression of cellular syndecan-1 at diagnosis are negative prognostic factors. Assessment of soluble syndecan-1 and beta2 microglobulin at diagnosis is an independent prognostic system for MM.     

Serum oncostatin M in multiple myeloma: association with prognostic factors

We report on five children with haematological malignancies who underwent allogeneic peripheral blood progenitor cell (PBPC) transplantation. PBPC were harvested from HLA-identical sibling donors after G-CSF (10 μg/kg/d s.c.) mobilization. Aphereses were carried out on day 5 after G-CSF using a Cobe Spectra blood cell separator. All PBPC allografts were cryopreserved before transplantation. The median of CD34⁺ cells and CD3⁺ cells infused were 14.1×10⁶/kg recipient body weight (range 4.92–22.3) and 2.40×10⁸/kg recipient body weight (range 0.54–4.82), respectively. Engraftment occurred in all cases. The median time to a neutrophil count >0.5×10⁹/l and a platelet count >20×10⁹/l were 15 and 14 d, respectively. The incidence of severe acute graft-versus-host disease was 20%. These data suggest that allogeneic PBPC transplantation might be an alternative to bone marrow transplantation in children.     

Autologous bone marrow transplantation in multiple myeloma: identification of prognostic factors

Multiple myeloma remains a universally fatal malignancy with a median survival time not exceeding 3 years. A clinical trial was undertaken to determine feasibility and efficacy of marrow-ablative chemoradiotherapy supported by unpurged autologous bone marrow (ABMT) and to define prognostic variables. Total body irradiation and either melphalan or thiotepa were administered to 55 patients (median age 53 years; range 20 to 66 years). The group of 21 patients with resistance to standard melphalan-prednisone and to continuous infusions of vincristine and Adriamycin with high dose dexamethasone (VAD) included 7 with primary unresponsive disease and 14 with resistant relapse; among the 34 patients achieving remission with the VAD regimen, 14 were in first and 20 in a subsequent remission. Marked cytoreduction by greater than or equal to 75% was observed among all 21 patients with refractory myeloma, whereas further cytoreduction of this magnitude was noted in only 56% of the 34 patients already in remission after VAD. Five of the 6 early deaths among all 55 patients occurred in the 14 patients with resistant relapse, none of whom achieved complete remission and who, as a group, had median durations of relapse-free and overall survival of only 8 and 7 months, respectively. Among the 41 remaining patients, there was only one early death, and 27% achieved complete remission including a 36% incidence among the 14 patients treated in first remission; their projected 4-year survival rate was 82% regardless of their disease status (first or later remission or primary resistance). When information about sensitivity to prior therapy is unavailable, the presence before ABMT of both high beta-2-microglobulin levels (greater than 3 mg/L) and non-IgG isotype helped identify 9 among the 55 patients with a very poor prognosis: all 8 responders relapsed within 9 months, and 8 patients died within 15 months. By contrast, a 4-year projected survival rate of over 70% for the other patients (about 80% of this series) justifies further investigation of this novel treatment approach in comparison with standard dose regimens. Our results indicate that marrow-ablative therapy cannot be recommended for myeloma patients with resistant relapse or those with a combination of risk factors (advanced tumor burden, absence of IgG isotype). The apparent lack of an adverse effect of even marked plasmacytosis in autografts (up to 30%) emphasizes the need for better cytoreduction rather than bone marrow purging.     

Severe acute pancreatitis: prognostic factors in 270 consecutive patients

Acute pancreatitis (AP) is a common abdominal disorder with severity varying from mild to fatal disease. Predicting a patient's outcome remains problematic. The aim of this study was to analyze a large consecutive series of patients with severe AP and to identify prognostic factors for hospital mortality. Between 1989 and 1997, a consecutive series of 270 patients with severe AP were included in the study. All patients fulfilled the criteria of Atlanta classification for severe AP. Retrospectively and prospectively collected data included age, gender, etiology, number of previous episodes of pancreatitis, medication history, type of admission, body-mass index (BMI), respiratory failure, renal failure, need for pressor support, and abdominal surgery performed during hospitalization. The overall mortality rate was 24.4%. In univariate survival analysis advanced age, history of continuous medication, patient transferred from other hospital, high BMI, respiratory or renal failure, need for pressor support, and need for abdominal surgery were significant prognostic factors for hospital mortality. In a multivariate stepwise logistic regression analysis, the need of pressor support, renal failure requiring dialysis, advanced age, history of continuous medication and need for abdominal surgery were identified as independent prognostic factors for mortality. A logistic regression analysis of variables available on admission (the first seven above mentioned variables) showed that transferral admission, advanced age, and history of continuous medication were independent prognostic factors for mortality. In patients with severe AP, advanced age, history of continuous medication, and need for dialysis, mechanical ventilator support, and pressor support predict fatal outcome and thus should be taken into account in clinical evaluation.     

Successful kidney transplantation in a patient with stable multiple myeloma

Renal failure is a common feature of multiple myeloma affecting 20–55% of patients at the initial presentation and is being associated with a significant increase in morbidity and mortality. Renal transplantation for patients with multiple myeloma is rarely considered given the incurable nature of the disease, the risk of post‐transplant disease progression and perceived high risk of infections. Here we report a 57‐year‐old man with end‐stage renal failure attributed to presumed IgA nephropathy, with pre‐existing stable multiple myeloma, who received a kidney transplant from a two haplotype‐matched sibling. Transplantation has been successful and with excellent kidney function and stable multiple myeloma 6 years post‐transplant. This case highlights the potential benefits of renal transplantation in highly selected patients with multiple myeloma.     

Immunoreactive interleukin-6 and acute phase proteins as prognostic factors in multiple myeloma. Finnish Leukemia Group

High serum level of bioactive interleukin-6 (IL-6) is regarded as a predictor of poor prognosis in multiple myeloma (MM). On the other hand, the reported levels of immunoreactive IL-6 have been highly variable, and the prognostic value of immunoreactive IL-6 in MM is not clear. We have analyzed the prognostic significance of serum immunoreactive IL-6, as measured by a sensitive immunosorbent assay, in 210 patients with newly diagnosed MM subsequently treated with intermittent melphalan and prednisone. The serum levels of acute phase proteins C-reactive protein (CRP), alpha 1-antitrypsin (alpha 1AT), and acid alpha 1-glycoprotein (orosomucoid; OM) were evaluated as surrogates for IL-6. Serum IL-6, CRP, alpha 1AT, and OM levels were raised in 42%, 40%, 41%, and 24% of the patients, respectively. There was a significant correlation between the clinical stage of the patients and serum IL-6 (P = .006), alpha 1AT (P = .001), and OM (P = .004) levels at diagnosis. At 3 years, 52% of the patients were alive. Univariate logistic regression analysis showed that high levels of IL-6 (P = .002), CRP (P = .02), alpha 1AT (P < .001), OM (P = .007), beta 2- microglobulin (beta 2M; P < .001), and thymidine kinase (P < .05) were all associated with 3-year mortality. In multivariate regression analysis, beta 2M (P < .0001) and alpha 1AT (P = .01) had independent prognostic significance. The patients with high levels of both beta 2M and alpha 1AT or IL-6 were at very high risk of dying within 3 years from diagnosis (16% and 21% of the patients in these groups were alive, respectively). When the patients were stratified according to the clinical stage, the prognostic significance of serum IL-6 and alpha 1AT was especially evident in stage II patients. When the patients were divided into two groups according to normal or raised serum IL-6 levels, the patients with high IL-6 levels had more frequent osteolytic bone lesions (P = .03) and a more aggressive disease. We conclude that serum immunoreactive IL-6 is a significant prognostic marker in MM.     

Severe metabolic alkalosis and recurrent acute on chronic kidney injury in a patient with Crohn's disease

Background

Diarrhea is common in patients with Crohn's disease and may be accompanied by acid base disorders, most commonly metabolic acidosis due to intestinal loss of bicarbonate.

Case Presentation

Here, we present a case of severe metabolic alkalosis in a young patient suffering from M. Crohn. The patient had undergone multiple resections of the intestine and suffered from chronic kidney disease. He was now referred to our clinic for recurrent acute kidney injury, the nature of which was pre-renal due to profound volume depletion. Renal failure was associated with marked hypochloremic metabolic alkalosis which only responded to high volume repletion and high dose blockade of gastric hypersecretion. Intestinal failure with stomal fluid losses of up to 5.7 litres per day required port implantation to commence parenteral nutrition. Fluid and electrolyte replacement rapidly improved renal function and acid base homeostasis.

Conclusions

This case highlights the important role of gastrointestinal function to maintain acid base status in patients with Crohn's disease.

     

A rare masquerader of lung cancer: nonsecretory multiple myeloma with plasmacytoma of bone presenting as acute kidney injury

Multiple myeloma (MM) is a neoplasm of B cell lineage characterized by excessive proliferation of abnormal plasma cells which produce immunglobulins. If a monoclonal spike is not found in serum or urine but the patient has clinical findings and bone marrow plasma cell infiltration suggestive of MM, then the patient may have a rare subtype known as nonsecretory multiple myeloma (NSMM). Here, we describe a rare case of NSMM with plasmacytoma of bone who presented with severe hypercalcemia, acute kidney injury and a large thoracal mass on chest X-ray masquerading as lung cancer.     

老年人心血管手术后急性肾功能损伤预后评价的临床观察

目的 探讨急性肾功能损伤(acute kidney injury,AKI)分级系统对老年心脏手术后患者预后的预测价值. 方法 收集2006年10月至2007年1月首次行冠状动脉移植术和(或)心脏瓣膜植换术的老年患者资料,记录患者性别、年龄、手术类型、尿量、血牛化指标和临床转归等,按照AKI网络工作组(acute kidney injury network,AKIN)分级及急性生理学和慢性健康状况评价系统(APACHEⅡ)评分在术后对患者进行评分并记录最高分值. 结果 225例患者中男169例(75.1%),女56例(24.9%),平均年龄(66.7±5.0)岁.住院病死率5.8%(13例).根据AKIN分级,最终发生不同程度AKI的患者占55.6%(125例);AKIN分级1级(96例)、2级(11例)、3级(18例)患者的住院病死率分别为2.1%(2例),9.1%(1例)和50.0%(9例).病死率随AKIN分级的递增有升高趋势(P<0.01).受试者工作特征曲线下面积分析AKIN和病死率具有相关性;Logistic回归分析结果显示,随AKIN分级的递增,相对死亡危险性增加. 结论 AKI是老年人心脏手术后的常见并发症之一,可增加术后病死率.AKIN分级系统对此类患者的预后及住院死亡有良好预测价值.     

造影剂引起急性肾损伤及死亡危险因素分析

目的探讨冠状动脉造影(CAG)及经皮冠状动脉介入治疗(PCI)患者造影剂引起急性肾损伤的危险因素及造影剂急性肾损伤及死亡的危险因素。方法回顾性分析2007年1月至2010年12月中国医科大学附属盛京医院253例支架植入患者的临床资料。分别比较造影剂引起的急性肾损伤和非急性肾损伤患者及造影剂引起的急性肾损伤生存与死亡患者的临床特点,分析造影剂引起急性肾损伤和造影剂急性肾损伤死亡的危险因素。结果 Logistic回归分析显示,造影剂引起急性肾损伤的危险因素为高龄(≥60岁)、女性、急性心肌梗死(AMI)、术前肾小球滤过率(eGFR)<60 mL/(min.1.73 m2)、造影剂剂量(≥180 mL)、心力衰竭。COX比例风险模型显示,造影剂急性肾损伤患者死亡的危险因素为高龄(≥60岁)、术前肾小球滤过率<60 mL/(min.1.73 m2)、AMI、心力衰竭、造影剂剂量(≥180 mL)、2型糖尿病、多支血管病变(>2)。结论高龄(≥60岁)、AMI、基础肾功能差、大剂量使用造影剂、心力衰竭既是急性肾损伤的危险因素,也是死亡的危险因素。此外,2型糖尿病、多支血管病变(>2)与急性肾损伤患者死亡密切相关。女性虽然是肾损伤的危险因素,但本身并不增加患者的死亡。     

Prognostic evaluation in multiple myeloma: an analysis of the impact of new prognostic factors

We have analysed the prognostic information for survival of presenting features in an unselected series of 394 myeloma patients. 15 variables with significant prognostic information were identified, among these were some not previously or only recently reported: serum levels of hepatocyte growth factor (HGF), interleukin-6 (IL-6), C-terminal cross-linked telopeptide of collagen I (ICTP) and soluble interleukin-6 receptor (sIL-6R). In a multivariate Cox analysis six variables were significantly and independently associated with poor survival: high age, low W.H.O.-performance status (PS), high serum levels of calcium, beta-2-microglobulin (beta-2M), IL-6 and sIL-6R. A risk score formed to predict survival for each percentile of the patient population allowed an efficient separation of prognostic groups. The discriminating power of the model compared favourably with three other previously published staging systems applied to the study population. Exclusion of IL-6 and sIL-6R from the model only marginally decreased the efficacy of the separation. The predictive value of some variables (sIL-6R, beta-2M and W.H.O.-PS) decreased significantly over time. We conclude that formation of a risk score based on independent variables is an efficient way to separate prognostic groups, that the contribution of new and not easily available parameters should be thoroughly evaluated before inclusion in prognostic models for clinical use and that the predictive value of parameters may decrease over time.     

重型肝炎预后因素分析与护理对策

目的:研究重型肝炎预后的影响因素,从中筛选出对预后有明显影响的因素,并探讨其与预后的相关程度,为护理干预提供依据.方法:将重庆医科大学附属第二医院感染病科2007-01/2010-06所收治201例重型肝炎患者分为治疗有效组和治疗无效组,分别从年龄、性别、临床分型、病原分型、并发症、既往病史、生化指标等方面进行回顾性研究,借助SPSS软件进行Logistic回归分析,确定这些因素与重型肝炎预后的相关程度.结果:年龄、临床分型、肝性脑病、电解质紊乱、原发性腹膜炎、酸碱失衡、肝肾综合征、胃肠道出血、既往肝硬化基础、PTA、总胆红素、尿素氮、肌酐、血钠等指标与预后有明显的关系(均P<0.01).PTA、尿素氮、血钠、肝性脑病为影响预后的独立危险因素,构成预后评分系统,预后评分=10×(1.082×肝性脑病分值+0.944×尿素氮分值+0.915×血钠分值+0.593×PTA分值).结论:PTA、尿素氮、血钠、肝性脑病作为独立的危险因素可用于判断患者的预后,使临床护理更有针对性和目的性.