Lessons for the clinical nephrologist: a rare case with MGRS characterized by combined crystalline light chain proximal tubulopathy and crystal-storing histiocytosis responding to daratumumab.
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SUBMITTER: Qin AB
PROVIDER: S-EPMC10227152 | biostudies-literature | 2023 May
REPOSITORIES: biostudies-literature
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Lessons for the clinical nephrologist: a rare case with MGRS characterized by combined crystalline light chain proximal tubulopathy and crystal-storing histiocytosis responding to daratumumab.
Qin Ai-Bo AB Yu Xiao-Juan XJ Zheng Xi-Zi XZ Wang Su-Xia SX Zhou Fu-de FD Zhao Ming-Hui MH
Journal of nephrology 20230301 4
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Project description:BackgroundLight chain proximal tubulopathy (LCPT) is a rare form of paraprotein-related disease, occurring in two main histopathological forms: crystalline and non-crystalline. The clinicopathological features, treatment strategies and outcomes, especially of the non-crystalline form, are not well described.MethodsWe conducted a single-centre retrospective case series of 12 LCPT patients, 5 crystalline and 7 non-crystalline, between 2005 and 2021.ResultsThe median age was 69.5 years (range 47-80). Ten patients presented with CKD and significant proteinuria (median estimated glomerular filtration rate of 43.5 ml/min/1.73 m2; urine protein:creatinine ratio 328 mg/mmol). Only six patients had known haematological disease at the time of renal biopsy. Multiple myeloma (MM) was diagnosed in seven patients cases and monoclonal gammopathy of renal significance (MGRS) in five patients. A clone was detected in all cases combining serum/urine electrophoresis and free light chain (LC) assays. Crystalline and non-crystalline variants had similar clinical presentations. For the non-crystalline variant, a diagnosis was reached based on a combination of CKD without another cause, haematological workup, LC restriction on immunofluorescence and abnormalities on electron microscopy (EM). Nine of 12 patients received clone-directed treatment. Patients who achieved haematological response (including all non-crystalline LCPT) had improved renal outcomes over a median follow-up of 79 months.ConclusionsThe non-crystalline variant may go unrecognised because of its subtle histopathological features and requires EM to distinguish it from 'excessive LC resorption without tubular injury'. Clone-directed treatment with good haematological response improves renal outcomes in both variants but limited data exist in MGRS. Multicentre prospective studies are needed to better define the clinicopathological characteristics associated with poor outcomes and optimize treatment strategies in patients with MGRS.
| S-EPMC10615624 | biostudies-literature
Project description:Crystal-storing histiocytosis is a rare condition that is histologically characterized by intracellular cytoplasmic crystalline inclusions. It usually presents monoclonal immunoglobulins that deposit within histiocytes, which accumulate and affect different organs of the human body and are commonly associated with lymphoproliferative conditions, especially those with plasmacytic differentiation. The prognosis of this condition is variable and related to the underlying clinical disease. In this review article, we aim to describe and discuss the clinical and pathological characteristics of crystal-storing histiocytosis based on the available literature and to provide a thorough differential diagnosis.
| S-EPMC9858286 | biostudies-literature
Project description: Not available
| S-EPMC6829195 | biostudies-literature
Project description:BackgroundMultiple myeloma (MM) often causes renal tubular damage, such as the light chain cast nephropathy (LCCN) and the light chain proximal tubulopathy (LCPT). The excessive light chains deposited in the proximal and distal tubules usually manifest with different characteristics, leading to a rare coexistence of the two pathological conditions. Here we report a unique case of a patient with multiple myeloma (MM) who presented with acute kidney injury (AKI) due to dual conditions of λ light chain-restricted non-crystalline LCPT and LCCN. This report reviews the clinical presentation and histological findings, comparing them with previously published cases.Case presentationA 49-year-old male patient was admitted with a chief complaint of "fatigue, loss of appetite for 40 days and elevated blood creatinine for 10 days." In serum and urine, the λ light chain level and the ratio of κ to λ free light chain were 1235 mg/dl and 93.25 mg/dl, 0.0022 and 0.0316, respectively. Additionally, serum protein electrophoresis showed an M-spike with monoclonal IgD-λ. Bone marrow puncture revealed 30.5% primitive naive plasma cells, indicative of IgD-λ MM. Light microscopy of kidney biopsy specimen showed periodic acid-Schiff (PAS)-negative cytoplasm in some proximal tubules and PAS-negative casts with a rigid appearance in some distal tubule lumens. On immunofluorescence, these proximal tubular epithelial cells cytoplasm and casts stained exclusively with λ-light chains. Electron microscopy did not reveal any crystalline inclusions. Given the clinical and bone marrow puncture findings, the overall pathological presentation was LCPT with LCCN secondary to IgD-λ MM. After chemotherapy and dialysis, the patient's condition was improved and he was tracked in follow-ups.ConclusionIn some tubular renal injuries caused by MM, the morphological changes are subtle and often overlooked. In this paper, we present a rare case of LCPT with LCCN showing λ restriction in patient with MM. Through the clinicopathological analysis of patients, the understanding of the disease can be deepened and the diagnosis rate improved.
| S-EPMC11443757 | biostudies-literature
Project description:Monoclonal gammopathy (MG) causes various nephropathies, which may suffice for cytoreductive therapy even in the absence of diagnostic criteria for multiple myeloma or B-cell non-Hodgkin lymphoma. The aim of this study was to better understand the significance of light chain (LC) restriction or crystals (LC-R/C) in proximal tubules in the spectrum of LC-induced nephropathies. A consecutive cohort of 320 renal specimens with a history of B-cell dyscrasia was characterized. Special attention was paid to immunohistochemical LC restriction in proximal tubules, tubular crystals or constipation, and ultrastructural findings. Complementary cell culture experiments were performed to assess the role of LC concentrations in generating LC restriction. Light chain restriction or crystals in proximal tubules was found in a quarter of analyzed cases (81/316) and was associated with another LC-induced disease in 70.4% (57/81), especially LC cast-nephropathy (cast-NP) and interstitial myeloma infiltration. LC restriction without significant signs of acute tubular injury was observed in 11.1% (9/81). LC-R/C was not associated with inferior renal function compared to the remainder of cases, when cases with accompanying cast-NP were excluded. Besides crystals, cloudy lysosomes were significantly associated with LC-R/C on an ultrastructural level. In summary, LC-R/C is frequent and strongly associated with cast-NP, possibly indicating that a high load of clonal LC is responsible for this phenomenon, supported by the observation that LC restriction can artificially be generated in cell culture. This and the lack of significant tubular injury in a subgroup imply that in part LC-R/C is a tubular trafficking phenomenon rather than an independent disease process.
| S-EPMC8995435 | biostudies-literature
Project description:BackgroundVolume-regulated anion channels (VRACs) are heterohexamers of LRRC8A with LRRC8B, -C, -D, or -E in various combinations. Depending on the subunit composition, these swelling-activated channels conduct chloride, amino acids, organic osmolytes, and drugs. Despite VRACs' role in cell volume regulation, and large osmolarity changes in the kidney, neither the localization nor the function of VRACs in the kidney is known.MethodsMice expressing epitope-tagged LRRC8 subunits were used to determine the renal localization of all VRAC subunits. Mice carrying constitutive deletions of Lrrc8b-e, or with inducible or cell-specific ablation of Lrrc8a, were analyzed to assess renal functions of VRACs. Analysis included histology, urine and serum parameters in different diuresis states, and metabolomics.ResultsThe kidney expresses all five VRAC subunits with strikingly distinct localization. Whereas LRRC8C is exclusively found in vascular endothelium, all other subunits are found in the nephron. LRRC8E is specific for intercalated cells, whereas LRRC8A, LRRC8B, and LRRC8D are prominent in basolateral membranes of proximal tubules. Conditional deletion of LRRC8A in proximal but not distal tubules and constitutive deletion of LRRC8D cause proximal tubular injury, increased diuresis, and mild Fanconi-like symptoms.ConclusionsVRAC/LRRC8 channels are crucial for the function and integrity of proximal tubules, but not for more distal nephron segments despite their larger need for volume regulation. LRRC8A/D channels may be required for the basolateral exit of many organic compounds, including cellular metabolites, in proximal tubules. Proximal tubular injury likely results from combined accumulation of several transported molecules in the absence of VRAC channels.
| S-EPMC9342636 | biostudies-literature
Project description:Crystal-storing histiocytosis (CSH) is a rare disorder characterized by the accumulation of non-neoplastic histiocytes that contain intracytoplasmic crystallized immunoglobulins. Although CSH can occur in various organs, gastric CSH is very rare. Therefore, diagnosing gastric CSH remains a challenge. Here, we present the case of a 69-year-old man with localized gastric CSH who presented with positive fecal occult blood for 2 days. Gastroscopy showed that there was a piece of irregular whitish focus in the big bend of the gastric antrum, which was soft and elastic. Histologically, the biopsied gastric mucosa showed chronic inflammation, mild activity with erosion, and numerous eosinophilic mononuclear cells containing fibrillary crystalloid inclusions in the lamina propria. Immunohistochemically, these crystal-containing cells were positive for CD68/PGM1 and Igk, which revealed that the cells were histiocytes harboring kappa light chain-restricted immunoglobulin crystals. Electron microscopic examination showed numerous high-electron-density particles in the cytoplasm of cells, with crystal structures of different sizes and shapes. This case highlights how immunohistochemistry can help with differential diagnosis and classification.
| S-EPMC9798227 | biostudies-literature
Project description:BackgroundChronic subclinical hemolysis is frequent in patients implanted with Left Ventricular Assist Device (LVAD) and is associated with adverse outcomes. Consequences of LVADs-induced subclinical hemolysis on kidney structure and function is currently unknown.MethodsThirty-three patients implanted with a Heartmate II LVAD (Abbott, Inc, Chicago IL) were retrospectively studied. Hemolysis, Acute Kidney Injury (AKI) and the evolution of estimated Glomerular Filtration Rate were analyzed. Proximal Tubulopathy (PT) groups were defined according to proteinuria, normoglycemic glycosuria, and electrolytic disorders. The Receiver Operating Characteristic (ROC) curve was used to analyze threshold of LDH values associated with PT.ResultsMedian LDH between PT groups were statistically different, 688 IU/L [642-703] and 356 IU/L [320-494] in the "PT" and "no PT" groups, respectively p = 0.006. To determine PT group, LDH threshold > 600 IU/L was associated with a sensitivity of 85.7% (95% CI, 42.1-99.6) and a specificity of 84.6% (95% CI, 65.1-95.6). The ROC's Area Under Curve was 0.83 (95% CI, 0.68-0.98). In the "PT" group, patients had 4.2 [2.5-5.0] AKI episodes per year of exposure, versus 1.6 [0.4-3.7] in the "no PT" group, p = 0.03. A higher occurrence of AKI was associated with subsequent development of Chronic Kidney Disease (CKD) (p = 0.02) and death (p = 0.05).ConclusionsLVADs-induced subclinical hemolysis is associated with proximal tubular functional alterations, which in turn contribute to the occurrence of AKI and subsequent CKD. Owing to renal toxicity of hemolysis, measures to reduce subclinical hemolysis intensity as canula position or pump parameters should be systematically considered, as well as specific nephroprotective therapies.
| S-EPMC7703997 | biostudies-literature
Project description:Light chain proximal tubulopathy (LCPT) is characterized by cytoplasmic inclusions of monoclonal LC within proximal tubular cells. The significance of crystalline versus noncrystalline LCPT and the effect of modern therapies are unknown. We reported the clinical-pathologic features of 40 crystalline and six noncrystalline LCPT patients diagnosed between 2000 and 2014. All crystalline LCPTs were κ-restricted and displayed acute tubular injury. One-third of noncrystalline LCPT patients displayed λ-restriction or acute tubular injury. Only crystalline LCPT frequently required antigen retrieval to demonstrate monoclonal LC by immunofluorescence. In five of 38 patients, crystals were not detectable by light microscopy, but they were visible by electron microscopy. Hematolymphoid neoplasms, known before biopsy in only 15% of patients, included 21 monoclonal gammopathies of renal significance; 15 multiple myelomas; seven smoldering multiple myelomas; and three other neoplasms. Biopsy indications included Fanconi syndrome (38%; all with crystalline LCPT), renal insufficiency (83%), and proteinuria (98%). Follow-up was available for 30 (75%) patients with crystalline LCPT and all six patients with noncrystalline LCPT, of whom 11 underwent stem cell transplant, 16 received chemotherapy only, and nine were untreated. Complete or very good partial hematologic remissions occurred in six of 22 treated crystalline LCPT patients. By multivariable analysis, the only independent predictor of final eGFR was initial eGFR, highlighting the importance of early detection. All patients with crystalline LCPT treated with stem cell transplant had stable or improved kidney function, indicating the effectiveness of aggressive therapy in selected patients.
| S-EPMC4849818 | biostudies-literature
Project description:BackgroundMonoclonal gammopathy of renal significance (MGRS) represents a range of disease processes arising from monoclonal proteins depositing in the kidney. These deposits vary and can be broadly grouped as containing a substructure or being non-organised. Their clinical phenotype can include proteinuria, haematuria, kidney injury and tubulopathies resulting in electrolyte changes.Case presentationCrystal storing histiocytosis (CSH) is a rare form of MGRS that typically deposits in the interstitium but rarely in the glomerulus to cause progressive kidney disease. We report a case of a male with known monoclonal protein and progressive proteinuria, whose biopsy showed glomerular histiocytosis with non-crystallizing IgG kappa inclusions.ConclusionThis case reviews an unusual case of a glomerular histiocytosis with non-crystallizing IgG kappa inclusions.
| S-EPMC11796192 | biostudies-literature