Concurrent nephrotic syndrome and acute renal failure caused by chronic lymphocytic leukemia (CLL): a case report and literature review. Dou Xianrui,Hu Haitang,Ju Yongle,Liu Yongdong,Kang Kaifu,Zhou Shufeng,Chen Wenfang Diagnostic pathology Kidney injury associated with lymphocytic leukemia (CLL) is typically caused by direct tumor infiltration which occasionally results in acute renal failure. Glomerular involvement presenting as proteinuria or even nephrotic syndrome is exceptionally rare. Here we report a case of 54-year-old male CLL patient with nephrotic syndrome and renal failure. The lymph node biopsy confirmed that the patients had CLL with remarkable immunoglobulin light chain amyloid deposition. The renal biopsy demonstrated the concurrence of AL amyloidosis and neoplastic infiltration. Combined treatment of fludarabine, cyclophosphamide and rituximab resulted in remission of CLL, as well as the renal disfunction and nephrotic syndrome, without recurrence during a 12-month follow-up. To our knowledge, this is the first case of CLL patient showing the nephrotic syndrome and acute renal failure caused by AL amyloidosis and neoplastic infiltration. Though AL amyloidosis caused by plasma cell dyscrasia usually responses poorly to chemotherapy, this patient exhibited a satisfactory clinical outcome due to successful inhibition of the production of amylodogenic light chains by combined chemotherapy. 10.1186/1746-1596-6-99
    Current multiple myeloma treatment strategies with novel agents: a European perspective. Ludwig Heinz,Beksac Meral,Bladé Joan,Boccadoro Mario,Cavenagh Jamie,Cavo Michele,Dimopoulos Meletios,Drach Johannes,Einsele Hermann,Facon Thierry,Goldschmidt Hartmut,Harousseau Jean-Luc,Hess Urs,Ketterer Nicolas,Kropff Martin,Mendeleeva Larisa,Morgan Gareth,Palumbo Antonio,Plesner Torben,San Miguel Jesús,Shpilberg Ofer,Sondergeld Pia,Sonneveld Pieter,Zweegman Sonja The oncologist The treatment of multiple myeloma (MM) has undergone significant developments in recent years. The availability of the novel agents thalidomide, bortezomib, and lenalidomide has expanded treatment options and has improved the outcome of patients with MM. Following the introduction of these agents in the relapsed/refractory setting, they are also undergoing investigation in the initial treatment of MM. A number of phase III trials have demonstrated the efficacy of novel agent combinations in the transplant and nontransplant settings, and based on these results standard induction regimens are being challenged and replaced. In the transplant setting, a number of newer induction regimens are now available that have been shown to be superior to the vincristine, doxorubicin, and dexamethasone regimen. Similarly, in the front-line treatment of patients not eligible for transplantation, regimens incorporating novel agents have been found to be superior to the traditional melphalan plus prednisone regimen. Importantly, some of the novel agents appear to be active in patients with high-risk disease, such as adverse cytogenetic features, and certain comorbidities, such as renal impairment. This review presents an overview of the most recent data with these novel agents and summarizes European treatment practices incorporating the novel agents. 10.1634/theoncologist.2009-0203
    Evaluation of the free α-hemoglobin pool in red blood cells: a new test providing a scale of β-thalassemia severity. Vasseur Corinne,Pissard Serge,Domingues-Hamdi Elisa,Marden Michael C,Galactéros Frédéric,Baudin-Creuza Véronique American journal of hematology β-Thalassemias are characterized by an imbalance of globin chains with an excess of α-chains which precipitates in erythroid precursors and red blood cells (RBCs) leading to inefficient erythropoiesis. The severity of the disease correlates with the amount of unpaired α-chains.Our goal was to develop a simple test for evaluation of the free α-hemoglobin pool present in RBC lysates. Alpha-Hemoglobin Stabilizing Protein (AHSP), the chaperone of α-Hb, was used to trap excess a-Hb. A recombinant GST-AHSP fusion protein was bound to an affinity micro-column and then incubated with hemolysates of patients. After washing, the α-Hb was quantified by spectrophotometry in the elution fraction. This assay was applied to 54 patients: 28 without apparent Hb disorder, 20 β-thalassemic and 6 α-thalassemic. The average value of free α-Hb pool was 93 ± 21 ppm (ng of free α-Hb per mg of Hb subunits)in patients without Hb disorder, while it varies from 119 to 1,756 ppm, in β-thalassemic patients and correlated with genotype. In contrast,the value of the free α-Hb pool was decreased in α-thalassemic patients (65 ± 26 ppm). This assay may help to characterize β-thalassemia phenotypes and to follow the evolution of the globin chain imbalance(α/β+γ ratio) in response to treatment. 10.1002/ajh.21918
    The pathogenesis of lupus nephritis. Lech Maciej,Anders Hans-Joachim Journal of the American Society of Nephrology : JASN Lupus nephritis is an immune complex GN that develops as a frequent complication of SLE. The pathogenesis of lupus nephritis involves a variety of pathogenic mechanisms. The extrarenal etiology of systemic lupus is based on multiple combinations of genetic variants that compromise those mechanisms normally assuring immune tolerance to nuclear autoantigens. This loss of tolerance becomes clinically detectable by the presence of antinuclear antibodies. In addition, nucleic acids released from netting or apoptotic neutrophils activate innate and adaptive immunity via viral nucleic acid-specific Toll-like receptors. Therefore, many clinical manifestations of systemic lupus resemble those of viral infection. In lupus, endogenous nuclear particles trigger IFN-α signaling just like viral particles during viral infection. As such, dendritic cells, T helper cells, B cells, and plasma cells all contribute to the aberrant polyclonal autoimmunity. The intrarenal etiology of lupus nephritis involves antibody binding to multiple intrarenal autoantigens rather than the deposition of circulating immune complexes. Tertiary lymphoid tissue formation and local antibody production add to intrarenal complement activation as renal immunopathology progresses. Here we provide an update on the pathogenic mechanisms that lead to lupus nephritis and provide the rationale for the latest and novel treatment strategies. 10.1681/ASN.2013010026
    Cognitive disorders and dementia in CKD: the neglected kidney-brain axis. Bugnicourt Jean-Marc,Godefroy Olivier,Chillon Jean-Marc,Choukroun Gabriel,Massy Ziad A Journal of the American Society of Nephrology : JASN Epidemiologic data suggest that individuals at all stages of CKD have a higher risk of developing cognitive disorders and dementia. This risk is generally explained by the high prevalence of both symptomatic and subclinical ischemic cerebrovascular lesions. However, other potential mechanisms, including direct neuronal injury by uremic toxins, could also be involved, especially in the absence of obvious cerebrovascular disease. We discuss the prevalence and characteristics of cognitive disorders and dementia in patients with CKD, brain imaging findings, and traditional and nontraditional risk factors. Understanding the pathophysiologic interactions between renal impairment and brain function is important in order to minimize the risk for future cognitive impairment. 10.1681/ASN.2012050536
    Light chain deposition disease without glomerular proteinuria: a diagnostic challenge for the nephrologist. Sicard Antoine,Karras Alexandre,Goujon Jean-Michel,Sirac Christophe,Bender Sébastien,Labatut Delphine,Callard Patrice,Sarkozy Clémentine,Essig Marie,Vanhille Philippe,Provot François,Nony Alain,Nochy Dominique,Ronco Pierre,Bridoux Frank,Touchard Guy Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association BACKGROUND:Renal involvement in light chain (LC) deposition disease (LCDD) is typically characterized by nodular glomerulosclerosis and nephrotic range proteinuria. Rare cases of LCDD without glomerular symptoms have been reported, but clinical and pathological characteristics of this entity remain poorly described. METHODS:This multi-centre retrospective study included 14 patients with biopsy-proven renal LCDD and proteinuria <0.5 g/day at diagnosis. RESULTS:Baseline median serum creatinine was 281 (136-594) μmol/L, with a glomerular filtration rate of 20 (6-48) mL/min/1.73 m(2). A serum monoclonal immunoglobulin was detected in 12 cases and LC proteinuria only in 7, always of kappa isotype. Monoclonal gammopathy of undetermined significance/indolent multiple myeloma (MM) was diagnosed in nine cases, symptomatic MM in three cases. Hypertension was almost constant (10 of 14). Immunofluorescence studies of kidney biopsies showed linear kappa LC deposition along tubular basement membranes in all cases, with linear glomerular and vascular LC deposits in 11 and 10 patients, respectively. By light microscopy, tubulo-interstitial lesions were prominent in all patients and focal nodular glomerulosclerosis was only observed in two cases. Identification of LCDD led to initiation of chemotherapy in 12 cases. After a median follow-up of 25.5 months, five patients died and four progressed to end-stage renal disease. Renal response occurred in five of the eight patients who achieved sustained haematological response. CONCLUSIONS:LCDD can cause severe renal dysfunction, despite the absence of glomerular symptoms. Early identification of the disease and introduction of a chemotherapy targeting the underlying plasma cell disorder may preserve long-term renal prognosis. 10.1093/ndt/gfu045
    Frailty and protein-energy wasting in elderly patients with end stage kidney disease. Kim Jun Chul,Kalantar-Zadeh Kamyar,Kopple Joel D Journal of the American Society of Nephrology : JASN Older people constitute an increasingly greater proportion of patients with advanced CKD, including those patients undergoing maintenance dialysis treatment. Frailty is a biologic syndrome of decreased reserve and resistance to stressors that results from cumulative declines across multiple physiologic systems and causes vulnerability to adverse outcomes. Frailty is common in elderly CKD patients, and it may be associated with protein-energy wasting (PEW), sarcopenia, dynapenia, and other complications of CKD. Causes of frailty with or without PEW in the elderly with CKD can be classified into three categories: causes primarily caused by aging per se, advanced CKD per se, or a combination of both conditions. Frailty and PEW in elderly CKD patients are associated with impaired physical performance, disability, poorer quality of life, and reduced survival. Prevention and treatment of these conditions in the elderly CKD patients often require a multifaceted approach. Here, we examine the causes and consequences of these conditions and examine the interplay between frailty and PEW in elderly CKD patients. 10.1681/ASN.2012010047
    Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. Dimopoulos Meletios A,Terpos Evangelos,Chanan-Khan Asher,Leung Nelson,Ludwig Heinz,Jagannath Sundar,Niesvizky Ruben,Giralt Sergio,Fermand Jean-Paul,Bladé Joan,Comenzo Raymond L,Sezer Orhan,Palumbo Antonio,Harousseau Jean-Luc,Richardson Paul G,Barlogie Bart,Anderson Kenneth C,Sonneveld Pieter,Tosi Patrizia,Cavo Michele,Rajkumar S Vincent,Durie Brian G M,San Miguel Jésus Journal of clinical oncology : official journal of the American Society of Clinical Oncology Renal impairment is a common complication of multiple myeloma (MM). The estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula is the recommended method for the assessment of renal function in patients with MM with stabilized serum creatinine. In acute renal injury, the RIFLE (risk, injury, failure, loss and end-stage kidney disease) and Acute Renal Injury Network criteria seem to be appropriate to define the severity of renal impairment. Novel criteria based on eGFR measurements are recommended for the definition of the reversibility of renal impairment. Rapid intervention to reverse renal dysfunction is critical for the management of these patients, especially for those with light chain cast nephropathy. Bortezomib with high-dose dexamethasone is considered as the treatment of choice for such patients. There is limited experience with thalidomide in patients with myeloma with renal impairment. Thus, thalidomide can be carefully administered, mainly in the context of well-designed clinical trials, to evaluate if it can improve the rapidity and probability of response that is produced by the combination with bortezomib and high-dose dexamethasone. Lenalidomide is effective in this setting and can reverse renal insufficiency in a significant subset of patients, when it is given at reduced doses, according to renal function. The role of plasma exchange in patients with suspected light chain cast nephropathy and renal impairment is controversial. High-dose melphalan (140 mg/m(2)) and autologous stem-cell transplantation should be limited to younger patients with chemosensitive disease. 10.1200/JCO.2010.30.8791
    The clinicopathologic characteristics of kidney diseases related to monotypic IgA deposits. Vignon Marguerite,Cohen Camille,Faguer Stanislas,Noel Laure-Hélène,Guilbeau Celine,Rabant Marion,Higgins Sarah,Hummel Aurélie,Hertig Alexandre,Francois Hélène,Lequintrec Moglie,Vilaine Eve,Knebelmann Bertrand,Pourrat Jacques,Chauveau Dominique,Goujon Jean-Michel,Javaugue Vincent,Touchard Guy,El Karoui Khalil,Bridoux Frank Kidney international Monoclonal gammopathy of renal significance (MGRS) regroups renal disorders caused by a monoclonal immunoglobulin without overt hematological malignancy. MGRS includes tubular disorders, glomerular disorders with organized deposits, and glomerular disorders with non-organized deposits, such as proliferative glomerulonephritis with monoclonal IgG deposits. Since glomerular involvement related to monotypic IgA deposits is poorly described we performed retrospective analysis and defined clinico-biological characteristics, renal pathology, and outcome in 19 referred patients. This analysis allowed distinction between 2 types of glomerulopathies, α-heavy chain deposition disease (5 patients) and glomerulonephritis with monotypic IgA deposits (14 patients) suggestive of IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits in 12 cases. Clinicopathologic characteristics of α-heavy chain deposition disease resemble those of the γ-heavy chain disease, except for a higher frequency of extra-capillary proliferation and extra-renal involvement. IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits should be differentiated from diseases with polytypic IgA deposits, given distinct clinical, histological, and pathophysiological features. Similarly to IgG-proliferative glomerulonephritis with monoclonal immunoglobulin deposits, overt hematological malignancy was infrequent, but sensitive serum and bone marrow studies revealed a subtle plasma cell proliferation in most patients with IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Anti-myeloma agents appeared to favorably influence renal prognosis. Thus, potential progression towards symptomatic IgA multiple myeloma suggests that careful hematological follow-up is mandatory. This series expands the spectrum of renal disease in MGRS. 10.1016/j.kint.2016.10.026
    Obesity in CKD--what should nephrologists know? Stenvinkel Peter,Zoccali Carmine,Ikizler T Alp Journal of the American Society of Nephrology : JASN Obesity, the epidemic of the 21st century, carries a markedly increased risk for comorbid complications, such as type 2 diabetes, cancer, hypertension, dyslipidemia, cardiovascular disease, and sleep apnea. In addition, obesity increases the risk for CKD and its progression to ESRD. Paradoxically, even morbid obesity associates with better outcomes in studies of ESRD patients on maintenance dialysis. Because the number of obese CKD and maintenance dialysis patients is projected to increase markedly in developed as well as low- and middle-income countries, obesity is a rapidly emerging problem for the international renal community. Targeting the obesity epidemic represents an unprecedented opportunity for health officials to ameliorate the current worldwide increase in CKD prevalence. Nephrologists need more information about assessing and managing obesity in the setting of CKD. Specifically, more precise estimation of regional fat distribution and the amount of muscle mass should be introduced into regular clinical practice to complement more commonly used practical markers, such as body mass index. Studies examining the effects of obesity on kidney disease progression and other clinical outcomes along with weight management strategies are much needed in this orphan area of research. 10.1681/ASN.2013040330
    Combined angiotensin inhibition for the treatment of diabetic nephropathy. Fried Linda F,Emanuele Nicholas,Zhang Jane H,Brophy Mary,Conner Todd A,Duckworth William,Leehey David J,McCullough Peter A,O'Connor Theresa,Palevsky Paul M,Reilly Robert F,Seliger Stephen L,Warren Stuart R,Watnick Suzanne,Peduzzi Peter,Guarino Peter, The New England journal of medicine BACKGROUND:Combination therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m(2) of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥ 30 ml per minute per 1.73 m(2) if the initial estimated GFR was ≥ 60 ml per minute per 1.73 m(2) or a decline of ≥ 50% if the initial estimated GFR was <60 ml per minute per 1.73 m(2)), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury. Results The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P=0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P=0.10) decreased with time (P=0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217.). 10.1056/NEJMoa1303154
    Integrins in kidney disease. Pozzi Ambra,Zent Roy Journal of the American Society of Nephrology : JASN A major hallmark of chronic kidney injury is fibrosis, which is characterized by increased accumulation of extracellular matrix components that replace the damaged tissue. Normally, the synthesis and degradation of extracellular matrix components are finely regulated; however, when matrix replacement goes unchecked, there is unwanted and irreversible tissue scarring with consequent organ damage, organ failure, and, in certain cases, death. Many factors, including cell-matrix interactions, play a role in the development of renal fibrosis. Cell-matrix interactions are made possible by integrins, a family of transmembrane receptors that, upon binding to the extracellular matrix, activate intracellular signaling. Thus, they control various cell functions, including survival, proliferation, migration, and matrix homeostasis. Genetic mutations in humans and the development of animal models lacking integrins in selective parts of the kidney have improved our understanding of molecular mechanisms and pathways controlling matrix remodeling in kidney disease. Here we outline the major integrins involved in kidney disease and some of the major molecular mechanisms whereby integrins contribute to kidney fibrosis. 10.1681/ASN.2013010012
    An atypical case of POEMS syndrome with IgG kappa M protein and end stage renal failure. Dursun Belda,Artac Mehmet,Varan Halil Ibrahim,Akkaya Bahar Kilicarslan,Karpuzoglu Gulten,Suleymanlar Gultekin International urology and nephrology POEMS syndrome is a rare plasma cell dyscrasia which is characterized by small amounts of monoclonal protein, and a multisystem complex manifested by various combinations of polyneuropathy, organomegaly, endocrinopathy and skin changes. Here, we presented an atypical case of POEMS syndrome with IgG kappa monoclonal protein, chronic demyelinating polyneuropathy, hepatosplenomegaly, hypothyroidism, gynecomastia and severe renal impairment. The finding of IgG kappa type of monoclonal protein in our patient was interesting because the majority of cases were reported to have lambda light chain. Also, the absence of typical skin and bone lesions were atypical. Though speculative, these atypical features may account for the unusual presentation of this case. Our patient rapidly progressed to end-stage renal failure and died of cachexia. Renal involvement in POEMS syndrome is rare but may show substantial clinical and pathological variations. Proteinuria, hematuria, renal dysfunction and renal failure requiring hemodialysis can be seen. The pathogenesis of renal dysfunction is unclear. As a conclusion, POEMS syndrome may present with diverse clinicopathologic manifestations. In this syndrome, renal involvement may lead to end stage renal failure and the course may be fatal due to severe polyneuropathy and wasting. 10.1007/s11255-004-0008-0
    Does my patient with a serum monoclonal spike have multiple myeloma? Bianchi Giada,Ghobrial Irene M Hematology/oncology clinics of North America A monoclonal spike on serum protein electrophoresis is a frequent finding in the general population and pathognomonic of a plasma cell dyscrasia. In otherwise healthy individuals, it is diagnostic of two asymptomatic, premalignant conditions called monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) which carry a lifelong risk of progression to multiple myeloma (MM) or related malignancy. This article discusses the criteria for diagnosis of MGUS, SMM, and MM; current recommendations for follow-up and risk factors for progression to MM of patients with MGUS and SMM; and diagnostic evaluation of suspected MM transformation. 10.1016/j.hoc.2012.02.009
    Mimicking the microenvironment in chronic lymphocytic leukaemia - where does the journey go? Asslaber Daniela,Grössinger Eva M,Girbl Tamara,Hofbauer Sebastian W,Egle Alexander,Weiss Lukas,Greil Richard,Hartmann Tanja N British journal of haematology 10.1111/bjh.12151
    Role of polyamines derived from arginine in differentiation and proliferation of human blood cells. Maeda Tomoji,Wakasawa Takeru,Shima Yoichiro,Tsuboi Isao,Aizawa Shin,Tamai Ikumi Biological & pharmaceutical bulletin L-Arginine is a precursor of polyamine, nitric oxide (NO), creatine, and agmatine and is essential for the differentiation and proliferation of blood cells, although the precise biological role of L-arginine is unclear. We have recently reported that the depletion of L-arginine in cultured medium prevented both proliferation and differentiation of blood cells (Shima et al., Blood First Edition Paper, October 6, 2005; DOI 10.1182). Since one of metabolic products of L-arginine in the cells is polyamine that associates with cell differentiation and proliferation, the effects of L-arginine on the human K562 cell line and human cord blood-derived CD34 positive cells were investigated by focusing on polyamines such as putrescine, spermidine, and spermine in the present study. When polyamines were added to the culture medium in the absence of L-arginine, the cells did not grow or differentiate well. However, when intracellular polyamines were depleted using ornithine decarboxylase inhibitor, alpha-difluoromethylornithine (DFMO), the proliferation and differentiation of K562 cells to erythrocytes were reduced even in the presence of L-arginine. Moreover, in the presence of DFMO, cell differentiation and proliferation were recovered by the addition of putrescine or spermidine in the presence of L-arginine. Accordingly, it was demonstrated that polyamines are essential for the proliferation and differentiation of the blood cells as the metabolites of L-arginine and the externally added polyamines are also effective by being taken up through polyamine transporter. 10.1248/bpb.29.234