Monoclonal immunoglobulin crystalline nephropathies.

Monoclonal Ig crystalline nephropathies are rare lesions resulting from precipitation of monoclonal Igs in the kidney as crystalline inclusions. They can be categorized into lesions with predominant intracellular crystals (light chain [LC] proximal tubulopathy, LC crystal-storing histiocytosis, and LC crystalline podocytopathy) and lesions with predominant extracellular crystals (crystalglobulin-induced nephropathy and crystalline variant of LC cast nephropathy). The majority of these lesions are associated with low tumor burden lymphoproliferative disorders, with the exception of crystalline variant of LC cast nephropathy. Extrarenal involvement (e.g., skin and cornea) is frequent. Kidney biopsy is the cornerstone for diagnosis, which often requires electron microscopy and antigen retrieval. A thorough hematologic workup and evaluation of extrarenal involvement is mandatory for management. Treatment of these lesions is with clone-directed therapy, with the goal of achieving hematologic very good partial response or complete response, which preserves or improves kidney function. In vitro and in vivo studies, animal models, and novel sequencing techniques have been invaluable tools to understand the pathogenesis of LC proximal tubulopathy and can be used to increase our limited knowledge of the pathogenesis of the other monoclonal Ig crystalline nephropathies. This review provides an update on the pathology, renal and hematologic characteristics, extrarenal manifestations, prognosis, treatment, and pathogenesis of monoclonal Ig crystalline nephropathies.

Cytogenetic abnormality in non-systemic light chain amyloidosis monoclonal gammopathy of renal significance: A field needs to be explored.

The role of cytogenetic abnormalities in non-systemic light chain amyloidosis monoclonal gammopathy of renal significance diseases still needs to be clarified. Bhutani et al. present the results of a study investigating the underlying plasma cell cytogenetic abnormalities in monoclonal immunoglobulin deposition disease (MIDD). The results show that translocation (11;14) is a common abnormality in MIDD and affects the presentation and outcomes. Commentary on: Bhutani et al. Translocation (11;14) is a common cytogenetic abnormality in clonal plasma cells in monoclonal immunoglobulin deposition disease. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19748.

Cryoglobulinemic Vasculitis in Disguise: Cryofibrinogenemia as Variant of Monoclonal Gammopathy of Renal Significance.

Monoclonal gammopathy with cryoactivity (ie, cryoglobulins) that causes glomerulonephritis is considered within the spectrum of monoclonal gammopathy of renal significance. Cryofibrinogenemia (cryoactivity of coagulation factors) is very rarely associated with glomerulonephritis. We present a 39-year-old woman with a relapsing nephrotic syndrome. Laboratory investigation detected cryofibrinogen; the precipitate consisted of fibrinogen and a monoclonal immunoglobulin (M-protein; IgG-λ), and the latter was also detected in serum (4g/L). Initial conventional immunosuppressive therapy resulted in temporary renal remission. In view of the M-protein, subsequent therapy consisted of bortezomib/dexamethasone and high-dose melphalan followed by autologous hematopoietic stem cell transplantation, and resulted in a very good partial hematological response and temporary renal remission. However, after hematological and renal relapse, we performed unique experiments to clarify the role of the M-protein. Mixing patient serum with donor plasma resulted in cryoactivity, composed of M-protein+fibrinogen. Patient plasma deprived of M-protein did not have cryoactivity. Therefore, cryoactivity was dependent on the M-protein. We started lenalidomide, which resulted in very good partial hematological and renal remission. Thus, cryofibrinogenemia can be the consequence of an M-protein, which we suggest should be defined as monoclonal gammopathy of renal significance.

Clinicopathologic Characteristics of Crystalglobulin-Induced Nephropathy: A Case Series.

RATIONALE & OBJECTIVE: Crystalglobulinemia is a rare syndrome characterized by intravascular crystallization of monoclonal immunoglobulins (MIg). Data on kidney involvement are limited to case reports. This series characterizes the clinicopathologic spectrum of crystalglobulin-induced nephropathy (CIN). STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Nineteen CIN cases identified from the nephropathology archives of Mayo Clinic and Columbia University. CIN was defined by intravascular (extracellular) MIg crystals visible by light microscopy (LM) and electron microscopy (EM). RESULTS: Among the cases, 68% were male, and 65% were Caucasian (median age, 56 years). Most patients presented with severe acute kidney injury (AKI) (median creatinine, 3.5mg/dL), hematuria, and mild proteinuria (median, 1.1g/day). Common extrarenal manifestations were constitutional (67%), cutaneous (56%), and rheumatologic (50%). Fifty percent of cases had hypocomplementemia. The hematologic disorders were monoclonal gammopathy of renal significance (MGRS) (72%), lymphoma (17%), or myeloma (11%), with 65% of these disorders discovered concomitantly with CIN. All patients had MIg identified on serum protein electrophoresis/immunofixation (IgGκ in 65%). The serum free light chain ratio was outside the renal range in 40%, and bone marrow biopsy detected the responsible clone in 67%. On LM, crystals involved glomeruli (100%) and vessels (47%), often with an inflammatory reaction (89%) and fibrin (58%). All cases exhibited crystal substructures (mostly paracrystalline) by EM. Immunofluorescence on paraffin-embedded tissue was more sensitive than frozen tissue (92% vs 47%) for demonstrating the crystal composition (IgGκ in 63%). Follow-up observation (median, 20 months) was available in 16 patients. Eighty-one percent received steroids, 44% plasmapheresis, 38% hemodialysis, and 69% chemotherapy. Ninety-percent of patients who received clone-directed therapy achieved kidney recovery versus 20% of those who did not (P=0.02). LIMITATIONS: Retrospective design, small sample size. CONCLUSIONS: CIN is a rare cause of nephropathy associated with lymphoplasmacytic disorders (mostly MGRS) and typically presents with severe AKI and extrarenal manifestations. Diagnosis often requires immunofluorescence performed on paraffin-embedded kidney tissue. Prompt initiation of clone-directed therapy, coupled with corticosteroids and plasmapheresis, may lead to recovery of kidney function.

Light chain deposition disease: pathogenesis, clinical characteristics and treatment strategies.

Light chain deposition disease (LCDD) is a rare hematologic disorder characterized by the deposition of non-amyloid monoclonal light chains in several organs. Together with renal impairment is being the primary morbidity associated with this disease. Due to its rarity, randomized clinical trials lack to explore treatment strategies and there are no approved or universally accepted standard of care treatment options. We aimed to provide a systematic summary of histological and clinical aspects of LCDD and treatment options of available literature therapies strategies. Currently, drugs used to treat multiple myeloma are recommended when LCDD patients also presented multiple myeloma. Anyway, in patients with LCDD that is not associated to multiple myeloma, haematopoietic stem cell transplantation (ASCT) and chemotherapy with thalidomide, dexamethasone, bortezomib are also recommended. In eligible patients, bortezomib-based chemotherapy followed by ASCT appears to be an effective treatment option with durable hematologic remission and organ responses. Although it appears that the patients undergoing ASCT seem to achieve deeper and durable hematologic remissions and organ responses, no statistically significant superiority can be demonstrated over non-transplant or standard chemotherapy-based approaches. As retrieved by our review, bortezomib-based therapy appears to be favorable strategy as long as no dose modification is required for renal impairment, and early hematologic responses as a recovery of renal function. Encouraging data were also demonstrated by treatment lenalidomide or melpalan based. Moreover, new myeloma treatment strategies, as monoclonal antibody Daratumumab, seem to be effective in LCDD. Instead, renal allograft is not recommended, due to high incidence of relapse.

Association of monoclonal gammopathy of undetermined significance and C3 glomerulopathy.

Monoclonal gammopathy of undetermined significance (MGUS) is usually an asymptomatic pre-malignant condition caused by the proliferation of clonal plasma cells. Often considered a benign condition, it has the potential to progress to malignant plasma cell or lymphoproliferative disorders. Moreover, MGUS can rarely cause glomerular disease by activating the alternative complement pathway resulting in immunoglobulin-negative C3-positive glomerulonephritis called C3 glomerulopathy. Because of its rarity, the diagnosis might not be considered by the treating physicians, leading to delayed diagnosis or misdiagnosis. Untreated C3 glomerulopathy can lead to irreversible glomerular damage and end-stage renal failure, and a high index of suspicion is essential for timely diagnosis and management. Here, we present the case of a patient with a prior diagnosis of MGUS who presented with proteinuria and microscopic haematuria and was diagnosed with C3 glomerulopathy. The patient had complete resolution of the disease after receiving treatment with a combination of dexamethasone, lenalidomide and bortezomib for the underlying MGUS.

The characteristics of seronegative and seropositive non-hepatitis-associated cryoglobulinemic glomerulonephritis.

The clinicopathologic characteristics and long-term outcome of non-hepatitis-associated cryoglobulinemic glomerulonephritis (CryoGN) are not well-defined and cases with undetectable serum cryoglobulin (seronegative CryoGN) have not been investigated. To resolve this, we retrospectively identified 81 patients with biopsy-proven non-hepatitis CryoGN, including 22 with seronegative CryoGN. The median age was 61 years and 76% presented with nephritic syndrome. A hematologic condition was found in 89% of patients, including monoclonal gammopathy of renal significance (65%) and symptomatic lymphoproliferative disorder (35%). In the seropositive group, 56% had type II, 29% type I, and 8% type III cryoglobulin. Extrarenal manifestations, mostly of skin, were present in 64% and were significantly less common in seronegative CryoGN. Glomerular deposits by immunofluorescence were IgM dominant (84%) and polytypic (70%) in the seropositive group, whereas 52% of seronegative cases had monotypic deposits (i.e., type I cryoglobulin). Ultrastructurally, the deposits were organized in 77% of cases. Substructure appearance significantly differed according to the type of CryoGN, forming most commonly short cylindrical structures in type II and other organized substructures in type I CryoGN. Most patients were treated with clone-directed therapy. On follow up (median 33 months), 77% had partial or complete remission, 10% reached kidney failure and 14% died. Predictors of kidney failure on univariate analysis were AKIN stage 3, positive rheumatoid factor and biclonal gammopathy at diagnosis. We conclude that most CryoGN cases (types I and II) are due to a hematologic condition and are associated with favorable outcome after clone-directed therapy. Seronegative CryoGN accounts for about a quarter of cases and is mostly a kidney-limited disease. Thus, further investigations are needed to unravel the pathophysiology of seronegative CryoGN.

The characteristics of patients with kidney light chain deposition disease concurrent with light chain amyloidosis.

The type of monoclonal light chain nephropathy is thought to be largely a function of the structural and physiochemical properties of light chains; hence most affected patients have only one light chain kidney disease type. Here, we report the first series of kidney light chain deposition disease (LCDD) concomitant with light chain amyloidosis (LCDD+AL), with or without light chain cast nephropathy (LCCN). Our LCDD+AL cohort consisted of 37 patients (54% females, median age 70 years (range 40-86)). All cases showed Congo red-positive amyloid deposits staining for one light chain isotype on immunofluorescence (62% lambda), and LCDD with diffuse linear staining of glomerular and tubular basement membranes for one light chain isotype (97% same isotype as the amyloidogenic light chain) and ultrastructural non-fibrillar punctate deposits. Twelve of 37 cases (about 1/3 of patients) had concomitant LCCN of same light chain isotype. Proteomic analysis of amyloid and/or LCDD deposits in eight revealed a single light chain variable domain mutable subgroup in all cases (including three with separate microdissections of LCDD and amyloid light chain deposits). Clinical data on 21 patients showed proteinuria (100%), hematuria (75%), kidney insufficiency and nephrotic syndrome (55%). Extra-kidney involvement was present in 43% of the patients. Multiple myeloma occurred in 68% (about 2/3) of these patients; none had lymphoma. On follow up (median 16 months), 63% developed kidney failure and 56% died. The median kidney and patient survivals were 12 and 32 months, respectively. LCDD+AL mainly affected patients 60 years of age or older. Thus, LCDD+AL could be caused by two pathological light chains produced by subclones stemming from one immunoglobulin light chain lambda or kappa rearrangement, with a distinct mutated complementary determining region.

Kidney Transplantation in Patients With Monoclonal Gammopathy of Renal Significance (MGRS)-Associated Lesions: A Case Series.

RATIONALE & OBJECTIVE: Data on kidney transplantation outcomes among patients with monoclonal gammopathy of renal significance (MGRS) are lacking. STUDY DESIGN: Case series of patients with MGRS, some of whom received clone-directed therapies before kidney transplantation. SETTING & PARTICIPANTS: 28 patients who underwent kidney transplantation from 1987 through 2016 after diagnosis with MGRS-associated lesions including light-chain deposition disease (LCDD), C3 glomerulopathy with monoclonal gammopathy (C3G-MG), and light-chain proximal tubulopathy (LCPT). FINDINGS: Of the 19 patients with LCDD, 10 were treated before kidney transplantation and 9 were treatment-naive. Among the treated patients with LCDD, 3 (30%) experienced histologic recurrence, 2 (20%) grafts failed, and 2 (20%) died during a median follow-up of 70 (range, 3-162) months after transplant. In the treatment-naive LCDD group, 8 (89%) had histologic recurrence, 6 (67%) grafts failed, and 4 (44%) patients died during a median follow-up of 60 (range, 35-117) months. Of the 5 patients who had a complete response before transplant, none died, and only 1 experienced graft failure, 162 months after transplant. Of 5 patients with C3G-MG, 3 were treatment-naive before transplant. Both patients who were treated before transplant had histologic recurrence, and 1 experienced graft failure and died. Among the 3 patients with treatment-naive C3G-MG, histologic recurrence occurred in all, and graft loss and death were observed in 2 and 1, respectively. In the LCPT group (n=4), histologic recurrence was observed in all 3 patients who did not receive clone-directed therapies before transplant, and 2 of these patients died, 1 with a functioning kidney. The 1 patient with LCPT who received therapy before transplant did not have histologic recurrence or graft loss and survived. LIMITATIONS: Small sample size, nonstandardized clinical management, retrospective design. CONCLUSIONS: Recurrence is very common in all MGRS-associated lesions after kidney transplant. Achieving a complete hematologic response may reduce the risks of recurrence, graft loss, and death. More studies are needed to determine the effects of hematologic response on outcomes for each MGRS-associated lesion.

Outcomes of kidney transplantation in patients with myeloma and amyloidosis in the USA.

BACKGROUND: Recent improvement in treatment and patient survival has opened the eligibility of kidney transplantation to patients who developed end-stage kidney disease (ESKD) from plasma cell dyscrasias (PCDs). Data on clinical outcomes in this population are lacking. METHODS: We conducted a retrospective study of United Network for Organ Sharing/Organ Procurement and Transplantation Network dataset (2006-2018) to compare patient and graft outcomes of kidney transplant recipients with ESKD due to PCD versus other causes. RESULTS: Among 168 369 adult first kidney transplant recipients, 0.22-0.43% per year had PCD as the cause of ESKD. The PCD group had worse survival than the non-PCD group for both living and deceased donor types {adjusted hazard ratio [aHR] 2.24 [95% confidence interval (CI) 1.67-2.99] and aHR 1.40 [95% CI 1.08-1.83], respectively}. The PCD group had worse survival than the diabetes group, but only among living donors [aHR 1.87 (95% CI 1.37-2.53) versus aHR 1.16 (95% CI 0.89-1.2)]. Graft survival in patients with PCD were worse than non-PCD in both living and deceased donors [aHR 1.72 (95% CI 1.91-2.56) and aHR 1.30 (95% CI 1.03-1.66)]. Patient and graft survival were worse in amyloidosis but not statistically different in multiple myeloma compared with the non-PCD group. CONCLUSION: The study data are crucial when determining kidney transplant eligibility and when discussing transplant risks in patients with PCD.

Immunofluorescence staining for immunoglobulin heavy chain/light chain on kidney biopsies is a valuable ancillary technique for the diagnosis of monoclonal gammopathy-associated kidney diseases.

Heavy chain/light chain (HLC) antibodies target conformational epitopes at the junctions of the heavy chain and light chain constant regions (CH1 and CL) of serum IgGκ, IgGλ, IgAκ, IgAλ, IgMκ, and IgMλ to provide quantitation of intact HLC pairs. Here, we developed an HLC tissue immunofluorescence protocol to test if it can complement conventional immunofluorescence in the diagnosis of monoclonal gammopathy-associated kidney diseases. HLC immunofluorescence was performed on archived frozen tissue of 104 kidney biopsies. The sensitivity and specificity of HLC immunofluorescence was confirmed by testing cases of lupus nephritis, other polyclonal immunoglobulin nephropathies, and light chain nephropathies (light chain amyloidosis and deposition disease). Testing of ten cases of the IgG variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits excluded monoclonal deposits in two by revealing positivity for IgGκ and IgGλ. Testing of 12 cases of monotypic IgA nephropathy excluded monoclonal deposits in six by revealing staining for IgAκ and IgAλ. Testing of six cases of monotypic fibrillary glomerulonephritis excluded monoclonal deposits in three by revealing positivity for IgGκ and IgGλ. None of 14 cases of glomerulonephritis in which HLC immunofluorescence unmasked polytypic deposits were associated with a serum or urine monoclonal immunoglobulins matching the conventional immunofluorescence results. HLC immunofluorescence outperformed paraffin immunofluorescence and IgG subclass staining in 10/13 (77%) of cases. Testing of 18 cases of cryoglobulinemic glomerulonephritis showed better correlation with serum cryoprecipitate immunofixation than conventional immunofluorescence with regards to the type of cryoglobulin in 47% of cases. Thus, HLC immunofluorescence is a valuable ancillary technique in kidney pathology for the diagnosis of monoclonal gammopathy-associated nephropathies, and could be utilized to confirm or exclude the monoclonal nature of deposits.

Immunotactoid glomerulopathy is a rare entity with monoclonal and polyclonal variants.

Immunotactoid glomerulopathy (ITG) is a rare form of glomerulonephritis for which our understanding is limited to case reports and small case series. Herein we describe the clinical, pathologic, and outcome characteristics of 73 patients with ITG who typically presented with proteinuria, hematuria, and renal insufficiency. Hematologic disorders were present in 66% of patients, including lymphoma in 41% (mainly chronic lymphocytic leukemia/small lymphocytic lymphoma), monoclonal gammopathy in 20%, and multiple myeloma in 6%. Light microscopy revealed endocapillary proliferative (35%), membranoproliferative (29%) and membranous (29%) patterns of glomerular involvement. Electron microscopy revealed characteristic microtubular deposits with a diameter of 14-60 nm, hollow cores, frequent parallel alignment, and a predominant distribution outside of the lamina densa of the glomerular basement membrane. Importantly, immunofluorescence revealed IgG-dominant staining which was light chain and IgG subclass restricted in 67% of cases, indicating monoclonal composition. This finding was used to distinguish monoclonal and polyclonal variants of ITG. As compared to polyclonal, monoclonal ITG had a higher incidence of lymphoma (53% vs. 11%), multiple myeloma (8% vs. 0), and monoclonal gammopathy (22% vs. 16%). Monoclonal ITG was more commonly treated with clone-directed therapy, which was associated with more frequent remission and less frequent end stage kidney disease. Thus, a third of ITG cases are polyclonal but a quarter of these cases are associated with hematologic conditions, underscoring the need for hematologic evaluation in all patients with ITG. Hence, based on these distinctions, ITG should be subclassified into monoclonal and polyclonal variants. Prognosis of ITG is good if the underlying hematologic condition is treated.

Proliferative Glomerulonephritis With Fibrils, Monoclonal κ Light Chain, and C3 Deposits.

There is increasing recognition of monoclonal gammopathy as a cause of proliferative glomerulonephritis (GN), including cases in which glomerular deposition of monoclonal immunoglobulin is demonstrated. Recently, proliferative GN with monoclonal immunoglobulin deposits (PGNMID) has incorporated a light chain variant of the disease (termed PGNMID-LC). Intriguingly, glomerular co-deposition of C3 is found in addition to monotypic light chain, implying complement activation via the alternative pathway (AP). We present a unique case of proliferative GN in a 42-year-old man who presented with nephrotic syndrome and was found to have κ light chain multiple myeloma. Immune staining of the glomerulus was positive only for κ light chain and C3, with the striking appearance of nonamyloid fibrils on electron microscopy. Following clonally targeted therapy for myeloma, the renal clinical abnormalities resolved completely. We present detailed molecular studies for light chain and complement and consider local mechanisms whereby monoclonal κ light chain fibrils may have triggered AP activation within the glomerulus.

Rate and Predictors of Finding Monoclonal Gammopathy of Renal Significance (MGRS) Lesions on Kidney Biopsy in Patients with Monoclonal Gammopathy.

BACKGROUND: Little is known about the rate and predictors of finding lesions of monoclonal gammopathy (MG) of renal significance (MGRS) on kidney biopsy specimens among patients with MG. METHODS: We reviewed the medical records from 2013 to 2018 at the Mayo Clinic in Rochester, Minnesota, to identify patients with MG and whether they had undergone a kidney biopsy. In a more select group of patients with MG from 2017 to 2018, we conducted a review of records to determine how many had underlying CKD, which of those with CKD had undergone a kidney biopsy, and reasons for deferring a kidney biopsy. RESULTS: Between 2013 and 2018, we identified 6300 patients who had MG, 160 (2.5%) of whom had undergone a kidney biopsy. Of the 160 patients, 64 (40%) had an MGRS lesion; amyloid light chain amyloidosis, the most common finding, accounted for nearly half of these lesions. In the non-MGRS group comprising 96 patients, 23 had arteriosclerosis, the most common finding. In multivariate analysis, strong predictors of finding an MGRS lesion included the presence of an elevated free light chain ratio, proteinuria, and hematuria. Among 596 patients with CKD and MG from 2017 to 2018, 62 (10.4%) underwent a kidney biopsy. Kidney biopsy was deferred for 70 patients (20%); for 62 of the 70, the diagnosis was already known, and eight were not candidates for therapy. Younger age and higher proteinuria and serum creatinine levels increased the likelihood that the patient would undergo a kidney biopsy. CONCLUSIONS: Proteinuria ≥1.5 g/d, hematuria, and an elevated free light chain ratio increase the likelihood of finding MGRS, and a kidney biopsy should be highly considered in such patients.

DNAJB9-positive monotypic fibrillary glomerulonephritis is not associated with monoclonal gammopathy in the vast majority of patients.

The association of fibrillary glomerulonephritis (FGN) with monoclonal gammopathy has been controversial, although monotypic FGN is currently classified as a monoclonal gammopathy of renal significance (MGRS) lesion. To define this lesion, we correlated findings by immunofluorescence on frozen and paraffin tissue, IgG subtype staining and serum protein electrophoresis with immunofixation in patients with monotypic FGN. Immunofluorescence was performed on paraffin sections from 35 cases of DNAJB9-associated FGN that showed apparent light chain restriction of glomerular IgG deposits by standard immunofluorescence on frozen tissue. On paraffin immunofluorescence, 15 cases (14 lambda and one kappa restricted cases on frozen tissue immunofluorescence) showed no light chain restriction, 19 showed similar light chain restriction, and one was negative for both light chains. Seven of the 15 cases with masked polyclonal deposits also had IgG subclass restriction and these cases would have been diagnosed as a form of monoclonal protein-associated glomerulonephritis if paraffin immunofluorescence was not performed. Monotypic FGN (confirmed by paraffin immunofluorescence and IgG subclass restriction) accounted for only one of 151 (0.7%) patients with FGN encountered during the last two years. Only one of 11 of cases had a detectable circulating monoclonal protein on serum protein electrophoresis with immunofixation. We propose that paraffin immunofluorescence is required to make the diagnosis of lambda-restricted monotypic FGN as it unmasked polytypic deposits in over half of patients. When confirmed by paraffin immunofluorescence and IgG subclass staining, DNAJB9-positive monotypic FGN is very rare and is not associated with monoclonal gammopathy in the vast majority of patients. Thus, there is a question whether this lesion should be included in MGRS-related diseases.

Light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits is associated with a high detection rate of the pathogenic plasma cell clone.

IgG (mainly IgG3) is the most commonly involved isotype in proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID). Here we describe the first series of PGNMID with deposition of monoclonal immunoglobulin light chain only (PGNMID-light chain). This multicenter cohort of 17 patients presented with nephritic or nephrotic syndrome with underlying hematologic conditions of monoclonal gammopathy of renal significance (71%) or multiple myeloma (29%). Monoclonal immunoglobulin was identified by serum and urine immunofixation in 65% and 73%, respectively, with abnormal serum free light chain in 83%, and a detectable bone marrow plasma cell clone in 88% of patients. Renal biopsy showed a membranoproliferative pattern in most patients. By immunofluorescence, deposits were restricted to glomeruli and composed of restricted light chain (kappa in 71%) and C3, with granular appearance and subendothelial, mesangial and subepithelial distribution by electron microscopy. Proteomic analysis in four cases of kappa PGNMID-light chain revealed spectra for kappa constant and variable domains, without evidence of Ig heavy chains; spectra for proteins of the alternative pathway of complement and terminal complex were detected in three. The classical pathway was not detected in three cases. After median follow up of 70 months, the renal response was dependent on a hematologic response and occurred in six of ten patients treated with plasma cell-directed chemotherapy but none of five patients receiving other therapies. Thus, PGNMID-light chain differs from PGNMID-IgG by higher frequency of a detectable pathogenic plasma cell clone. Hence, proper recognition is crucial as anti-myeloma agents may improve renal prognosis. Activation of an alternative pathway of complement by monoclonal immunoglobulin light chain likely plays a role in its pathogenesis.

Heavy Chain Deposition Disease: Clinicopathologic Characteristics of a Chinese Case Series.

RATIONALE & OBJECTIVE: Heavy chain deposition disease (HCDD) is a rare consequence of monoclonal immunoglobulin deposition disease that has not been well characterized in non-white populations. To explore the clinicopathologic characteristics and outcomes of HCDD in Chinese individuals, we report on a case series assembled in a single center in China. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 25 patients with biopsy-proven HCDD were studied retrospectively. RESULTS: 14 men and 11 women with an average age of 50.3 years were studied. The patients presented with hypertension (76%), edema (96%), anemia (84%), serum creatinine level > 1.2mg/dL (68%), nephrotic-range proteinuria (56%), and microscopic hematuria (80%). One (4%) patient had multiple myeloma diagnosed. Serum immunofixation electrophoresis showed that 10 of 21 (48%) patients were positive for monoclonal immunoglobulin. Hypocomplementemia of C3 was found in 68% of patients. Nodular mesangial sclerosis was identified in all patients by using light microscopy. Using immunofluorescence, all 25 patients had deposition of heavy chains of immunoglobulin G class (γ1, 13; γ2, 2; γ3, 6; γ4, 2; γ1 and γ4, 1; and γ2 and γ4, 1). During an average of 40.1 months of follow-up of 20 patients, 65% had improved kidney function, 10% had worsening kidney function, and 25% progressed to kidney failure. Mean values for kidney and patient survival were 37.8 and 40.1 months, respectively. Kidney survival was higher among patients who received chemotherapy. LIMITATIONS: Retrospective study, single-center experience. CONCLUSIONS: In this case series of HCDD in a single center in China, the heavy chain deposits seen in the kidney biopies of all individuals were of immunoglobulin G class. Chemotherapy improved kidney function, especially among individuals in an early stage of the disease.

Renal pathologic spectrum and clinical outcome of monoclonal gammopathy of renal significance: A large retrospective case series study from a single institute in China.

OBJECTIVES: To analysis the pathological spectrum and prognosis of monoclonal gammopathy of renal significance (MGRS) patients. METHODS: Patients with renal biopsy-proven MGRS from 1999 to 2017 in Peking University First Hospital were included, clinical data, renal pathology type, treatment and prognosis were collected. RESULTS: One hundred and eighty-seven patients were enrolled, accounting for 0.7% of renal biopsies. Seventy-seven per cent of the MGRS patients were amyloidosis. Eighteen patients (9.6%) were monoclonal immunoglobulin deposition disease. Others included 10 patients (5.3%) with proliferative glomerulonephritis with monoclonal immunoglobulin (G) deposits, seven patients (3.7%) with cryoglobulinaemic glomerulonephritis, five patients (2.6%) with light chain proximal tubulopathy, two patients (1.1%) with fibrillary disease and one patient (0.5%) with C3 glomerulonephritis. Sixty-three per cent were treated with chemotherapy and/or stem cell transplantation. The mean follow-up time was 27 ± 32 months. One patient developed multiple myeloma at 17-month during follow-up. At the end of follow-up, 61 patients (33%) died, and 47 patients (25%) reached end-stage renal disease (ESRD). For the 144 amyloid patients, low estimated glomerular filtration rate (eGFR), decreased blood pressure, presence of cardiac involvement and absence of chemotherapy or high-dose melphalan/autologous peripheral blood stem cell transplantation were identified as independent risk factors for death. Low eGFR, decreased blood pressure, and presence of cardiac involvement were identified as independent risk factors for ESRD. For the 43 non-amyloid patients, no factor was identified for the risk of death. Low eGFR was identified as independent risk factor for ESRD. CONCLUSION: MGRS was an uncommon form of hematologic disorder related renal injury with a wide spectrum of pathologic lesions, and amyloidosis was the most common type. Treatment with chemotherapy and/or high-dose melphalan/autologous peripheral blood stem cell transplantation improved amyloid patients' survival.

A diagnostician's field guide to crystalline nephropathies.

The kidney's role in filtration of blood and production of urine occurs via a combination of size and charge filtration at the glomerular basement membrane and resorption and excretion of molecules through a complex tubular system embedded within an ion gradient. This delicate system provides the kidney with a unique propensity for substrate saturation and crystal nucleation within the nephron. While crystalline nephropathies may seem exotic to the uninitiated, they are comprised of easily recognizable morphologies and generally lack complicated classification schemas. Additionally, unlike many intrinsic kidney diseases, crystalline nephropathies are often associated with systemic conditions that, upon further investigation, may elucidate critically important information. This review focuses on practical, diagnostically relevant and high yield information that can be utilized by diagnosticians. Our hope is to equip the reader who reviews renal tissue with a practical toolkit that they feel empowered to use when faced with crystal formation in a kidney biopsy, pre-implantation biopsy, or nephrectomy specimen. Short Abstract The kidney's role in filtration of blood and production of urine provides a unique propensity for substrate saturation and crystal nucleation within the nephron. While crystalline nephropathies may seem exotic to the uninitiated, they are comprised of easily recognizable morphologies and generally lack complicated classification. Additionally, crystalline nephropathies are often associated with systemic conditions that, upon further investigation, may elucidate critically important information.

An uncertainty estimate of the prevalence of stunting in national surveys: the need for better precision.

BACKGROUND: Stunting is determined by using the World Health Organization (WHO) child growth standard which was developed using precise measurements. However, it is unlikely that large scale surveys maintain the same level of rigour and precision when measuring the height of children. The population measure of stunting in children is sensitive to over-dispersion, and the high prevalence of stunting observed in surveys in low and middle-income countries (LMIC) could partly be due to lower measurement precison. OBJECTIVES: To quantify the incongruence in the dispersion of height-for-age in national surveys of < 5 y children, in relation to the standard WHO Multicenter Growth Reference Study (MGRS), and propose a measure of uncertainty in population measures of stunting. METHODS: An uncertainty factor was proposed and measured from the observed incongruence in dispersion of the height-for-age of < 5 y children in the MGRS against carefully matched populations from the Demographic Health Survey of 17 countries ('test datasets', based on the availability of data). This also allowed for the determination of uncertainty-corrected prevalence of stunting (height-for-age Z score < - 2) in < 5 y children. RESULTS: The uncertainty factor was estimated for 17 LMICs. This ranged from 0.9 to 2.1 for Peru and Egypt respectively (reference value 1). As an explicit country example, the dispersion of height-for-age in the Indian National Family Health Survey-4 test dataset was 39% higher than the MGRS study, with an uncertainty factor of 1.39. From this, the uncertainty-adjusted Indian national stunting prevalence estimate reduced to 18.7% from the unadjusted estimate of 36.2%. CONCLUSIONS: This study proposes a robust statistical method to estimate uncertainty in stunting prevalence estimates due to incongruent dispersions of height measured in national surveys for children < 5 years in relation to the WHO height-for-age standard. The uncertainty is partly due to population heterogeneity, but also due to measurement precision, and calls for better quality in these measurements.