Novel Antigens and Clinical Updates in Membranous Nephropathy.

Membranous nephropathy (MN), an autoimmune kidney disease and leading cause of nephrotic syndrome, leads to kidney failure in up to one-third of affected individuals. Most MN cases are due to an autoimmune reaction against the phospholipase A2 receptor (PLA2R) located on kidney podocytes. Serum PLA2R antibody quantification is now part of routine clinical practice because antibody titers correlate with disease activity and treatment response. Recent advances in target antigen detection have led to the discovery of more than 20 other podocyte antigens, yet the clinical impact of additional antigen detection remains unknown and is under active investigation. Here we review recent findings and hypothesize how current research will inform future care of patients with MN.

Lipoic acid supplementation associated with neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy.

Lipoic acid (alpha lipoic acid, thioctic acid) is a popular over-the-counter antioxidant and insulin-mimetic supplement under investigation in a variety of conditions including multiple sclerosis, diabetes, and schizophrenia. Unfortunately, high-grade proteinuria was an unexpected adverse event specific to the treatment arm of our clinical trial investigating lipoic acid supplementation in patients with multiple sclerosis. This observation led to detection of similar patients in our nephrology practice. Here, we describe four biopsy-proven cases of neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy following lipoic acid supplementation and a fifth suspected case. Discontinuation of lipoic acid and supportive therapy resulted in remission.

DNA J homolog subfamily B member 9 and other advances in fibrillary glomerulonephritis.

PURPOSE OF REVIEW: Fibrillary glomerulonephritis (FGN) involves ∼1% of native kidney biopsies and is characterized by glomerular deposition of fibrils larger than amyloid (12-24 nm diameter) composed of polyclonal immunoglobulin G (IgG). The recent discovery of DNA J homolog subfamily B member 9 (DNAJB9) in FGN glomerular deposits has contributed a specific and sensitive biomarker, informing morphologic classification and pathogenesis. This review will consider contemporary FGN incidence and genetics, pathogenesis, (lack of) paraprotein association, variants, treatment, and transplantation. RECENT FINDINGS: DNAJB9 tissue assays have enabled the identification of morphologic variants and improved classification of fibrillary-like glomerular diseases. Together with paraffin immunofluorescence and IgG subclass studies, these have established that FGN is only rarely monoclonal and these patients usually do not have an monoclonal gammopathy. The discovery of DNAJB9 opens new avenues of investigation into FGN pathogenesis, especially those of the unfolded protein response. Treatment for FGN remains empiric, with some encouraging data on rituximab-based therapy. Transplantation is a good option for patients progressing to end-stage kidney disease. SUMMARY: Advances building on the discovery of DNAJB9 in FGN should lead to long-term evolution in targeted treatment and outcome of this glomerular disease.

Association of HLA Typing and Alloimmunity With Posttransplantation Membranous Nephropathy: A Multicenter Case Series.

RATIONALE & OBJECTIVES: Posttransplantation membranous nephropathy (MN) represents a rare complication of kidney transplantation that can be classified as recurrent or de novo. The clinical, pathologic, and immunogenetic characteristics of posttransplantation MN and the differences between de novo and recurrent MN are not well understood. STUDY DESIGN: Multicenter case series. SETTING & PARTICIPANTS: We included 77 patients from 5 North American and European medical centers with post-kidney transplantation MN (27 de novo and 50 recurrent). Patients with MN in the native kidney who received kidney allografts but did not develop recurrent MN were used as nonrecurrent controls (n = 43). To improve understanding of posttransplantation MN, we compared de novo MN with recurrent MN and then contrasted recurrent MN with nonrecurrent controls. FINDINGS: Compared with recurrent MN, de novo MN was less likely to be classified as primary MN (OR, 0.04; P < 0.001) and had more concurrent antibody-mediated rejection (OR, 12.0; P < 0.001) and inferior allograft survival (HR for allograft failure, 3.2; P = 0.007). HLA-DQ2 and HLA-DR17 antigens were more common in recipients with recurrent MN compared with those with de novo MN; however, the frequency of these recipient antigens in recurrent MN was similar to that in nonrecurrent MN controls. Among the 93 kidney transplant recipients with native kidney failure attributed to MN, older recipient age (HR per each year older, 1.03; P = 0.02), recipient HLA-A3 antigen (HR, 2.5; P = 0.003), steroid-free immunosuppressive regimens (HR, 2.84; P < 0.001), and living related allograft (HR, 1.94; P = 0.03) were predictors of MN recurrence. LIMITATIONS: Retrospective case series, limited sample size due to rarity of the disease, nonstandardized nature of data collection and biopsies. CONCLUSIONS: De novo and recurrent MN likely represent separate diseases. De novo MN is associated with humoral alloimmunity and guarded outcome. Potential predisposing factors for recurrent MN include recipients who are older, recipient HLA-A3 antigen, steroid-free immunosuppressive regimen, and living related donor kidney.

Collapsing glomerulopathy in older adults.

Collapsing glomerulopathy has been described in settings of viral infections, drug, genetic, ischemic, renal transplant, and idiopathic conditions. It has a worse prognosis than other morphologic variants of focal segmental glomerulosclerosis, and may be treated with aggressive immunosuppression. In this study, we sought to characterize the clinical and morphologic findings in older adults with collapsing glomerulopathy. Renal biopsies and associated clinical data from patients aged 65 or older with a diagnosis of collapsing glomerulopathy were retrospectively reviewed at 3 academic institutions. Patients (n = 41, 61% male, median age 71) usually had hypertension (88%), nephrotic range proteinuria (91%), and renal insufficiency (median serum creatinine 2.5 mg/dL). A likely precipitating drug (5%) or vascular procedure (5%) was identified in a minority of cases; viral infections were infrequent. Renal biopsies contained a median of 40% globally and 16% segmentally sclerotic glomeruli. Approximately 60% of cases had moderate or severe arteriosclerosis, arteriolar hyalinosis, and/or tubular atrophy and interstitial fibrosis; 7% had atheroembolic disease and 5% had thrombotic microangiopathy. In 28 patients with available follow-up information, eight (19%) were treated with immunosuppressives, which were not tolerated by 2. At a median interval of 14 months, 5 (18%) patients had died, 12 (43%) had end stage renal disease, and 12 were alive with renal insufficiency and proteinuria. Treatment with immunosuppressive therapy did not have a significant benefit with regard to the primary outcome of overall or renal survival. One steroid-treated patient with diabetes died 6 weeks after biopsy, with invasive rhinoorbital Rhizopus infection. In conclusion, collapsing glomerulopathy in older patients is usually not associated with viral infections, and is accompanied by significant chronic injury in glomeruli, vasculature, and tubulointerstitium. Aggressive immunosuppression likely contributed to one death in a patient with diabetes, and did not yield an overall or renal survival advantage in this cohort.

Anti-LRP2 Nephropathy With Abundant IgG4-Positive Plasma Cells: A Case Report.

In older adults, the most common kidney biopsy diagnoses include pauci-immune crescentic glomerulonephritis, membranous nephropathy, and focal segmental glomerulosclerosis. Recently, investigators described a small series of older patients (aged 66-80 years) with acute kidney injury and a kidney biopsy demonstrating tubular basement membrane (TBM) immune deposits of polytypic immunoglobulin G (IgG) and C3, acute tubular injury, and tubulointerstitial inflammation. They identified a circulating antibody against kidney tubular low-density lipoprotein (LDL) receptor-related protein 2 (LRP2; also known as megalin) in patients' sera and colocalization of LRP2 with IgG in TBM deposits. We present a rare case of anti-LRP2 nephropathy/anti-brush border antibody disease and describe the novel feature of abundant IgG4-positive interstitial plasma cells. Along with the combination of TBM deposits, tubulointerstitial nephritis (TIN), and segmental glomerular subepithelial immune deposits seen in both entities, this newly described feature adds to the morphologic overlap with IgG4-related TIN. Identification of large TBM deposits using light microscopy and IgG staining of apical aspects of proximal tubules using immunofluorescence microscopy can point to the correct diagnosis of anti-LRP2 nephropathy and prompt confirmatory studies. Particularly in older patients with immune complex-mediated TIN who lack clinical, laboratory, radiographic, and/or characteristic histologic features of IgG4-TIN or other autoimmune, infectious, or drug-related injury, a diagnosis of anti-LRP2 nephropathy should be considered.

Kidney Transplantation in C3 Glomerulopathy: A Case Series.

RATIONALE & OBJECTIVE: C3 glomerulopathy (C3G), a form of glomerulonephritis associated with dysregulation of the alternative complement pathway, occurs either as dense deposit disease (DDD) or C3 glomerulonephritis (C3GN). Few studies have reported outcomes of patients with C3G after transplantation since its formal classification and the advent of complement-targeting therapies such as eculizumab. STUDY DESIGN: Case series of C3G. SETTING & PARTICIPANTS: We reviewed laboratory testing, native and allograft biopsy reports, and clinical charts of the 19 patients (12, C3GN; and 7, DDD) from our C3G registry who underwent transplantation between 1999 and 2016. RESULTS: During a median follow-up of 76 months, 16 patients had recurrent disease (10 of 12, C3GN; and 6 of 7, DDD), with median time to recurrence of 14 months in C3GN versus 15 months in DDD. Graft failure was more frequent in patients with DDD (6 of 7) than in patients with C3GN (3 of 12), occurred at a median time of 42 months posttransplantation, and was attributed to recurrent disease in half the failures. A rare genetic variant or autoantibody associated with alternative complement pathway abnormalities was detected in 9 of 10 screened patients. Treatment of 7 patients (8 allografts) with eculizumab was associated with variable clinical outcomes. LIMITATIONS: Incomplete testing for complement pathway abnormalities and genetic defects, incomplete records of HLA antigen matching, lack of centralized biopsy review, and limited sample size. CONCLUSIONS: In a case series of C3G transplant recipients, the proportion of disease recurrence was high in both C3GN and DDD, although graft loss appeared to occur more frequently in DDD. In a small subset of study patients, eculizumab therapy was not consistently followed by salutary outcomes.

C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy.

C3 glomerulonephritis (C3GN) and dense deposit disease comprise the two classes of C3 glomerulopathy. Studies from Europe and Asia have aided our understanding of this recently defined disorder, but whether these data apply to a diverse United States patient population remains unclear. We, therefore, reviewed clinical and histopathological data, including generation of a C3 Glomerulopathy Histologic Index to score biopsy activity and chronicity, to determine predictors of progression to end-stage renal disease (ESRD) and advanced chronic kidney disease (CKD) in 111 patients (approximately 35% non-white) with C3 glomerulopathy: 87 with C3GN and 24 with dense deposit disease. Complement-associated gene variants and autoantibodies were detected in 24% and 35% of screened patients, respectively. Our C3 Glomerulopathy Histologic Index denoted higher activity in patients with C3GN and higher chronicity in patients with dense deposit disease. Over an average of 72 months of follow-up, remission occurred in 38% of patients with C3GN and 25% of patients with dense deposit disease. Progression to late-stage CKD and ESRD was common, with no differences between C3GN (39%) and dense deposit disease (42%). In multivariable models, the strongest predictors for progression were estimated glomerular filtration rate at diagnosis (clinical variables model) and tubular atrophy/interstitial fibrosis (histopathology variables model). Using our C3 Glomerulopathy Histologic Index, both total activity and total chronicity scores emerged as the strongest predictors of progression. Thus, in a large, diverse American cohort of patients with C3 glomerulopathy, there is a high rate of progression to CKD and ESRD with no differences between C3GN and dense deposit disease.

Plasma metabolite profiles, cellular cholesterol efflux, and non-traditional cardiovascular risk in patients with CKD.

BACKGROUND: Patients with chronic kidney disease (CKD) experience high rates of atherosclerotic cardiovascular disease and death that are not fully explained by traditional risk factors. In animal studies, defective cellular cholesterol efflux pathways which are mediated by the ATP binding cassette transporters ABCA1 and ABCG1 are associated with accelerated atherosclerosis. We hypothesized that cholesterol efflux in humans would vary in terms of cellular components, with potential implications for cardiovascular disease. METHODS: We recruited 120 CKD patients (eGFR<30mL/min/1.73m2) and 120 control subjects (eGFR ≥60mL/min/1.73m2) in order to measure cholesterol efflux using either patients' HDL and THP-1 macrophages or patients' monocytes and a flow cytometry based cholesterol efflux assay. We also measured cell-surface levels of the common ß subunit of the IL-3/GM-CSF receptor (IL-3Rß) which has been linked to defective cholesterol homeostasis and may promote monocytosis. In addition, we measured plasma inflammatory cytokines and plasma metabolite profiles. RESULTS: There was a strong positive correlation between cell-surface IL-3Rß levels and monocyte counts in CKD (P<0.001). ABCA1 mRNA was reduced in CKD vs. control monocytes (P<0.05), across various etiologies of CKD. Cholesterol efflux to apolipoprotein A1 was impaired in monocytes from CKD patients with diabetic nephropathy (P<0.05), but we found no evidence for a circulating HDL-mediated defect in cholesterol efflux in CKD. Profiling of plasma metabolites showed that medium-chain acylcarnitines were both independently associated with lower levels of cholesterol transporter mRNA in CKD monocytes at baseline (P<0.05), and with cardiovascular events in CKD patients after median 2.6years of follow-up. CONCLUSIONS: Cholesterol efflux in humans varies in terms of cellular components. We report a cellular defect in ABCA1-mediated cholesterol efflux in monocytes from CKD patients with diabetic nephropathy. Unlike several traditional risk factors for atherosclerotic cardiovascular disease, plasma metabolites inversely associated with endogenous cholesterol transporters predicted cardiovascular events in CKD patients. (Funded by the National Institute of Diabetes and Digestive and Kidney DiseasesK23DK097288 and others.).

Predicting Post-Transplant Recurrence of IgA Nephropathy: The Importance of Crescents.

BACKGROUND: Most studies that have assessed the predictors of recurrent IgA nephropathy (IgAN) in the renal allograft have focused on post-transplant features. Identifying high-risk pre-transplant features of IgAN is useful for counseling patients and may help in tailoring post-transplant immunosuppression. METHODS: We investigated the pre-transplant clinical and biopsy features of 62 patients with IgAN who received transplants at Columbia University Medical Center from 2001 to 2012 and compared the characteristics and outcomes of patients with IgAN recurrence to those without recurrence. The primary outcome was time to recurrent IgAN. Secondary outcomes were a composite of doubling of creatinine or allograft failure, and recurrent IgAN as a cause of allograft dysfunction. RESULTS: Of the 62 patients, 14 had recurrent IgAN in the allograft. Mean time to recurrence was 2.75 years. Those with recurrent disease were younger at the time of native kidney biopsy (29 vs. 41 years, p < 0.0009). Black race and Hispanic ethnicity composed a higher proportion of the recurrent disease group. On multivariable analysis, significant predictors of recurrent IgAN included age at diagnosis (hazards ratio (HR) 0.911, 95% CI 0.85-0.98), burden of crescents on native biopsy (HR 1.21 per 10% increase in crescents, 95% CI 1.00-1.47) and allograft rejection (HR 3.59, 95% CI 1.10-11.7). CONCLUSIONS: Features of native IgAN can help predict the risk of recurrent disease in the renal allograft. In particular, immunologically active disease represented by earlier age of onset and greater burden of crescents on native biopsy is more likely to recur after transplant.

Filgrastim-Induced Crescentic Transformation of Recurrent IgG2λ GN.

Proliferative GN with monoclonal IgG deposits is an increasingly recognized form of GN, but its relation to hematologic malignancy remains poorly understood. Filgrastim, an analog for granulocyte colony-stimulating factor produced by recombinant DNA technology, is frequently used to stimulate bone marrow release of hematopoietic progenitor cells in preparation for stem cell transplant. We report an exceptional case of proliferative GN with monoclonal IgG2λ deposits in a young man whose disease progressed slowly to CKD, which was followed by a preemptive kidney transplant. The patient developed recurrent GN in the allograft and clinically detectable plasma cell neoplasm 9 years after the first renal manifestations. Contemporaneous with filgrastim administration for stem cell mobilization, the patient's slowly progressive GN underwent severe crescentic transformation, leading to rapidly progressive and irreversible allograft failure. This report explores the spectrum of GN with monoclonal IgG deposits and the pathophysiologic role of granulocyte colony-stimulating factor in exacerbation of preexisting GN.

Proteinuria as a surrogate marker for renal outcome: are we there yet?

Observational studies in glomerular diseases suggest that proteinuria reduction translates to improved outcomes. Because of a dearth of high-quality studies supporting this association, proteinuria is not universally recognized as a surrogate end point. Barbour et al. report on the longitudinal measure of proteinuria that best predicts hard renal outcomes. Their finding that time-varying proteinuria is the most reliable proteinuria metric is a necessary step in establishing proteinuria as a surrogate end point.

Aldosterone blockade as an alternative renin-angiotensin-aldosterone system blocking agent in cases of treatment associated anemia.

Blockade of the renin-angiotensin-aldosterone system (RAAS) is a mainstay of therapy for proteinuric kidney disease due to effects on blood pressure, proteinuria, and overall cardiovascular risk. In this case series, we highlight one of the rare but serious side effects of the most commonly used RAAS blocking drugs, angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs): a severe anemia due to impaired erythropoiesis. The four patients presented here were switched to a mineralocorticoid receptor blocker (MRB) that targets aldosterone without any inhibition of angiotensin II, and resulting in significant rebounds back to baseline hemoglobin levels. Furthermore, all patients had optimal blood pressure control and proteinuria reductions. These data support the use of aldosterone blocking agents in kidney disease patients with anemia secondary to ACE-Is or ARB. Presumably, any patient - regardless of kidney status - for whom RAAS blockade is indicated (e.g., diabetic patients or patients with congestive heart failure) should be switched to MRB therapy if significant anemia develops after starting an ACE-Is or ARB.

NELL1 membranous nephropathy: clinical associations provide mechanistic clues.

Neural epidermal growth factor-like 1 (NELL1) membranous nephropathy (MN) is notable for its segmental deposit distribution, IgG1 dominant deposits, and comparatively high rate of spontaneous remission. It has been associated with a variety of exposures and secondary conditions, specifically use of thiol-containing medications - including lipoic acid, bucillamine, and tiopronin - as well as traditional indigenous medications (TIM) particularly those with high mercury content, and non-steroid anti-inflammatory drugs (NSAIDs). Malignancies, graft vs. host disease (GVHD), infection, and autoimmune conditions have also been associated with NELL1 MN. Herein, we provide a detailed summary of the clinicopathologic features of NELL1 and associations with underlying conditions, with a focus on treatment and outcomes. Rare cases of dual NELL1 and phospholipase A2 receptor (PLA2R) positive MN are reviewed. Genome-wide association study of NELL1, role of NELL1 in other physiologic and pathologic processes, and connection between NELL1 MN and malignancy with relevance of NELL1 tumor staining are examined. Finally, relationships and potential disease mechanisms of thiol- and mercury- associated NELL1 MN are discussed.

Characteristics and Outcomes of NELL1 Membranous Nephropathy in Lipoic Acid Users and Nonusers.

Introduction: Neural epidermal growth factor like 1 membranous nephropathy (NELL1 MN) is associated with various secondary etiologies. However, previous studies on the frequency of these associations and their impact on outcomes are limited. We report a large multiinstitutional series of patients with NELL1 MN with a focus on secondary associations, pathology findings, and their impact on outcome. Methods: We retrospectively reviewed clinicopathologic features of NELL1 MN from 3 institutions and analyzed clinical and histologic associations with outcome. Results: Of 70 patients, 53% were male with a median age of 66 years; median proteinuria was 5.9 g/d. NELL1 MN was associated with lipoic acid (36%), heavy nonsteroidal antiinflammatory drug (NSAID) use (27%), autoimmune disease (23%), malignancy (10% recent, 23% any), mercury exposure (1%), and 11% had no known secondary association. At median follow-up of 11 months, 72% achieved complete or partial remission. Remission rate was 91% in patients with lipoic acid-associated NELL1 MN and ≥6 months of follow-up. On multivariable analyses, patients with primary NELL1 MN (adjusted odds ratio [OR]: 19.7, P = 0.01) and increasing degree of tubular atrophy and interstitial fibrosis (IFTA) (adjusted OR 1.1, P = 0.01) were less likely to achieve any remission, whereas complete remission (CR) was associated with lipoic acid use (adjusted OR: 10.9, P = 0.04, 95% confidence interval [CI]: 1.2-100) and lesser degrees of IFTA (adjusted OR: 0.79, P = 0.16, 95% CI: 0.66-0.96). Conclusion: Our findings strengthen the association between lipoic acid and NELL1 MN. Furthermore, our findings suggest that discontinuation of lipoic acid without immunosuppression should be considered as the first-line treatment.

Management of Lupus Nephritis: New Treatments and Updated Guidelines.

Management of lupus nephritis has evolved considerably over the past years. Here, we provide a comprehensive review of clinical trials that form the basis for the Kidney Disease: Improving Global Outcomes and EULAR/ERA-EDTA updated guidelines and present day trials that will change the landscape of lupus nephritis therapy in years to come. In addition, we highlight the issues related to cost of therapy, resistant disease, and downstream adverse effects of specific therapies.

Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response.

Background: Fibrillary glomerulonephritis (FGN) is found in approximately 1% of native kidney biopsies and was traditionally defined by glomerular deposition of fibrils larger than amyloid (12-24 nm diameter) composed of polyclonal IgG. Recent identification of DNAJB9 as a sensitive and specific marker of FGN has revolutionized FGN diagnosis and opened new avenues to studying FGN pathogenesis. In this review, we synthesize recent literature to provide an updated appraisal of the clinical and pathologic features of FGN, discuss diagnostic challenges and pitfalls, and propose molecular models of disease in light of DNAJB9. Summary: DNAJB9 tissue assays, paraffin immunofluorescence studies, and IgG subclass testing demonstrate that FGN is distinct from other glomerular diseases with organized deposits and highlight FGN morphologic variants. Additionally, these newer techniques show that FGN is only rarely monoclonal, and patients with monoclonal FGN usually do not have a monoclonal gammopathy. DNAJB9 mutation does not appear to affect the genetic architecture of FGN; however, the accumulation of DNAJB9 in FGN deposits suggests that disease is driven, at least in part, by proteins involved in the unfolded protein response. Treatments for FGN remain empiric, with some encouraging data suggesting that rituximab-based therapy is effective and that transplantation is a good option for patients progressing to ESKD. Key Messages: DNAJB9 aids in distinguishing FGN from other glomerular diseases with organized deposits. Further investigations into the role of DNAJB9 in FGN pathogenesis are necessary to better understand disease initiation and progression and to ultimately develop targeted therapies.

A Diverse Spectrum of Immune Complex- and Complement-Mediated Kidney Diseases Is Associated With Mantle Cell Lymphoma.

Introduction: There are limited reports on kidney biopsy findings in patients with mantle cell lymphoma (MCL). Methods: We initiated a multi-institutional, retrospective review of kidney biopsy findings in patients with active and treated MCL. Results: A total of 30 patients with MCL and kidney biopsies were identified, with a median age of 67 (range 48-87) years, 73% of whom were men. A total of 20 patients had active MCL at the time of biopsy, of whom 14 (70%) presented with acute kidney injury (AKI), proteinuria and/or hematuria, and biopsy findings potentially attributable to lymphoma. Of the 14, 11 had immune complex (IC) or complement-mediated (C3) disease including proliferative glomerulonephritis (GN) with monotypic Ig deposits (PGNMID [2]), C3GN, (2), secondary membranous nephropathy (MN [3]), tubular basement membrane (TBM) deposits (2), and modest lupus-like GN (2). Lymphomatous infiltration was present in 8 of the 20 patients, 5 with coincident IC or C3 lesions. A total of 6 patients with available follow-up were treated for MCL, all with clinical remission of GN (2 PGNMID, 2 C3GN, and 2 MN). Conclusion: MCL is associated with diverse monoclonal and polyclonal glomerular and extra-glomerular IC and C3 disease. For patients with active MCL and kidney dysfunction requiring biopsy, 70% had findings due or potentially due to lymphoma, including 55% with IC or C3 disease and 40% had lymphomatous kidney infiltration. IC and C3GN in the setting of active MCL was responsive to lymphoma-directed therapy.

The Clone Wars: Diagnosing and Treating Dysproteinemic Kidney Disease in the Modern Era.

Dysproteinemic kidney diseases are disorders that occur as the result of lymphoproliferative (B cell or plasma cell) disorders that cause kidney damage via production of nephrotoxic monoclonal immunoglobulins or their components. These monoclonal immunoglobulins have individual physiochemical characteristics that confer specific nephrotoxic properties. There has been increased recognition and revised characterization of these disorders in the last decade, and in some cases, there have been substantial advances in disease understanding and treatments, which has translated to improved patient outcomes. These disorders still present challenges to nephrologists and patients, since they are rare, and the field of hematology is rapidly changing with the introduction of novel testing and treatment strategies. In this review, we will discuss the clinical presentation, kidney biopsy features, hematologic characteristics and treatment of dysproteinemic kidney diseases.