Monoclonal immunoglobulin-associated renal diseases can display a wide range of phenotypic variations probably linked to as yet undefined differences in immunoglobulin structure and affinity. One such example is presented.
Clinical and pathological features of the case are presented with a brief review of the literature.
A 55-year-old-man presented with nephrotic syndrome. Urine protein excretion was 10 g/24 h, serum albumin 2,8 g/dL and serum creatinine 1,24 mg/dL. Serum free light chain assay showed elevated κ (426 mg/L) with a κ:λ ratio of 31. Serum protein electrophoresis was normal. Renal biopsy showed diffuse mesangial expansion with glomerular basement membrane (GBM) PAS+ thickening and focal endocapillary hypercellularity. Immunofluorescence revealed strong monoclonal mesangial, GBM and focal tubular basement membrane staining for kappa light chains and moderate to strong glomerular staining for C3. Electron microscopy revealed abundant granular electron dense deposits with massive thickening of GBM by peculiar subendothelial deposits giving scalloped borders to its inner contour.
A diagnosis of kappa light chain deposition disease with atypical features is favored. C3 positivity and ultrastructural appearance are unusual, but similar to a case previously reported in the literature1. C3 positivity despite absence of evidence of a heavy chain component could potentially be explained by alternative complement pathway dysregulation by the monoclonal immunoglobulin. Focal tubular basement membrane staining is another particularity of this case.
Reference: 1SALANT, SANCHORAWALA & D'AGATI (2007). A case of atypical light chain deposition disease—diagnosis and treatment. CJASN, 2(4), 858-867.
Introduction: The utility of a repeat kidney biopsy in AL amyloidosis patients with worsening renal function and/or proteinuria after achievement of hematologic response to treatment is not clear.
Methods: We present 8 patients who were followed at the Amyloidosis Center at Boston University in whom a repeat kidney biopsy was performed.
Results: AL amyloidosis was diagnosed by a kidney biopsy. All patients had either complete or very good partial hematologic response to treatment directed against plasma cell dyscrasia, and 5 of them had renal organ response (stabilization or improvement of renal function and >30% decrease in proteinuria). Repeat biopsy was done after a median time of 4.3 years (range, 2.4-11.3) due to deterioration in kidney function and/or worsening of proteinuria, in the setting of continued hematologic response. All repeat biopsies showed findings consistent with amyloid deposits. Seven patients had renal progression with 4 of them requiring dialysis initiation. One patient who had subacute kidney injury with pyuria and white cells casts was found to have granulomatous interstitial nephritis due to sarcoidosis in addition to amyloid deposition and responded to steroid treatment.
Conclusions: Amyloid deposits persist in the kidneys even after successful hematologic treatment and organ response, and differentiation between new versus old amyloid deposits is impossible. A repeat kidney biopsy is therefore not helpful in most cases, as it does not aid in the management. A kidney biopsy should, however, be considered when a specific alternative diagnosis is suspected based on relevant new clinical, laboratory or urine findings.
Monoclonal gammopathies of clinical significance are commonly characterized by small plasma cells (PC) clones with low proliferation rates and high sensitivity to proteasome inhibitors. We hypothesize that the nature of the pathogenic monoclonal Ig produced by the PC clone could account for these peculiarities. Therefore, this project aims to explore its direct effects exert on PCs proliferation and the therapeutic potential of targeting Ig in PC dyscrasias, using an inducible PC-specific mouse model.
We created a conditional deleter mouse model using a Tamoxifen-dependent CRE recombinase under the control of the regulatory elements of a gene (J chain) exclusively expressed in PCs. These mice were crossed with another mouse strain producing a human γ1 heavy chain (HC) containing LoxP sites flanking the CH1 domain (Bonaud et al., 2015). Tamoxifen induction led to the production of a truncated HC exclusively in PCs.
Results and Conclusion
In the first ex vivo tests, PC population decreased drastically after hydroxytamoxifen treatment. Therefore, inducing an abnormal Ig causes deleterious stress in already differentiated PCs. In vivo, we will analyse the precise mechanism involved in PC cell death. This proof of concept of Ig-induced PC death has direct implications in the treatment of PC dyscrasias. The laboratory develops antisense oligonucleotides-based therapy to force CH1 exon skipping to generate Igs toxic to the cell (Ashi et al., 2018). Additionally, we work on other models of pathogenic Ig (AL amyloidosis and LCDD) to confirm and better understand the direct toxicity of such abnormal Ig on PCs.
A 33 year-old woman presented in March 2010 a nephrotic syndrome with normal renal function and hypocomplementemia. Serum immunofixation/immunoblot revealed a small IgG1κ and free κ. Immunoblot detected also a truncated γ1 heavy chain with a total deletion of VH domain by cDNA analysis. Bone marrow showed 6% plasma cells and two clonal lymphoid populations (γκ and γλ). Renal biopsy showed a pattern consistent with FGN, with positive staining for anti-γ, γ1, κ, λ, C3 and C1q conjugates. Congo-red staining was faintly positive. EM showed amyloid fibrils mean 10 nm in diameter negative for anti-DNAJB9. A splenectomy for hematoma in January 2014 showed lymphocytic lymphoma with plasmacytic differentiation. After four lines of chemotherapy, serum/urine immunofixation was negative but nephrotic syndrome and hypocomplementemia persisted. A second kidney biopsy showed persistent glomerular deposits with strong positivity for anti-λ (+++) and faintly positivity for anti-γ and γ1 (+) conjugates. Tumoral lymphocytic and plasmacytic interstitial infiltrates were present. ASCT was performed in August 2014. Six months later, nephrotic syndrome disappeared, complement was normal, serum/urine immunofixation was negative and FLC ratio was normal.
This case highlights the difficulties in the diagnosis of amyloidosis with sometimes false positivity due to trapping of a nonamyloidogenic protein. In our case, IgG1κ was trapped in AL-λ deposits and could suggest FGN or AHL deposits. When IgG1κ disappeared, amyloid deposits were predominantly positive for anti-λ conjugate. Whether or not the trapped component(s) could be detected with small or large spectra by LMD/MS based proteomic analysis need to be studied.
Background: Bone marrow biopsy is the method of choice for follow up/diagnosis of patients with hematologic disorders including those associated with immunoglobulin monoclonal tissue deposits. Detection of amyloid deposits in the bone marrow can be the first evidence of concurrent amyloidosis. Majority of bone marrow reports merely describe the presence or absence of amyloid and do not specify its precise location.
Methods: we reviewed 775 bone marrow reports and identified 79 cases (10%) that were positive for amyloid by Congo red stain. In 19 cases slides were no longer available for review, in 65 cases the location and type of amyloid deposits was recorded. Clinico-pathologic correlation was performed.
Results: among 79 cases 71 cases (89%) had AL amyloidosis while 2 cases had AA and 2 cases
had ATTR amyloidosis; 4 cases had insufficient data. Deposits were located in the stroma, vessel wall and/or extramedullary soft tissue in 20 and 45 cases respectively. Non-AL deposits were extramedullary while in AL deposits could be seen in any of the compartments.
Conclusions: amyloid deposits in the bone marrow specimens are not always AL and medullary amyloid deposits are rarer than extramedullary deposits and hence attention to the periosseous soft tissue may increase the yield of detection of amyloid.
We know that the incidence of monoclonal gammopathy is higher among patients with autoimmune diseases. Also, the coexistence of primary Sjögren's syndrome and sarcoidosis has been well documented in previous studies. However, to our knowledge, the present case is the first describing both isolated IgM Lambda monoclonal plasmacytic renal infiltration and Sarcoidosis-Sjogren’s overlap syndrome.
Our patient, a 70-year-old woman was referred for xerostomia, xerophthalmia and Raynaud's syndrome for the past 6 months. The autoimmune assessment showed a positive ANA> 1:320 and anti-DNA = 725. The anti-Ro and anti-La were negative.
Over the same period, the patient presented a rapidly progressive renal failure, with a serum creatinine passing from 60 to 159 μmol/L.
We performed a renal biopsy, which showed a predominantly monotypic IgM Lambda plasmocytic infiltrate over the interstitium; and, surprisingly, the bone marrow biopsy was completely normal.
After discovering hypermetabolic mediastinal-hilar lymph nodes and ground-glass opacities at the scan, the pulmonary biopsy showed the presence of sarcoidosis.
Because of sicca symptoms relapse upon prednisolone therapy withdraw, we performed a salivary gland biopsy that showed grade 2 lymphocytic sialadenitis.
The current histopathologic diagnosis is an isolated IgM Lambda plasmacytic infiltration of the kidney in the setting of a Sarcoidosis-Sjogren's overlap syndrome.
According to recent studies, our best hypothesis is that inflammation occurring in autoimmune conditions drives germinal center formation in ectopic sites, in our case, the kidney; and that the large amount of autoantigen, such as dsDNA, creates an environment leading to B-cells hypermutation and differentiation into monoclonal plasma cells.
Background: Recent studies identified DNAJB9 as specific tissue biomarker for fibrillary GN (FGN).To date, no study has evaluated risk of recurrence of DNAJB9 positive FGN.
Methods: 19 transplant patients with diagnosis of FGN or microfibrillary GN were reviewed.15 patients fulfilled criteria for inclusion (positive DNAJB9 and/or typical IF/EM features on native biopsy). Recurrence (rFGN) was defined by positive DNAJB9 allograft staining. Clinico-pathological characteristics and outcomes were compared.
Results: 4 patients recurred. Median time to recurrence was 10.1y (range 0.9-10.5),median proteinuria 170.5 mg & iothalamate clearance 58.5 ml/min at time of recurrence.Median follow-up time was 5.3y (range 0.3-14). Compared to non-recurrent, rFGN had longer follow-up (12.5 vs 5.6 y, p=0.02).No statistically significant difference was noted between groups regarding age, gender, transplant type, HLA mismatches, induction/maintenance therapy. 3 patients had circulating monoclonal protein (2 MGUS, 1 PTLD).No patient with rFGN had monoclonal protein detected in blood or urine. A mesangioproliferative pattern of injury was seen in all four cases. DNAJB9 staining detected very early recurrence in one case with minimal light microscopic changes.Only 1 rFGN patient lost allograft:this was in setting of recurrence noted at 10.5 y & lost at 14 y post-tx. 4/11 non-recurrent (36.4%) failed (complication of sepsis or malignancy).By Cox regression analysis for time dependent covariate,HR for death censored graft loss was not statistically different in recurrent vs non recurrent FGN (HR 0.63, p=0.74).
Conclusion:DNAJB9 positive fibrillary GN has an indolent course of recurrence post-transplant, with late recurrence. In DNAJB9+ FGN, circulating monoclonal protein did not associate with recurrence.
Background: Light chain proximal tubulopathy (LCPT) is characterized by crystalline or noncrystalline cytoplasmic inclusions of monoclonal light chains within proximal tubules. The clinical significance of crystalline versus noncrystalline LCPT remains unknown.
Methods: The clinicopathological characteristics of 17 crystalline and 9 noncrystalline LCPTs diagnosed based on renal biopsies in our institution were retrospectively analyzed.
Results: The LCPT patients included 19 males and 7 females, with an average age of 54 years (range 40-79). They presented with acute (4%) or chronic kidney diseases (96%), proteinuria , hematuria (46%) and Fanconi syndrome (FS, 68%), with hematologic disorders of 18 monoclonal gammopathy of renal significance (MGRS) and 8 MM. All 17 crystalline LCPTs were κ-restricted, 56% of noncrystalline LCPTs displayed λ-restricted. Compared with noncrystalline LCPT, the crystalline LCPTs presented with higher proteinuria and serum creatinine, higher incidence of FS, lower incidence of MM and more severe acute tubular injury than that of noncrystalline LCPT, but there was no significant difference between two groups. Furthermore, crystal-storing histiocytosis (CSH) were found in 29% of crystalline LCPT, whereas light chain cast nephropathy (LCCN) were coexisted with higher frequency in noncrystalline LCPT (22%) than crystalline LCPT (6%). Patients of LCPT coexisted with LCCN and CSH exhibited more severe renal insufficiency, tubular atrophy and interstitial fibrosis as compared with other LCPT patients.
Conclusion: Crystalline LCPT tended to display more severe clinicopathological features than that of noncrystalline LCPT. The coexistence of LCCN and CSH with LCPT may predict poor prognosis.
Background: Progress in treatment of systemic amyloidoses has created the need for defining organ specific involvement. Hence, not only the presence but also the location of deposits in various organs has been included in the definition of organ involvement, except in the bone marrow specimens.
Methods: 65 bone marrow biopsies reported as positive for amyloid were retrospectively reviewed and the location of amyloid deposits was recorded and correlated with amyloid type.
Results and conclusion: amyloid deposits were located in the vessel wall, marrow stroma, periosteal soft tissue as well as combination of these locations. Stromal deposits were seen in 20 cases while non-stromal deposits in 45 cases. In the non-AL cases (n= 4) amyloid was seen only in the extramedullary location while in AL cases deposits were seen in medullary stroma and/or in extramedullary location.
There is significant heterogeneity of amyloid distribution in AL with extramedullary/periosseous amyloid deposits being more frequent than medullary.
Although AL is the most common type of amyloid in the bone marrow specimens, non-AL can also be detected, especially if the deposits are limited to the vessel wall or extramedullary soft tissue.
Our data suggests that the definition of bone marrow involvement in systemic AL should be limited to stromal (medullary) involvement (with or without other sites) while extramedullary deposits should be reported as soft tissue involvement.
Heavy chain deposition disease (HCDD) is a rare disorder characterized by the deposition of a truncated heavy chain (HC) mainly in the kidney. We are trying to decipher the early events leading to the production of a truncated HC by the plasma cell (PC) clone.
We performed the complete sequencing of the Ig genes in a patient with HCDD and generated a cellular model allowing us to decipher the molecular events leading to the production of HC chain only by PC. To deepen our studies, we generated a new mouse model with an inducible LC deletion in PC.
Beside the truncated HC, the PC clone in the patient produced a truncated light chain (LC). LC and HC co-transfection experiments showed that this truncated LC could not associate with the full-length reconstituted HC and that the deletion of the HC CH1 domain relieved the endoplasmic reticulum stress induced by the full-length HC. We hypothesized that the LC deletion is the first genetic event in HCDD enforcing the subsequent CH1 deletion that favors PC survival. To confirm this assumption, we have now created a new mouse model in which we are able to induce the deletion of the LC specifically in PC.
Thanks to the complete analysis of the Ig genes in a HCDD patient, we hypothesize that deletion of the LC arises first and then lead to the generation of a truncated HC. We have now developed a new mouse model that could confirm this hypothesis.
Multiple myeloma (MM) has one of the longest pathways to diagnosis of any cancer in the UK. Patients presenting with acute kidney injury (AKI) require prompt diagnosis and treatment to prevent long term kidney dysfunction. We reviewed the diagnostic pathway in newly diagnosed myeloma patients with AKI at two tertiary centres in the UK.
All patients who presented to the two centres with AKI (any stage) and a serum free light chain concentration (sFLC) >=500 mg/l from 1 April 2015 to 31 Dec 2017, were included in the study. A total of 77 patients were identified, patients known to have MM were excluded. Both centres identified 28 patients.
The median time to; sFLC request was 1 day, treatment with dexamethasone was 5 days and for a bone marrow biopsy was 6 days. The timing of treatment with dexamethasone in relation to bone marrow aspirate was varied in the two centres.
An early re audit at one centre has shown improvement in the median time to dexamethasone at 2.5 days.
The results from the two centres are similar suggesting that they are representative of the investigation and management pathways in large hospital trusts, both hospitals have on site sFLC testing and smaller hospitals may well incur an even longer time to diagnosis. Delays occur throughout the pathway; from requesting sFLC to delay in anti-myeloma therapy. The main delay often is related to patients being directed to the correct specialty for disease specific management.
Monoclonal gammopathy of renal significance (MGSR)-related lesions are infrequent entities. There are no reported data on these disorders in Latin America (LA).
The aim of this study was to describe epidemiological and clinical characteristics of these patients in LA.
Multicentric retrospective study. Patients with diagnosis of MGRS between 2012 and 2018 according to the current definition were included. Epidemiological and clinical data were collected from clinical records.
Twenty-six patients from Chile, Argentina, Ecuador and Uruguay were included. Half debuted with a nephrotic syndrome, and 35% requiered dyalisis. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMD) was found in 31%, amyloidosis in 27%, and light chain deposition disease (LCDD) in 23%. The immunoglobulin most frequently found in renal biopsies was IgG Kappa. In 62% paraprotein was found. Seventeen received an anti-plasma cell regimen, and 3 a rituximab-based regimen (IgM-MGRS). Renal response was achieved in 58%. Early treatment (≤ 3months) was asociated with higher renal responses (83% vs 38%). Three patients relapsed within 21,5 months, and 3 progressed: 1 to multiple myeloma, 1 to systemic amyloidosis and another to systemic LCDD. Two patients died, both due infection during tratment.
There was a higher than expected frequency of patients requiring dialysis. The most common MGRS-related lesion was PGNMD. More than half of patients achieved renal responses, especially those who receive early treatment, which reinforces the need of prompt treatment. Increasing awareness is therefore crucial.
INTRODUCTION. Excessive endocytosis of free light chains (FLC) in proximal tubule cells (PTC) activates cell stress responses and inflammatory pathways resulting in injury. The role of innate-immunity mediated by toll-like receptors (TLRs) in FLC-associated kidney injury (KI) has not been previously explored.
METHODS. Human kidney PTC cultures were exposed to six different κ and λ FLCs isolated from the urine of multiple myeloma patients. Pooled-siRNAs were used to silence specific genes. ELISA, qPCR, western blotting and immunocytochemistry were done to analyze gene/protein expressions in FLCs-exposed PTCs. Data were analyzed using one-way ANOVA with post-hoc Tukey test.
RESULTS. Both κ and λ FLCs induced TNFα, IL6 secretion and suppressed proliferation of PTCs in a dose/time-dependent manner. Along with known KI biomarkers (LCN2, KIM1), FLCs upregulated the expression of pro-inflammatory cytokines (TNFα, IL6 and IL1β), TLR-2/4/6 and their adapter proteins MYD88/TRIF. Silencing TLR-2/4/6 decreased FLC induced TNFα expression in PTCs. FLC exposure also induced HMGB1 secretion, a known activator of TLR-2/4. In-vitro HMGB1 expression modulation through extracellular HMGB1 (overexpression) and HMGB1-siRNA (knock-down) regulated expressions of TLR-2/4 suggesting HMGB1 as a likely candidate damage-associated molecular pattern (DAMP) activating TLR-2/4 in FLC-exposed PTCs. Knocking-down megalin, cubilin complexes with siRNAs or using endocytosis inhibitors like Bafilomycin A1, hypertonic sucrose solution provided alternative strategies to block endocytosis of FLCs and prevent PTC injury.
CONCLUSION: PTCs exposed to FLCs release HMGB1, which induces TLR-2/4 expressions and downstream inflammation leading to KI. Maneuvers to block FLCs’ Endocytosis, HMGB1 inhibition or TLR-2/4/6 knock-down rescue PTCs from FLC-induced injury.
Background: Epigallocatechin-3-gallate (EGC3G) can inhibit the amyloid aggregation of the light chains (LC) by direct interaction with the protein. and the treatment of mesangial cells (MCs) with amyloidogenic LC results in aggregation of the protein into fibrils in the lysosomal compartment. In this study we show that EGC3G can interfere with LC amyloidogenesis by stabilizing a non-amyloidogenic conformation of the LC and by inhibiting a MCs signaling pathway linked to both phenotypic transformation and intracellular amyloid formation in lysosomes.
Methods: Inhibitory activity of EGC3G was determined in a thioflavin-based fibrillogenesis assay with the lambda-6 light chain variable domain protein 6aJL2. Conformational changes of 6aJL2 caused by interaction with EGC3G were evaluated in dot-blot assays. The inhibitory activity of EGC3G on the amyloidogenesis of LC in MCs was performed in cell culture, ex-vivo kidney perfusion model.
Results: EGC3G inhibited the in vitro fibrillogenesis of the lambda-6 protein 6aJL2. After incubation with AL-LC and ex-vivo kidney experiment, fibrillar aggregates were observed in mesangial areas and c-fos was translocated into nuclei. In EGC3G treated group,c-fos translocation was inhibited and intracellular amyloid fibril formation significantly decreased.
Conclusion: The amyloid aggregation of light chain in kidney can be inhibited by ECG3G by two different mechanisms. One of them is the stabilization of the amyloid precursor in a conformer not apt to aggregate into fibrils. The second depends on the inhibition of the c-fos cytoplasm-to-nuclei translocation of in MCs.
Background: Seventy percent of patients with light chain (AL) amyloidosis present with renal involvement. The phases of the disease include asymptomatic seeding, increasing proteinuria, and progression to end stage renal disease. In an attempt to identify genes relevant to renal reprogramming due to persistent disease,renal biopsies from treated AL patients were obtained for systematic histologic evaluation and transcriptional profiling. Correlates were sought between these two approaches. Methods: Renal biopsies from 10 patients with persistent proteinuria following hematologic responses to anti-plasma cell therapy were scored independently by 2 renal pathologists employing a novel histologic tool that assessed scarring, fibrosis and the distribution of amyloid, and were successfully evaluated by transcriptional profiling in the Michigan Kidney Translational Medicine Core lab. Clinical data and histologic scores (CSIC = composite scarring injury score, AS = amyloid score) were correlated to the expression profiles of specific tubular and glomerular gene sets. Results:Baseline characteristics and histologic scores are in Table 1. Using a false discovery rate corrected P-value of < 0.10, numerous genes of interest were identified (Table 2). Transcriptional profiling revealed 2 distinct patient clusters within the tubular and glomerular gene expression sets. Conclusion: This effort has generated multiple genes of interest.ICQD, NMRK2 and PODXL, in particular, correlated with the distribution of amyloid in the capillaries and mesangium. We are currently comparing these expression profiles to those of other nephropathies to identify genes whose expression levels may be specific to AL nephropathy, hopefully leading to further novel histologic and protein-based investigations.
BACKGROUND: Due to existing differences among the diverse healthcare institutions in Mexico, the approach and management of the patients with renal diseases associated with monoclonal gammopathies has been poorly defined, including the most frequent patterns of histological damage in kidney biopsies.
METHODS: We reviewed registries of kidney biopsies referred to Hospital General de México and Instituto Nacional de Cardiologia. Both receive kidney biopsies from institutions with no renal pathologist available.
RESULTS: We found 129 kidney biopsy reports with histological findings in agreement with monoclonal protein deposition. Those reports belong to 129 different patients, 58% are men, ages 21 to 85 years, median age of 56.5 +/- 11.86 years. The main histological patterns found were: light chain amyloidosis (LCA) in 49.6%, cast nephropathy (CN) in 29.5%, monoclonal immunoglobulin deposition disease (MIDD) in 11.6%, proliferative glomerulonephritis with monoclonal Ig deposits (PGMID) in 5.4%, tubulointerstitial nephritis in 2.3%, immunotactoid glomerulonephritis in 0.8% and fibrillary glomerulonephritis in 0.8%. The specificity of the light chain deposition was found to be kappa in 16.3% of the cases and lambda in 83.7% of cases.
Median fibrosis grade for the patients with LCA was grade 0-I, for patients with CN was grade II, and for patients with MIDD or PGMID was grade III.
CONCLUSIONS: In our population, LCA accounts for half of the patients with a kidney biopsy reporting monoclonal protein deposition. The assembly of histological and clinical information is the first step towards a consensus on the local options available to treat these patients.
Monoclonal LC can form fibrillar or non-fibrillar renal deposits in the two most common MGRS: AL amyloidosis and LCDD, respectively. LCDD is rare and few small case series have been reported so far, while renal outcome in AL amyloidosis is better known.
We compared two consecutive series of LCDD [N=74: 61 Pavia, 8 Padova (Italy) and 5 Calgary (Canada)] and renal AL amyloidosis (N=207 from Pavia). Only stage I non-cardiac amyloidosis patients were included in order to avoid the confounding effect of heart involvement.
Patients with LCDD were younger (median age 56 vs. 62 years, P<0.001) and had more advanced renal dysfunction (median eGFR 32 vs. 70 mL/min, P<0.001) with lower proteinuria (2.6 vs. 6.2 g/24h, P<0.001). As expected k-LC type was more frequent in LCDD (85 vs. 23%, P<0.001). Median BMPC infiltrate was 10% in both groups, but dFLC was significantly higher in LCDD (90 vs. 75 mg/L, P<0.001) probably reflecting differences in involved isotype and eGFR. Time to dialysis was longer in AL amyloidosis (median not-reached vs. 9 years, P<0.001). Forty-two (20%) patients required dialysis in the AL-group and 32 (43%) in the LCDD-cohort (P<0.001). In AL amyloidosis the proteinuria/eGFR staging system predicted renal survival, whereas in LCDD patients eGFR (best cutoff 30 mL/min [HR 5.3, P<0.001]) but not proteinuria predicted dialysis. Obtaining ≥VGPR was associated with prolonged renal survival in both groups.
In LCDD proteinuria is less prominent than in AL amyloidosis and does not predict renal outcome. Treatment should be aimed at obtaining VGPR or better.
Background: Light chain proximal tubulopathy (LCPT) is characterized by clinical and pathologic signs of proximal tubular injury caused by monoclonal LC. LCPT is associated with MGUS or smoldering myeloma, but may also coexist with overt myeloma and other forms of dysproteinemia-related renal disease. Typical features of isolated LCPT include Fanconi syndrome, chronic renal insufficiency, and mild proteinuria. Pathologic findings include crystalline or noncrystalline monotypic LC inclusions in proximal tubules, with variable features of acute tubular injury and/or acute interstitial nephritis. There are currently no evidence-based managment guidelines, reflecting the rarity and clinical-pathologic heterogeneity of this condition, and the absence of a consensus definition.
Methods: LCPT cases will be requested from IKMG members for clinical-pathologic correlation. Digitized pathologic images will be reviewed and graded. Inclusion criteria include: (1) LCPT with isotype restricted LC within proximal tubule epithelium; (2) Available data on renal and proximal tubule function. Clinical outcomes examined will include effect of chemotherapy on renal and hematological parameters, tolerance, renal and patient survival. Molecular studies on bone marrow RNA will be performed in a subset of cases.
Conclusion: This IKMG-sponsored study will define the spectrum of LCPT by comprehensive clinical and pathological correlation, and help identify specific molecular characteristics of mLC that contribute to FS and pathogenesis if LCPT.
First line treatment of systemic non IgM AL amyloidosis is well defined but at relapse there are no precise guidelines. Here we report a multicenter retrospective study assessing treatment at relapse and evaluating their impact on hematologic and organ responses, progression-free survival (PFS), and overall survival (OS). We included 108 patients who received, as first line treatment, a conventional chemotherapy. At diagnosis, 60% of patients had heart (all Mayo Clinic stages) and kidney involvement. At relapse, 52% of patients received a 3 drug-combination resulting in 68% of very good partial response (VGPR) or better, 30% of organ response, an estimated median PFS and OS at 15 and 63 months whereas 12 and 46 months for patients receiving a 2-drug regimen (p=0,033 and p=0,41 respectively). Fifty five percent of patients received a proteasome inhibitor (PI) resulting in 73% of VGPR or better, 26% of organ response, an estimated 17 months median PFS and 9 months for other treatments (p=0,0001). Immunomodulatory drugs (IMIDs) seem to be associated with lower response rates and median PFS or OS, excepted with the bortezomib, lenalidomide and dexamethasone combination (VRD) resulting in 67% of VGPR or better, and 55% of organ response, with all patients except one being alive at 3 years, without more grade 3/4 adverse events compared to bitherapy by lenalidomide dexamethasone. In conclusion, patients at relapse are still sensitive to treatment. A tritherapy including a PI seems to be more effective to obtain a high rate of deep hematologic responses.
Background: Glomerulopathic light-chain (G-LC) induced glomerular damage could hardly be reversed. This study is to further facilitate the HMSCs ability to repair the G-LC induce mesangium damage by modifying the Cell Culture Environment.
Method: HMCs and HMSCs were cultured with medium either glucose or Betahydroxybutyrate under room temperature condition or incubator condition. HMCs were first treated with G-LC and then with or without HMSCs. HMCs and/or HMSCs (GFP labeled) were video recorded for up to 22 days of the treatment and the ultrastructural morphology were identified with electron transmit microscope (TEM) at the end of experiment. Culture medium in different time spot were tasted for the LDH as the cell toxicity index.
Result: LDH test showed that LDH of all groups under the room temperature condition were lower than that under the incubator temperature conditions. All groups of the medium with ketone but without glucose showed much higher LDH level than that of the ones with glucose. LDH were also higher in the D22 than that in D12. Both live cell imaging and TEM showed that the apoptogenic environment could cause the G-LC treated HMCs have more apoptosis and the extra cellular matrix (ECM) is more likely dissolved with the HMSCs treatment.
Conclusion: This study showed that by changing the incubation condition that enhance the apoptosis in the HMCs would facilitate the repair and remodeling of the HMSCs for the G-LC induced mesangium damage.
Background: Monoclonal gammopathy of renal significance (MGRS) describes a subtype of patients with monoclonal gammopathy of unknown significance (MGUS) who have kidney disease due to immunoglobulin deposition. Early identification of MGRS and treatment with chemotherapy can prevent progression to kidney failure. There is limited data on the characteristics of populations with concomitant MGUS and chronic kidney disease (CKD), and on the prevalence of diagnosed MGRS in this population.
Methods: Through retrospective chart review, we identified 246 patients with ICD-9 or -10 codes denoting bothMGUS and chronic kidney disease (CKD) between the years of 2000 and 2017. Patients with related overt malignancies such as multiple myeloma, Waldenstrom’s
macroglobulinemia, and amyloidosis at onset were excluded, leaving 144 evaluable patients.
Results: The median age was 78, and females made up 41.0% of the population. At time of MGUS diagnosis, the median eGFR was 48 mL/min/1.73 m², and in patients with a quantifiable gammopathy, the median M-protein was 0.54 g/dL. A total of 53/144 (36.8%) patients had a bone marrow biopsy and 19/144 (13.2%) underwent kidney biopsy. In 3/144 (2.1%) patients, MGRS was confirmed by kidney biopsy, and in 14/144 (9.8%) patients, MGRS was considered without further workup with kidney biopsy. Ten of (6.9%) the total population and 1 of the 20 (5.0%) patients with possible or confirmed MGRS or other related kidney biopsy findings developed malignant transformation.
Conclusion: MGRS should be considered in patients with MGUS and chronic kidney disease. Based on our findings, we propose an algorithm for workup of suspected MGRS.
Background: MGRS is a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin without meeting hematological criteria for a specific malignancy. M-secreting B-cell lymphoproliferative disorders have been associated with a multitude of kidney diseases, including in the setting of MGRS. We describe an unusual case of M-secreting MGRS presenting with intracapillary monoclonal deposits disease and renal thrombotic microangiopathy (TMA).
Methods: An 86-year-old woman presented with acute renal failure after a few years of uneventful evolution following an IgM MGUS diagnosis. We describe her clinical presentation, workup, treatments and follow-up.
Results: The patient was initially admitted for pneumonia and developed a rapidly progressive acute renal failure requiring dialysis, with proteinuria and clinical signs of TMA, including schistocytes on the peripheral blood smear. Renal biopsy showed numerous intracapillary monotypic IgM-Kappa pseudothrombi associated with TMA changes with multiple intracapillary fibrin thrombi. Hematological investigations confirmed a 2,2g/L monoclonal IgM-Kappa spike. Cryoglobulins were negative. Both C3 and C4 were low. Bone marrow biopsy did not show a lymphoplasmacytic clone, and TEP-scan was negative. These findings are consistent with MGRS related intracapillary monoclonal deposits disease and TMA. This led to an effective treatment incorporating solumedrol, plasmapheresis and clone targeted chemotherapy using rituximab.
Conclusion: Intracapillary monoclonal deposits disease is a well-recognized renal lesion associated with monoclonal IgM gammopathy. It has rarely been described in association with TMA. TMA was recently introduced by the IKMG in the spectrum of MGRS-related renal diseases with a provisional status. This case adds to the growing evidences linking TMA to monoclonal gammopathy.
Monoclonal immunoglobulin deposition disease (MIDD) caused by monoclonal gammopathy of renal significance (MGRS) is a rare glomerular disease. Optimal treatment for most subtypes of MGRS, including MIDD, is not known.
All native renal biopsies performed at the Hammersmith Hospital between 2006 and 2017 were analysed. 12 patients with MGRS with MIDD were identified.
Mean age at presentation was 63, 75% were men, mean eGFR was 34 mL/min/1.73m3and mean uPCR 293 mmol/mol. A circulating paraprotein was detectable in 50%. Four of these patients also had a detectable clone on bone marrow aspiration and trephine (BMAT). In total, nine patients (75%) underwent BMAT, with a plasma cell clone identified in seven (78% of those tested).
All patients with a detectable clone on BMAT underwent clone-directed therapy. One had complete response to treatment, two had partial response and four had no response, with progression to ESRD. One ESRD patient was transplanted post treatment, with no recurrence in the graft. One patient had a circulating paraprotein but no clone on BMAT, and another had a paraprotein but no known BMAT result. These patients both achieved complete remission with clone-directed treatment. Three patients had no circulating paraprotein and no detectable clone; one had progressive renal impairment, one had stabilisation of creatinine but progressive proteinuria, and a third progressed to ESRD.
Treatment remains varied in this population. Further studies are required to establish the safety and efficacy of clone-directed therapy, and to guide early detection and optimal management in patients with MIDD.
Plasma cell disorders (PCD), particularly monoclonal gammopathy of undetermined significance (MGUS), are seen with aging. Patients on chronic immunosuppression after renal transplant can develop post-transplant lymphoproliferative disorder from immune dysregulation. It is unclear if patients are at a risk for PCD. We identified patients at our center with a new diagnosis of a PCD after renal allograft. A total of 71 patients with a preceding renal allograft and on active immunosuppression had a new PCD between 01/01/2014 and 12/31/2018. Of these patients, 59 patients had MGUS, 6 patients with MM, 4 patients with monoclonal gammopathy of renal significance (MGRS), 1 patient with light chain amyloidosis (AL) and 1 patient with extramedullary plasmacytoma (EMP). In the table, we show the characteristics of patients who developed a symptomatic PCD (see attachment). In the final presentation, we will show the characteristics of the entire cohort. We conclude that patients can develop PCD after a renal allograft. Males seem to be at higher risk. This series highlights the need for assessing monoclonal protein studies in patients who develop renal disease after renal transplant and biopsy when indicated. Consideration should be given for screening patients for monoclonal protein studies prior to renal allograft.
Background. Hepatitis C infection (HCV) can lead to the formation of circulating immune complexes, with either a polyclonal rheumatoid factor (RF) (type III cryoglobulins) or a monoclonal RF from a B-cell clone (type II cryoglobulins), that can deposit and cause organ damage. Interferon therapy with or without immunosuppression, direct targeting of clonal B-cells and the physical removal of cryoglobulins with plasma exchanges was once used with varying success due to its inability to eradicate the virus or intolerance to the drug. With the advent of direct-acting antiviral (DAA) treatment, viral eradication in almost all cases of hepatitis C has lowered the risk of cryoglobulinemia.
Results. We present here a case of severe relapsing membranoproliferative cryoglobulinemic glomerulonephritis (GN) despite eradication of HCV. A 47 year-old man presented with a rapidly progressive GN. He initially responded to rituximab and HCV eradication with DAA. When he relapsed, a serum IgM-k M-spike (RF) was newly found, without signs of hematologic malignancy. His disease was resistant to rituximab, cyclophosphamide, bortezomib and bendamustine based regimens. During these treatments, his monoclonal RF remained elevated indicating a B-cell disorder. Interestingly, this monoclonal gammopathy of renal significance was stabilized by chronic plasma exchanges therapy and immunosuppression with high-dose azathioprine, guided by measurements of 6-thioguanine and 6-methylmercaptopurine.
Conclusion. This clinical course highlights the need for nephrologists to familiarize with renal disorders secondary to monoclonal B-cell disorders, different from lymphoma or myeloma, as well as the various potential treatment options once reserved for only hematologists.
A 58 year-old man presented to our institution with acute renal failure and microscopic hematuria. The patient was known for psoriasis, but had no other history of chronic medical conditions or neoplasia. At presentation, serum creatinine was 2.3 mg/dL. Sub-nephrotic range proteinuria (<1g/day) was present in addition to hematuria. Serologies for hepatitis B, hepatitis C and cryoglobulinemia were negative. ANA was positive (titer unavailable), with a decreased serum C3 and normal C4. Serum protein electrophoresis was within normal limits.
Light microscopy revealed a diffuse glomerulonephritis with a membranoproliferative pattern. Interstitial fibrosis and tubular atrophy were mild to moderate. Moderate arteriosclerosis was noted. Direct immunofluorescence revealed strong IgM (3+), C3 (3+) and kappa-restricted (2+) granular deposits along the glomerular basement membrane. The rest of the panel (Lambda, IgG, IgA, C1q) was negative. On electron microscopy, subendothelial pseudo-linear and mesangial electron-dense deposits were noted. They did not show any sub-structure.
A diagnosis of proliferative glomerulonephritis with monoclonal IgM deposits was made. The differential diagnosis includes immunotactoid glomerulopathy and type 1 cryoglobulinemia, but the absence of microtubular deposits on electron microscopy, the absence of hyaline thrombi and negative serology for cryoglobulinemia make these diagnoses unlikely.
Of the 21 cases of proliferative glomerulonephritis with monoclonal IgM deposits reported in the literature, most were associated with MGUS, Waldenstrom’s macroglobulinemia or chronic lymphocytic leukemia. This patient’s clinical work-up was negative for lymphoproliferative disorders. Optimal management of proliferative glomerulonephritis with monoclonal deposits without a lymphoproliferative disorder or paraproteinemia at presentation remains to be explored.
PGNMID is a well-defined entity among monoclonal gammopathy of renal significance. However, with around 100 cases reported in the literature, prognosis and therapeutic management remain poorly described. We reviewed a French cohort of PGNMID with particular focus on hematological characteristics and outcome.
Seventy-one patients (M/F ratio=1.6) with a median age of 59 years were included. At diagnosis, 73% had renal insufficiency (median serum creatinine=146 µmol/L). All patients had proteinuria associated with nephrotic syndrome in 59% and microscopic hematuria in 85% of cases. No patient had extra-renal manifestations. Serum and/or urine immunofixation was positive in 32 cases (46%). Kidney biopsy revealed by light microscopy membranoproliferative glomerulonephritis (74%) or mesangial glomerulonephritis (14%) or membranous glomerulonephritis (12%). By immunofluorescence, deposits stained for IgG in 55 cases (IgG3>>IgG1>IgG2, κ>λ), IgM in 7 cases, IgA in 2 cases or LC only in 7 cases. An underlying B-cell clone was found in 21 cases (30%). The nature of the clone differs according to the type of PGNMID: lympho/plasmacytic in IgM-PGNMID, plasmacytic in IgA- and LC-PGNMID, and more heterogeneous in IgG-PGNMID. When standard techniques failed to detect the clone, the use of high-throughput sequencing assay from mRNA encoding immunoglobulins allowed detection of the clone in only 1/14 patients. Treatment with chemotherapy adapted to the nature of the underlying B-cell clone was associated with better renal outcome.
The clinicopathological features of PGNMID are heterogeneous. Therapeutic management remains challenging, particularly in the absence of B-cell clone detection. More specific tools are needed for better hematological evaluation in these patients.
PGNMID is a rare glomerular disease,most often seen in the context of MGRS. At present, optimal treatment is not established.
All native renal biopsies performed at the Hammersmith Hospital between 2006 and 2017 were analysed. 16 cases of PGNMID were identified. Baseline characteristics and clinical outcomes during follow-up to January 2019 are summarised in Table 1.
Mean age was 62, 31% were men, mean eGFR was 48 mL/min/1.73m2and mean uPCR 442 mmol/mol. A circulating paraprotein was detectable in 5 (31%) of 16 patients. Most (75%) underwent BMAT, with a clone identified in two of 12. One patient had a plasma cell clone and was not immunosuppressed, having presented at end stage with an eGFR of 7 mL/min/1.73m2and 50% IFTA. The second had an eGFR of 83 mL/min/1.73m2and 0% IFTA and had a complete response to prednisolone and rituximab.
Three (19%) patients had a detectable paraprotein but no clonal population on BMAT. Two progressed to ESRD despite steroids, rituximab and cyclophosphamide. One patient initially responded to steroids, MMF, rituximab and bortezomib, but relapsed following cessation of bortezomib due to peripheral neuropathy.
10 of 16 (63%) patients had no detectable paraprotein at diagnosis. Of these, 78% had partial or complete response. Treatment of this group was variable, and one case was lost to follow-up.
Our cohort corroborates the previously-described low rate of detection of circulating paraprotein and pathogenic clones on BMAT. Further studies are required to establish the safety and efficacy of clone-directed therapy, and guide management.
Monoclonal gammopathy of renal significance (MGRS) is a non-malignant hematologic condition causing paraprotein-mediated kidney disease. We recently published our experience using clone-directed therapy for patients with PGNMID. Here, we present our experience using this approach in 20 patients with non-PGNMID MGRS.
We retrospectively reviewed charts of 20 patients with MGRS whose kidney biopsies did not show PGNMID. Hematologic response was assessed using AL amyloidosis criteria in patients with LCDD , ITG, HCDD , monoclonal fibrillary GN, and monoclonal membranous nephropathy, and using IMWG criteria in patients with C3G, LCPT , and cryoglobulinemic GN. Renal response was defined as CR or PR with improved/stable eGFR and proteinuria as follows: if >3.5 g baseline proteinuria, CR and PR required proteinuria <0.5 and <3.5 g, respectively. If baseline proteinuria 0.5-3.5 g, CR and PR required <0.49 g and ≥50% reduction in proteinuria, respectively. If <0.5 g baseline proteinuria, CR required <0.3 g proteinuria, PR required improved or stable eGFR only.
A circulating paraprotein was identified in 17/20 (85%) patients. A clone was identified in 16/20 (80%) patients. Fourteen of 16 (87.5%) patients with identified clones were treated with clone-directed therapy. Of patients treated with clone-directed therapy, a hematologic response of PR or better was reached in 12/14 (86%) patients. Of those who had a hematologic response, 9/12 (75%) had a renal PR or CR.
Clone-directed therapy results in hematologic and renal responses in the majority of patients with MGRS.
Background: The term monoclonal gammopathy of renal significance (MGRS) comprises a group of diseases characterized by proliferation of small B-cell or plasma cell clone that synthesizes and secretes a monoclonal immunoglobulin or its components, that may deposit and cause glomerular, tubular, interstitial and/ or vascular damage. MGRS can present with varied histomorphological features.
Aim & Objective : Published data related to MGRS in Indian population is very limited. The present study retrospectively analyzed renal disease spectrum of 51 MGRS cases diagnosed in last 2 years (January 2017 – January 2019). The purpose of this analysis is to describe histopathological spectrum of MGRS in Indian population
Materials & Methods: Among 4500 renal biopsies (including native and transplant) during the study period, 51 cases fulfilled criteria of MGRS. The most common lesion was primary amyloidosis (41.1%), followed by proliferative glomerulonephritis with monoclonal immunoglobulin deposits (23.5%) and monoclonal immunoglobulin deposition disease (17.6%). There were 2 cases each of membranous glomerulopathy with dysproteinemia, fibrillary glomerulonephritis and C3 glomerulopathy. In addition, there was one case of lambda light chain proximal tubulopathy occurring in a renal transplant. The most common clinical presentation with nephrotic syndrome followed by mixed nephrotic-nephritic clinical picture.
Conclusion: Renal pathology associated with MGRS is heterogeneous, and therefore renal biopsy is a key diagnostic tool for early and definitive diagnosis of these entities.
Renal injury is a common complication of multiple myeloma. We have utilised data from the Myeloma XI study to determine renal outcomes.
All 4158 patients recruited to the trial were included.
Patients with baseline and 12 month eGFR results were included in the renal response assessment (n = 2334). Patients were categorized into 3 renal outcome groups; decline in eGFR (>= 25%), improvement in eGFR (>=25%) and no change (<25% change).
Renal function at baseline for patients in the intensive arm was; CKD stage 1-2, 1,514 (62%), CKD 3, 658 (27%), CKD 4-5 122 (5%).
Renal outcome at 12 months (of 1,450 evaluable patients) was; 204 (14%) declined, 341 (23.5%) improved and 905 (62%) had no change. Results in the non-intensive pathway were comparable.
Median follow-up for the whole cohort was 24 months (range 0 - 72.5). Median survival stratified by stage of CKD in the intensive arm was; 65 months (95% CI 60.5 to 71) for stage 1-2, 67 months (95% CI 56 to 78) for stage 3, and 50 months for CKD 4-5 (p=0.04). Survival in the non-intensive arm was; 54 months (95% CI 49 to 59) for CKD 1-2, 55 months (95% CI 45 to 65) for CKD 3 and 37 months (95% CI 31.5-42) in CKD 4-5 (p =0.001).
The majority of patients present with mild renal impairment and only a minority (16%) have a significant decline by 12 months. Patients with CKD stage 4-5 at baseline have significantly worse survival.
BACKGROUND: The kidney is affected in ~70% of patients with AL amyloidosis, with both hematologic and organ responses needed to avoid ESRD which occurs in up to 30% of patients.[3-6] Yet, AL patients are infrequently referred for kidney transplant due to concerns of amyloid recurrence in the transplanted kidney and/or cumulative immunosuppression. Favorable outcomes of patients who undergo kidney transplantation, regardless of hematologic response to high-dose melphalan/ASCT, are not well appreciated.
METHODS: Between 2000-2018, sixteen patients underwent kidney transplantation for AL. Hematologic and renal responses were determined using validated criteria.[1,7]
RESULTS: Patient data are summarized in Tables 1 and 2. Median time from diagnosis/ESRD to renal transplantation was 41.2(12.8-130) and 21.4(2.6-58.4) months, respectively. Of 3 patients with <VGPR at kidney transplant [PR(N=1) and PD(N=2)], only 1 had post-transplant hematologic and organ progression. One case each of BK viremia, disseminated zoster and pulmonary aspergillosis occurred in the total population and all were effectively treated. No PTLD or secondary malignancy occurred except for one thyroid Hurthle cell tumor. Four patients were effectively treated for rejection. At median follow-up from diagnosis of 90(32.9-218) and 21.8(1.1-205.6) months post-transplant, 13/16 patients are alive, all with functioning grafts.
CONCLUSION: Excellent outcomes in AL patients who underwent kidney transplantation following ASCT suggest that hematologic CR/VGPR is not mandatory pre-transplant. Organ access has grown substantially with directed-donor/exchange kidney transplantation programs. Despite sample size and selection bias, our data suggest a definite role for kidney transplantation in AL amyloidosis and the need to establish eligibility criteria.
Monoclonal gammopathy of renal significance is increasingly diagnosed and proliferative glomerulonephritis with monoclonal immunoglobin deposition (PGNMID) is a particularly challenging subtype. Prior to classification and IgG3-subclass staining, it was likely misdiagnosed as idiopathic membranoproliferative glomerulonephritis (MPGN).
We present three cases of PGNMID highlighting the pertinent diagnostic and management challenges. All presented with heavy, nephrotic-range proteinuria and renal histopathology demonstrated MPGN-pattern, with IgG3-subclass staining on immunofluorescence. A pathological B- or plasma cell clone only detected in one case.
Case 1 was previously misdiagnosed with C3GN but achieved remission with plasma-exchange. He relapsed due to non-compliance with steroids/mycophenolate and repeat biopsy showed PGNMID with small B-cell clone on bone marrow. He again achieved remission, this time with steroids and rituximab.
Case 2 with progressive kidney disease was treated with cyclophosphamide/bortezomib/dexamethasone but progressed to dialysis-dependence. The challenge here now lies in the anti-B/plasma cell clone management leading up to and post transplantation.
Case 3 received a cadaveric renal transplant, but a biopsy 12-months later for nephrotic range proteinuria revealed relapse of PGNMID. He has responded to the addition of rituximab to his maintenance transplant immunosuppression.
There is increasing awareness and diagnosis of PGNMID and now the challenge now lies in the management. Current treatment focuses on clearance of the pathological (often undetectable) B- or plasma cell clone with empiric anti-B cell or plasma cell therapy. In order to move beyond empiric therapies and to improve outcomes to refine future the challenge lies in developing more sensitive tests to define the small clones involved.