Light chain proximal tubulopathy diagnosed solely by electron microscopy of a renal biopsy specimen in a patient with monoclonal gammopathy of undetermined significance

Background:Monoclonal immunoglobulin–mediated kidney disease with various patterns of damage may occur in patients with B-cell malignancies and non-malignant monoclonal gammopathies, and the latter are actually merged under the umbrella of monoclonal gammopathy of renal significance. Amyloidosis is the most well-known monoclonal immunoglobulin–related kidney damage. We focused on the rarer conditions and aimed to evaluate the non-amyloid spectrum of monoclonal immunoglobulin–mediated patterns of renal damage in real clinical practice.Methods:A single-center non-interventional retrospective study included 45 patients with pathology-proven non-amyloid monoclonal immunoglobulin–mediated kidney disease, followed during 2002–2018. Disease duration, proteinuria, serum creatinine, need for dialysis at the time of kidney biopsy, clinical diagnosis, and kidney pathology findings were analyzed.Results:No significant differences in the median age, disease duration at the time of biopsy, or main clinical presentation of kidney disease were found between patients with monoclonal gammopathy of renal significance and patients with B-cell malignancies. Pathology patterns like proliferative glomerulonephritis with monoclonal immunoglobulin deposits, membranous nephropathy, C3 glomerulopathy, cryoglobulinemic glomerulonephritis, and combinations of light chain proximal tubulopathy with monoclonal immunoglobulin deposition disease, and of C3 glomerulopathy with light chain proximal tubulopathy were found in monoclonal gammopathy of renal significance setting only. In contrast, light chain proximal tubulopathy alone, anti-glomerular basement glomerulonephritis, and combinations of cast nephropathy with light chain proximal tubulopathy, and cast nephropathy with monoclonal immunoglobulin deposition disease were associated with multiple myeloma only. Monoclonal immunoglobulin deposition disease, intracapillary monoclonal immunoglobulin M deposits, and cast nephropathy alone were seen in both settings.Conclusion:The presence of monoclonal gammopathy in patients with proteinuria and/or impaired kidney function demands kidney biopsy. Neither duration of kidney disease nor its clinical presentation allows differentiating malignant and non-malignant causes of monoclonal immunoglobulin–mediated renal damage. Several pathology patterns, even cast nephropathy, can be found both in cases of monoclonal gammopathy of renal significance and in cases of B-cell malignancies. Dual patterns of damage, including combinations of organized and non-organized deposits, or organized deposits with monoclonal immunoglobulin–induced damage without monoclonal immunoglobulin deposition, constitute up to 9%, mostly in multiple myeloma cases.

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MPGN Type 3 Associated with Pemphigus Herpetiformis Mimicking PGNMID and Dermatitis Herpetiformis

Case Reports in Nephrology and Dialysis ◽

10.1159/000498939 ◽

2019 ◽

Vol 9 (1) ◽

pp. 15-24

Author(s):

Yoshio Shimizu ◽

Keiichi Wakabayashi ◽

Yoko Hayashi ◽

Kazuaki Hara ◽

Rumi Aoyama ◽

...

Keyword(s):

Electron Microscopy ◽

Renal Biopsy ◽

Biopsy Specimen ◽

Dermatitis Herpetiformis ◽

Complex Type ◽

Renal Abnormality ◽

Renal Disorder ◽

Renal Biopsy Specimen ◽

Blistering Disease ◽

Type 3

A 45-year-old man suffering from dermal blistering disease with proteinuria and hematuria underwent renal biopsy. The renal biopsy specimen suggested proliferative glomerulonephritis with monoclonal IgG deposits under routine light, immunofluorescence and electron microscopy. The staining for IgG subclasses (IgG1 and IgG2) and κ/λ light chain indicated secondary immune complex type MPGN type 3. The patient had been diagnosed as having dermatitis herpetiformis (DH), a phenotype of gluten hypersensitivity prior to the appearance of the renal abnormality. Although common autoantibodies might be related to the pathogenesis of disorders in the skin and kidney, DH is mainly driven by IgA autoantibody, while MPGN is induced by IgG immune complexes. IgA was not observed in the glomeruli by immunofluorescence. Neither the examination for DH specific autoantibodies nor HLA-DQB1 genotype supported the diagnosis of DH. Reassessment of the skin biopsy record revealed that the blister was localized in the epidermis, suggesting pemphigus herpetiformis by IgG class anti-epidermal autoantibody, which also affected the renal disorder.

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Light chain proximal tubulopathy with cast nephropathy in monoclonal gammopathy of renal significance

BMJ Case Reports ◽

10.1136/bcr-2020-234361 ◽

2020 ◽

Vol 13 (6) ◽

pp. e234361

Author(s):

Rebaika Chopra ◽

Rosalba Santana de Roberts ◽

Ibrahim Batal ◽

Sachin Batra ◽

Belinda Jim

Keyword(s):

Light Chain ◽

Monoclonal Gammopathy ◽

Fanconi Syndrome ◽

Cell Damage ◽

Biochemical Properties ◽

Light Chains ◽

Immunoglobulin Light Chains ◽

Cast Nephropathy ◽

Proximal Tubulopathy ◽

Light Chain Proximal Tubulopathy

Kidney tubular disorders due to monoclonal immunoglobulin light chains are common manifestations of B-cell neoplasm. Cast nephropathy (CN) is the most frequent type of these disorders and may present with acute kidney injury (AKI) due to the presence of excess light chains in the distal tubules. Light chain proximal tubulopathy (LCPT) is an uncommon form of renal disease and may present as Fanconi syndrome due to proximal tubular cell damage by intracellular deposition of light chains. The concomitant disorder of both CN and LCPT is rare given the inherent differences in the biochemical properties of the immunoglobulin light chains of each disorder. We report a 64-year-old man who presented with AKI and Fanconi syndrome who was discovered to have both CN and LCPT due to the underlying disorder of monoclonal gammopathy of renal significance and who has responded favourably with conventional chemotherapy. We also review the existing literature on this interesting subject.

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Light Chain Proximal Tubulopathy: Expanding the Pathologic Spectrum with and without Deposition of Crystalline Inclusions

ISRN Pathology ◽

10.5402/2012/541075 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 7

Author(s):

Shree G. Sharma ◽

Steven M. Bonsib ◽

Didier Portilla ◽

Ashutosh Shukla ◽

Adam B. Woodruff ◽

...

Keyword(s):

Electron Microscopy ◽

Multiple Myeloma ◽

Renal Disease ◽

Physicochemical Properties ◽

Light Chain ◽

Proximal Tubules ◽

Light Chains ◽

Proximal Tubulopathy ◽

Light Chain Proximal Tubulopathy ◽

Crystal Accumulation

Light chain proximal tubulopathy (LCPT) is an uncommon form of renal disease associated with dysproteinemias. It is characterized by intracytoplasmic deposition of crystallized mostly kappa monoclonal light chains in proximal tubules (PTs). Crystals are located within lysosomes by electron microscopy (EM). Rare lambda LCPT cases without crystals by EM were described. Retrospectively, we reviewed clinical, light microscopic (LM), immunofluorescence (IF), and EM findings in 9 cases) (8 males, 1 female; mean age 57 years (38–81)) with multiple myeloma. LM showed abundant cytoplasmic droplets in PT cells in all cases. Droplets were also present in the podocytes, endothelial and parietal cells in one case. IF revealed staining of crystals with kappa in 3 and lambda in 6. EM showed electron dense rectangular, rhomboid, or needle shaped crystals in PT cells in 3 cases (33%), one of which had crystals in podocytes and interstitial cells. Six lambda LCPT cases showed no crystals by EM (67%). This may reflect differences in the physicochemical properties of light chains. The mechanisms of crystal accumulation in these cells and the significance of this finding are unknown.

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Monoclonal gammopathy of renal significance: A novel combination of C3 glomerulopathy and light-chain proximal tubulopathy

Journal of Onco-Nephrology ◽

10.1177/2399369320916467 ◽

2020 ◽

Vol 4 (1-2) ◽

pp. 59-63 ◽

Cited By ~ 1

Author(s):

Elena V Zakharova ◽

Tatyana A Makarova ◽

Ekaterina S Stolyarevich ◽

Olga A Vorobyeva ◽

Irina G Rekhtina

Keyword(s):

Serum Creatinine ◽

Light Chain ◽

Immunoglobulin G ◽

Monoclonal Gammopathy ◽

Plasma Cells ◽

Bence Jones Protein ◽

Monoclonal Immunoglobulin ◽

Monoclonal Gammopathies ◽

Proximal Tubulopathy ◽

Light Chain Proximal Tubulopathy

Introduction: According to the recent International Kidney and Monoclonal Gammopathy Research Group Consensus report, the spectrum of monoclonal gammopathies of renal significance merges more than 12 conditions; and combinations of various patterns of monoclonal gammopathies of renal significance–associated kidney damage have already been described. We present a case of a previously unreported combination of C3 glomerulopathy and light-chain proximal tubulopathy. Case description: A 53-year-old Caucasian man presented with general weakness. Three years prior, a check-up revealed proteinuria and microhematuria, later accompanied by arterial hypertension, elevated serum creatinine, and a low serum C3 levels. On admission, his creatinine was 1.5 mg/dL; his protein excretion was 1900 mg/24 h with microhematuria at 150 hpf. His serum C3 was 79 mg/dL with a normal C4 level. Serum protein electrophoresis revealed an M-spike, immunochemistry confirmed monoclonal immunoglobulin G kappa secretion of 920 mg/dL, and traces of Bence–Jones protein kappa in his urine. A kidney biopsy showed mesangial hypercellularity with diffuse fine granular C3 mesangial expression and tubular atrophy with diffuse coarse granular kappa light-chain tubular epithelial cytoplasmic expression. Computed tomography did not reveal any destructive lesions. A bone marrow smear showed 5% plasma cells, and bone marrow cell flow cytometry demonstrated 87.4% of plasma cells with an aberrant phenotype. The patient was diagnosed with an monoclonal gammopathy of renal significance and administered bortezomib–cyclophosphamide–dexamethasone. After four courses, his monoclonal immunoglobulin G kappa secretion halved, but his serum creatinine and proteinuria remained almost unchanged. Chemotherapy was switched to lenalidomide–dexamethasone, and after five courses his immunoglobulin G kappa secretion decreased to traces, Bence–Jones protein was not observed and his urinalysis, serum creatinine, and C3 levels were detected as normal. Conclusion: The combination of kidney damage patterns, one of which was directly and the other indirectly associated with monoclonal gammopathy, complements the monoclonal gammopathies of renal significance spectrum. Chemotherapy led to a very good partial response and kidney function recovery.

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Development of Renal Failure without Proteinuria in a Patient with Monoclonal Gammopathy of Undetermined Significance: An Unusual Presentation of AL Kappa Amyloidosis

Case Reports in Nephrology ◽

10.1155/2012/573650 ◽

2012 ◽

Vol 2012 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Yijuan Sun ◽

Amarpreet Sandhu ◽

Darlene Gabaldon ◽

Jonathan Danaraj ◽

Karen S. Servilla ◽

...

Keyword(s):

Renal Failure ◽

Renal Biopsy ◽

Light Chain ◽

Monoclonal Gammopathy ◽

Outlet Obstruction ◽

Renal Ultrasound ◽

Al Amyloidosis ◽

Kappa Light Chain ◽

Severe Renal Failure ◽

Undetermined Significance

AL amyloidosis complicating monoclonal gammopathy of undetermined significance (MGUS) has usually a predominant glomerular deposition of lambda light chain. Heavy proteinuria is one of its cardinal manifestations. A 78-year-old man with a 9-year history of IgG kappa light-chain-MGUS and normal urine protein excretion developed severe renal failure. Serum levels of kappa light chain and serum IgG had been stable while proteinuria was absent throughout the nine-year period. For the first eight years, he had stable stage III chronic kidney disease attributed to bladder outlet obstruction secondary to prostatic malignancy. In the last year, he developed progressive serum creatinine elevation, without any increase in the serum or urine levels of paraproteins or any sign of malignancy. Renal ultrasound and furosemide renogram showed no evidence of urinary obstruction. Renal biopsy revealed AL amyloidosis, with reactivity exclusive for kappa light chains, affecting predominantly the vessels and the interstitium. Glomerular involvement was minimal. Melphalan and prednisone were initiated. However, renal function continues deteriorating. Deposition of AL kappa amyloidosis developing during the course of MGUS predominantly in the wall of the renal vessels and the renal interstitium, while the involvement of the glomeruli is minimal, leads to progressive renal failure and absence of proteinuria. Renal biopsy is required to detect both the presence and the sites of deposition of renal AL kappa light chain amyloidosis.

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Prevalence of Monoclonal Gammopathy of Undetermined Significance in a Large Population with Annual Physical Examination in Beijing, China

Blood ◽

10.1182/blood-2019-124715 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5519-5519

Author(s):

Jinuo Wang ◽

Jian-Hua Han ◽

Yue-lun Zhang ◽

Xin-xin Cao ◽

Dao-Bin Zhou ◽

...

Keyword(s):

Physical Examination ◽

Light Chain ◽

Chinese Population ◽

Monoclonal Gammopathy ◽

Conflicts Of Interest ◽

Large Population ◽

M Protein ◽

Monoclonal Protein ◽

Significant Difference ◽

Undetermined Significance

Introduction Monoclonal gammopathy of undetermined significance (MGUS) is a clinically asymptomatic premalignant plasma cell disorder. Previous studies in Western countries have described the prevalence of MGUS in Caucasians. However, data is limited in Chinese population. We therefore performed this study to ascertain the prevalence and characteristics of MGUS among Chinese population. Methods A total of 154597 consecutive healthy participants from Beijing who underwent annual physical examination between December 2013 and April 2019 at Peking Union Medical College Hospital were enrolled. Serum M protein was evaluated by capillary electrophoresis. Patients with a positive or suspicious serum M protein were suggested to be referred to the hematological clinic for immunofixation electrophoresis (IFE) and free light chain (FLC) assays. MGUS was defined in accordance with previous definitions. We calculated age-specific and sex-specific prevalence and described laboratory characteristics of patients with MGUS among those participants. Results MGUS were diagnosed in 843 patients (0.55%, 95%CI 0.51% to 0.59%). The median age at presentation was 58 years, with a range of 25-96 years. The overall prevalence of MGUS was 1.14% among participants aged 50 years or older and 2.6% among those aged 70 years or older. In both sexes, the prevalence increased with age: 0.1% (<40 years), 0.36% (40-49 years), 0.78% (50-59 years), 1.28% (60-69 years), 2.19% (70-79 years), and 3.77% (≥80 years) separately (Figure 1). The prevalence among men were higher than that among women (0.67% vs. 0.40%, OR =1.719, 95% CI 1.490 to 1.983, P<0.001) (Figure 1). The median concentration of serum Monoclonal protein was 1.4 g/L (0.1 -27.8 g/L). M protein level was less than 0.5g/L in 220 patients (26.1%), less than 5 g/L in 81.1% and more than 15 g/L in only 1.9% of 843 persons. There was no significant difference in the concentration of the monoclonal protein among the age groups. Of the 519 patients who were tested for IFE, the isotype of the monoclonal immunoglobulin was IgG in 344 (66.3%), IgA 112 (21.6%), IgM in 48 (9.2%), IgD in 2 (0.4%), light-chain in 3 (0.6%) and biclonal in 10 (1.9%). The serum light-chain type was kappa in 260 (50.1%), lambda in 255 (49.1%) patients, while 4 patients (0.8%) with biclonal M protein have both kappa and lambda light-chain. Of the 180 people who were tested for FLC, 42 (23.3%) had an abnormal FLC ratio. IgG isotype, M protein <15 g/L and normal FLC ratio were found in 102 patients (56.7%) and the remaining 78 people (43.4%) had 1(30.6%) or 2(12.8%) abnormal factors. Conclusions MGUS was found in 1.14% of persons 50 years of age or older and 2.6% among those 70 years of age or older among healthy Chinese population. The prevalence of MGUS increases with age. Males have a higher frequency of MGUS than Females. These observations offer the overall situation of MGUS epidemiology in a large Chinese population. Disclosures No relevant conflicts of interest to declare.

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