Light Chain Proximal Tubulopathy Research Articles

Light-chain proximal tubulopathy: a retrospective study from a single Chinese nephrology referral center

Background: Light-chain proximal tubulopathy (LCPT) is a rare disease characterized by the accumulation of monoclonal light chains within proximal tubular cells. This study aimed to investigate the clinical characteristics of LCPT from a single Chinese nephrology referral center.Methods: Patients with kidney biopsy-proven isolated LCPT between 2016 and 2022 at Peking University First Hospital were retrospectively included. Clinical data, kidney pathological type, treatment, and prognosis were analyzed.Results: Nineteen patients were enrolled, the mean age at diagnosis was 57 ± 11 and the sex ratio was 6/13 (female/male). Mean proteinuria was 2.44 ± 1.89 g/24 hr and the mean estimated glomerular filtration rate (eGFR) at the point of biopsy was 59.640 ± 27.449 ml/min/1.73 m2. κ-restriction (84%) was dominant among LCPTs. An abnormal free light chain ratio was observed in 86% of the patients. Proximal tubulopathy with cytoplasmic inclusions accounted for the majority (53%), followed by tubulopathy associated with interstitial inflammation reaction (26%), proximal tubulopathy without cytoplasmic inclusions (16%), and proximal tubulopathy with lysosomal indigestion/constipation (5%). One patient presented with acute kidney injury and 16 patients presented with chronic kidney disease. Regarding follow-up, patients received bortezomib-based or R-CHOP chemotherapy or supportive treatment only. The mean follow-up time was 22 ± 16 months, and the mean eGFR was 63.098 ± 27.439 ml/min/1.73 m2 at the end of follow-up. These patients showed improved or stable kidney function.Conclusions: This is the first case series report of LCPT in four different pathological types in northern China. Clone-targeted chemotherapy may help preserve the kidney function in these patients.

Successful autologous stem cell transplantation for light chain proximal tubulopathy with severe kidney injury

Key Clinical MessageLight chain proximal tubulopathy (LCPT) is a rare type of monoclonal gammopathy of renal significance. Clinicians should consider LCPT in the differential diagnosis of patients with renal or proximal tubular dysfunction with monoclonal gammopathy. They should confirm diagnosis by renal biopsy and initiate chemotherapy before disease progression.

#5788 MONOCLONAL GAMMOPATHY OF RENAL SIGNIFICANCE: A SINGLE CENTER EXPERIENCE

Abstract Background and Aims Monoclonal gammopathy of renal significance is an organ-threatening manifestation of paraproteinemia. It can be secondary to the clonal proliferation of either plasma cells or mature B-lymphocytes. The underlying clonal disorder does not meet the current hematologic criteria for immediate myeloma-specific therapy. With the advent of routine use of light chain detection by immunofluroscence technique in tissue biopsy, more cases of monoclonal gammopathy of renal significance are being diagnosed but there remains a therapeutic uncertainty. Data regarding the prognosis and outcomes of the various clinical manifestations of monoclonal gammopathy of renal significance is limited due to its rarity and under diagnosis. MGRS if left untreated can lead to end-stage renal disease and premature death. Method This is a retrospective study conducted at the Institute of Nephro-urology, Bangalore by retrieving the data from the digital medical records of our institute. Demographic and clinical details of the patients diagnosed with monoclonal gammopathy of renal significance from 1 st January 2018 to 31 st October 2022 were collected. Myeloma related light chain cast nephropathy was excluded from the study. Follow-up data were collected usingout patient data base, through telephone, and from the records at the cancer institute where the patient was referred post-diagnosis at our institute. The data collected was entered in excel and analyzed using SPSS software version 27.0. Results Fifty eight patients (n = 52) were diagnosed with the disease during the study period. MGRS contributed to 1.27% of all the renal biopsies conducted at our institute during the study period. The mean age of the study population was 52.1 with 95% CI [48.5 to 55.6] with a male: female ratio of 1.36:1 and 36.5% (n = 19) ofstudy cohort aged above 60 years. Among clinical presentations CKD (n = 23) was the main clinical presentation followed by AKI, Nephrotic syndrome, Nephritic syndrome and RPGN as the other presentations. Dialysis requirement was noted in 35% at initial presentation. Most common histiopathological presentation was Amyloidosis (n = 15) followed by Light chain deposition disease LCDD (n = 14), monoclonal non-amyloid deposition disease NADD (n = 6), Light chain proximal tubulopathy LCPT (n = 5), Proliferative glomerulonephritis with monoclonal immunoglobulin deposition disease PGNMIDD (n = 9) and others (n = 3). The patient survival at the time of analysis was 22.7% and death censored renal survival was 80%. Conclusion MGRS contributed to 1.27% of all the renal biopsies conducted at our institute during the study period. Because of its variable clincal presentation,one needs high degree of clinical suspicion for early diagnosis. MGRS unlike MGUS carries significant morbidity and mortality.

Non-crystalline light chain proximal tubulopathy, a morphologically protean entity.

Light 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. We conducted a single-centre retrospective case series of 12 LCPT patients, 5 crystalline and 7 non-crystalline, between 2005 and 2021. The median age was 69.5years (range 47-80). Ten patients presented with CKD and significant proteinuria (median estimated glomerular filtration rate of 43.5ml/min/1.73m2; urine protein:creatinine ratio 328mg/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 79months. The 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.

Combined crystal-storing histiocytosis, light chain proximal tubulopathy, and light chain crystalline podocytopathy in a patient with multiple myeloma: a case report and literature review

Background Crystal-storing histiocytosis (CSH), light chain proximal tubulopathy (LCPT), and light chain crystalline podocytopathy (LCCP) are rare complications of multiple myeloma (MM) or monoclonal gammopathy of renal significance, and their diagnoses are challenging. Case presentation In this case, a 69-year-old Chinese woman presented with suspicious Fanconi syndrome with renal insufficiency. Immunofixation electrophoresis of both serum and urine revealed elevated immunoglobulin G kappa (IgGkappa) and kappa light chain. Bone marrow aspirate revealed 15% plasma cells with considerable cytoplasmic granular inclusions and needle-shaped crystals. Renal biopsy confirmed the final pathologic diagnosis of kappa-restricted CSH, combined LCPT and LCCP by immunoelectron microscopy. A number of special casts were present which could easily be misdiagnosed as light chain cast nephropathy. Immunofluorescence on frozen tissue presented false negative for kappa light chain, as ultimately proven by paraffin-embedded tissue after pronase digestion. MM and CSH were diagnosed, and two cycles of chemotherapy were given. The patient subsequently refused further chemotherapy, and her renal function remained relatively stable during a 2.5-year follow-up period. Conclusions In conclusion, we report a rare case of generalized kappa-restricted CSH involving bone marrow and kidney, combined with LCPT and LCCP, provide a comprehensive summary of renal CSH, and propose a new nomenclature of monoclonal immunoglobulin-induced crystalline nephrology. The presentation of monoclonal immunoglobulin and Fanconi syndrome should suggest the presence of monoclonal immunoglobulin-induced crystalline nephrology. Use of paraffin-embedded tissue after pronase digestion and immunoelectron microscopy is beneficial to improve the sensitivity of diagnosis.

Delayed diagnosis of plasma cell disorder-related Fanconi syndrome in young adults presenting as osteomalacia: report of two cases with normokalemia and normal haematological parameters at the time of presentation.

Adult-onset hypophosphatemic osteomalacia is rare and diagnosis is frequently delayed. Fanconi syndrome (FS) due to monoclonal gammopathy is a well-recognized, but rare cause of hypophosphatemia. The relatively young age of patients and normal routine hematological parameters often results in late recognition of this treatable disease entity. Low phosphorus, elevated alkaline phosphatase, mildly impaired renal function and hypokalemia are often the only abnormalities on routine evaluation. We summarize the clinico-pathological features of two cases who initially presented with fractures and proximal myopathy and were subsequently found to have FS secondary to light chain proximal tubulopathy. Atypical features like absence of hypokalemia at presentation and elevated Fibroblast Growth Factor 23(FGF 23), a marker of oncogenic osteomalacia were noted. Marked clinical improvement and recovery of renal parameters were evident with phosphate supplements and chemotherapy for the plasma cell disorder. FS due to monoclonal gammopathy may present with atypical features and diagnosis may be challenging

Delayed diagnosis of plasma cell disorder-related Fanconi syndrome in young adults presenting as osteomalacia: report of two cases with normokalemia and normal haematological parameters at the time of presentation

Adult-onset hypophosphatemic osteomalacia is rare and diagnosis is frequently delayed. Fanconi syndrome (FS) due to monoclonal gammopathy is a well-recognized, but rare cause of hypophosphatemia. The relatively young age of patients and normal routine hematological parameters often results in late recognition of this treatable disease entity. Low phosphorus, elevated alkaline phosphatase, mildly impaired renal function and hypokalemia are often the only abnormalities on routine evaluation. We summarize the clinico-pathological features of two cases who initially presented with fractures and proximal myopathy and were subsequently found to have FS secondary to light chain proximal tubulopathy. Atypical features like absence of hypokalemia at presentation and elevated Fibroblast Growth Factor 23(FGF 23), a marker of oncogenic osteomalacia were noted. Marked clinical improvement and recovery of renal parameters were evident with phosphate supplements and chemotherapy for the plasma cell disorder. FS due to monoclonal gammopathy may present with atypical features and diagnosis may be challenging

Non-crystalline light chain proximal tubulopathy associated with monoclonal gammopathy of renal significance: A case report and review of the literature.

Light chain proximal tubulopathy (LCPT) is a rare M-proteinemia-related nephropathy. Non-crystalline LCPT is even rarer. We herein report an unusual case of renal dysfunction and proteinuria due to κ-restricted and non-crystalline LCPT in a context of monoclonal gammopathy of renal significance (MGRS) without Fanconi syndrome (FS). A 67-year-old man was admitted for a 2-year history of proteinuria and renal dysfunction. Fanconi syndrome (FS) was not observed. He was noted to have IgG-κ M protein, and the previous bone marrow biopsy revealed that atypical plasma cells accounted for 1.5% of the cells, which did not meet the diagnostic criteria for multiple myeloma. A renal biopsy revealed proximal tubular injury, including increased lysosomes with irregular contours and a mottled appearance without crystalline structure and the accumulation of κ light chains. He was diagnosed with non-crystalline LCPT with MGRS. Concurrently, we reviewed the non-crystalline LCPT cases previously published in the literature. Our patient finally received chemotherapy with a bortezomib and dexamethasone regimen. The patient did not seem to achieve evident nephrological and hematological remission after chemotherapy, but he was in a stable condition. Very few similar cases are reported in the literature. It is considered crucial to enhance our knowledge about these cases to establish the definition of the non-crystalline LCPT entity and allow for early diagnosis. Chemotherapy may not be necessary for all patients to maintain good renal function. Future prospective clinical research studies are necessary.

Pathological characteristics of light chain crystalline podocytopathy

Monoclonal immunoglobulin light chain (LC) crystalline inclusions within podocytes are rare, poorly characterized entities. To provide more insight, we now present the first clinicopathologic series of LC crystalline podocytopathy (LCCP) encompassing 25 patients (68% male, median age 56 years). Most (80%) patients presented with proteinuria and chronic kidney disease, with nephrotic syndrome in 28%. Crystalline keratopathy and Fanconi syndrome were present in 22% and 10%, respectively. The hematologic condition was monoclonal gammopathy of renal significance (MGRS) in 55% and multiple myeloma in 45%. The serum monoclonal immunoglobulin was IgG κappa in 86%. Histologically, 60% exhibited focal segmental glomerulosclerosis (FSGS), often collapsing. Ultrastructurally, podocyte LC crystals were numerous with variable effacement of foot processes. Crystals were also present in proximal tubular cells as light chain proximal tubulopathy (LCPT) in 80% and in interstitial histiocytes in 36%. Significantly, frozen-section immunofluorescence failed to reveal the LC composition of crystals in 88%, requiring paraffin-immunofluorescence or immunohistochemistry, with identification of kappa LC in 87%. The LC variable region gene segment, determined by mass spectrometry of glomeruli or bone marrow plasma cell sequencing, was IGKV1-33 in four and IGKV3-20 in one. Among 21 patients who received anti-plasma cell-directed chemotherapy, 50% achieved a kidney response, which depended on a deep hematologic response. After a median follow-up of 36 months, 26% progressed to kidney failure and 17% died. The mean kidney failure-free survival was 57.6 months and was worse in those with FSGS. In sum, LCCP is rare, mostly associates with IgG κappa MGRS, and frequently has concurrent LCPT, although Fanconi syndrome is uncommon. Paraffin-immunofluorescence and electron microscopy are essential to prevent misdiagnosis as primary FSGS since kidney survival depends on early diagnosis and subsequent clone-directed therapy.

Clinic-pathological characteristics of rare tubulointerstitial diseases.

Tubulointerstitial diseases is one of the common causes of renal dysfunction. Some rare pathological types are easy to be misdiagnosed and missedly diagnosed because of their low prevalence and relatively insufficient understanding, which affects the treatment and prognosis of patients. This study aims to explore clinical manifestations and pathological characteristics of several rare tubulointerstitial diseases, and therefore to improve their diagnosis and treatment. A total of 9 363 patients diagnosed by renal biopsy in the Department of Nephrology, Second Xiangya Hospital, Central South University from November 2011 to September 2021 were selected. Six cases of light chain cast nephropathy (LCCN), 2 cases of light chain proximal tubulopathy (LCPT), 1 case of LCCN with LCPT, 4 cases of genetic tubulointerstitial disease, and 6 cases of non-genetic related tubulointerstitial lesion were screened out, and their clinical manifestations and renal biopsy pathological results were collected, compared, and analyzed. Patients with LCCN presented with mild to moderate anemia, microscopic hematuria, and mild to moderate proteinuria. Compared with patients with LCPT, proteinuria and anemia were more prominent in patients with LCCN. Five patients with LCCN and 2 patients with LCPT had elevated serum free kappa light chain. Five patients with LCCN presented clinically with acute kidney injury (AKI). Two patients with LCPT and 1 patient with LCCN and LCPT showed CKD combined with AKI, and 1 LCPT patient presented with typical Fanconi syndrome (FS). Five patients with LCCN, 2 patients with LCPT, and 1 patient with LCCN and LCPT were diagnosed with multiple myeloma. Five patients with LCCN had kappa light chain restriction in tubules on immunofluorescence and a "fractured" protein casts with pale periodic acid-Schiff (PAS) staining on light microscopy. Immunohistochemical staining of 2 LCPT patients showed strongly positive kappa light chain staining in the proximal tubular epithelial cells. And monoclonal light chain crystals in crystalline LCPT and abnormal lysosomes and different morphological inclusion bodies in noncrystalline LCPT were observed under the electron microscope. Six patients with LCCN were mainly treated by chemotherapy. Renal function was deteriorated in 1 patient, was stable in 4 patients, and was improved in 1 patient. Two patients with LCPT improved their renal function after chemotherapy. Four patients with genetic tubulointerstitial disease were clinically presented as CKD, mostly mild proteinuria, with or without microscopic hematuria, and also presented with hyperuricemia, urine glucose under normal blood glucose, anemia, polycystic kidneys. Only 1 case had a clear family history, and the diagnosis was mainly based on renal pathological characteristics and genetic testing. Compared with patients with non-genetic related tubulointerstitial lesion, patients with genetic tubulointerstitial disease had an earlier age of onset, higher blood uric acid, lower Hb and estiated glomemlar fitration (eGFR), and less edema and hypertension. Renal pathology of genetic tubulointerstitial disease presented tubular atrophy and interstitial fibrosis, abnormal tubular dilation, glomerular capsuledilation, and glomerular capillary loop shrinkage. Glomerular dysplasia and varying degrees of glomerular sclerosis were observed. Genetic tubulointerstitial disease patients were mainly treated with enteral dialysis, hypouricemic and hypoglycemic treatment. Two genetic tubulointerstitial disease patients had significantly deteriorated renal function, and 2 patients had stable renal function. Patients with AKI or FS, who present serum immunofixation electrophoresis and/or serum free kappa light chain abnormalities, should be alert to LCCN or LCPT. Renal biopsy is a critical detection for diagnosis of LCCN and LCPT. Chemotherapy and stem cell transplantation could delay progression of renal function in patients with LCCN and LCPT. If the non-atrophic area of the renal interstitium presents glomerular capsule dilatation, glomerular capillary loop shrinkage, and abnormal tubular dilatation under the light microscopy, genetic tubulointerstitial disease might be considered, which should be traced to family history and can be diagnosed by genetic testing.

Crystal-induced collapsing podocytopathy and light chain proximal tubulopathy in monoclonal gammopathy of renal significance.

Crystal-induced collapsing podocytopathy and light chain proximal tubulopathy in monoclonal gammopathy of renal significance.

MO135: Efficacy and Safety of Bortezomib Combined with Autologous Stem Cell Transplantation in the Treatment of MGRS

Abstract BACKGROUND AND AIMS To evaluate the efficacy and safety of bortezomib combined with autologous stem cell transplantation (ASCT) in the treatment of monoclonal gammopathy of renal significance (MGRS). METHOD The clinicopathologic data of 16 patients with non-AL MGRS who received bortezomib combined with ASCT in Jinling Hospital of Nanjing University School of Medicine from February 2012 to June 2021 were retrospectively analysed. RESULTS Twelve patients were male and four were female, with a median age of 49 years, a median serum creatinine was 1.71 mg/ dL (1.45, 2.09) and a median eGFR wad 42.1 mL/min/1.73 m2 (29.0, 51.6). Renal pathological types included seven patients were light chain deposition disease, two patients were heavy chain deposition disease, one patient was light and heavy chain deposition disease, five patients were light chain proximal tubulopathy and one patient was proliferative glomerulonephritis with monoclonal immunoglobulin deposition. Sixteen patients received bortezomib-based induction therapy with a median three courses before transplantation. Stem cells were successfully collected from all patients and CD34 + cell counts were 4.4–13.55 × 106/kg (8.77 ± 3.29 × 106/kg). All patients had successful haematopoietic reconstitution, and a median time of achieving granulocyte count of 500/L was 10 (9, 10) days, and a median time of achieving platelet count of 20 000/L was 12 (11, 13) days. The major treatment complications during transplantation were mucositis (87.5%), diarrhoea (62.5%), fever (56.3%), and nausea and vomiting (18.8%); the other rare complications were acute kidney injury, skin rashes and liver function damage. Haematologic responses were achieved in 15 patients (93.8%), with 10 patients (62.5%) achieved complete responses, 3 patients (18.8%) achieved very good partial responses, 2 patients (12.5%) achieved partial responses, and 1 patient had no haematologic responses. Before treatment with ASCT, seven patients (43.8%) achieved partial response, of which four achieved complete response after ASCT, and one patient did not achieve hematologic response but achieved complete response after ASCT. A total of 12 patients (75%) achieved renal response before ASCT and 14 patients (87.5%) achieved renal response after ASCT. The median follow-up time was 43.5 months. One patient died during the follow-up due to infection, and one patient developed end-stage renal disease during the follow-up. Three patients relapsed, with a median time of 49 months. CONCLUSION Our data demonstrated that ASCT is a safe and effective treatment for rigorously selected non-AL MGRS patients, with few serious treatment complications and high haematological and organ response rates.

Morphometric Analysis of Lysosomes in the Renal Tubule in Monoclonal Gammopathy Using Transmission Electron Microscopy: "Mottled Appearance" and Beyond.

Lysosomal “mottled appearance”, or uneven electron-dense content related to monoclonal gammopathy (MG), has been mainly described in light chain proximal tubulopathy (LCPT). We aimed to determine the ultrastructural characteristics of lysosomal mottled appearance in kidney biopsies and its association with LCPT and MG. Seventy-seven biopsies were grouped into LCPT (n = 5), MG conditions other than LCPT (n = 43), and non-MG conditions (n = 29). The mottled lysosomes in the renal tubules were evaluated using transmission electron microscopy and morphometric analysis. Mottled lysosomes were more prevalent (% of present cases) and frequent (no. of mottled lysosomes/20,000× ultramicroscopic field) in the LCPT group (100% and 8.20 ± 4.15/field) than in the MG (41.9% and 1.13 ± 2.05/field) and non-MG (37.9% and 0.80 ± 1.44/field) groups. In morphometric analysis of all mottled lysosomes (n = 520) detected from the 34 biopsies (5 LCPT, 18 MG, and 11 non-MG), we found that mottled lysosomes were larger, more irregular, and more electron-dense for the LCPT group than for the MG and non-MG groups. Therefore, mottled lysosomes can be present in disorders other than LCPT or even without MG. The morphological characteristics of mottled lysosomes could provide objective guidance for the diagnosis of LCPT.

Combined Heart Kidney Transplantation in a Previous Heart Transplant Recipient with Pheochromocytoma and Monoclonal Gammopathy of Uncertain Significance

Introduction Cancer survivors and patients with active malignancies are considered high risk for solid organ transplantation, as there is concern for recurrence and their concurrent co-morbidities. We present a case of combined kidney and repeat heart transplant (HT) for a patient with cardiac allograft vasculopathy (CAV) found to have pheochromocytoma and monoclonal gammopathy of unknown significance (MGUS) on pre-transplant evaluation. Case Report A 47-year-old male with a history of orthotopic HT 20 years prior due to viral myocarditis with post-transplant course complicated by CAV, chronic kidney disease stage 4 (presumed due to tacrolimus), MGUS, and atrial fibrillation presented with acute decompensated heart failure requiring inotropes. Echocardiogram revealed EF of 35%, global hypokinesis; RHC showed RA 19, RV 37/2, PA 38/17/25, PW 27, CI 1.6. LHC showed ISHLT CAV3: 70% mLAD lesion and diffuse 50-80% disease in distal LAD, Cx, and RCA. An IABP was placed and the patient was managed in the cardiac intensive care unit. Imaging revealed a right adrenal mass. He underwent an IR guided adrenal biopsy that demonstrated a pheochromocytoma, with biochemical markers of active tumor. The patient received a laparoscopic adrenalectomy and was listed for dual organ transplant. With worsening hemodynamics, he required peripheral VA-ECMO and received combined heart and renal transplant a month later. His post-operative course was complicated by RV dysfunction requiring central VA-ECMO, transplant pyelonephritis, and delayed renal allograft function requiring transient hemodialysis. Cardiac function recovered in 2 weeks post-transplant. Two and a half months post-transplant, a renal biopsy was performed for worsening acute kidney injury and demonstrated kappa light chain proximal tubulopathy. Given known MGUS, patient was diagnosed with monoclonal gammopathy of renal significance and started on started on Ixazomib-Cytoxan-Dexamethasone. He has shown improvement clinically and is now over one year post-transplant. Summary Combined heart kidney transplantation may be an option for selected patients with active malignancies like localized pheochromocytoma with MGUS. Long term follow up outcomes are unknown in this patient population. Cancer survivors and patients with active malignancies are considered high risk for solid organ transplantation, as there is concern for recurrence and their concurrent co-morbidities. We present a case of combined kidney and repeat heart transplant (HT) for a patient with cardiac allograft vasculopathy (CAV) found to have pheochromocytoma and monoclonal gammopathy of unknown significance (MGUS) on pre-transplant evaluation. A 47-year-old male with a history of orthotopic HT 20 years prior due to viral myocarditis with post-transplant course complicated by CAV, chronic kidney disease stage 4 (presumed due to tacrolimus), MGUS, and atrial fibrillation presented with acute decompensated heart failure requiring inotropes. Echocardiogram revealed EF of 35%, global hypokinesis; RHC showed RA 19, RV 37/2, PA 38/17/25, PW 27, CI 1.6. LHC showed ISHLT CAV3: 70% mLAD lesion and diffuse 50-80% disease in distal LAD, Cx, and RCA. An IABP was placed and the patient was managed in the cardiac intensive care unit. Imaging revealed a right adrenal mass. He underwent an IR guided adrenal biopsy that demonstrated a pheochromocytoma, with biochemical markers of active tumor. The patient received a laparoscopic adrenalectomy and was listed for dual organ transplant. With worsening hemodynamics, he required peripheral VA-ECMO and received combined heart and renal transplant a month later. His post-operative course was complicated by RV dysfunction requiring central VA-ECMO, transplant pyelonephritis, and delayed renal allograft function requiring transient hemodialysis. Cardiac function recovered in 2 weeks post-transplant. Two and a half months post-transplant, a renal biopsy was performed for worsening acute kidney injury and demonstrated kappa light chain proximal tubulopathy. Given known MGUS, patient was diagnosed with monoclonal gammopathy of renal significance and started on started on Ixazomib-Cytoxan-Dexamethasone. He has shown improvement clinically and is now over one year post-transplant. Combined heart kidney transplantation may be an option for selected patients with active malignancies like localized pheochromocytoma with MGUS. Long term follow up outcomes are unknown in this patient population.

Light Chain Restriction in Proximal Tubules-Implications for Light Chain Proximal Tubulopathy.

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.

Chronic lymphocytic leukemia and light chain proximal tubulopathy: A rare presentation of a common disease

Chronic lymphocytic leukemia (CLL) is the most common leukemia in developed countries. Kidney injuries related to CLL can occur via several mechanisms. Approximately 30%–40% of CLL patients with a kidney biopsy have monoclonal-protein related lesions. However, such lesions mostly involve glomeruli with only rare instances of tubule-interstitial disorders. There is only a single case report of a CLL patient who presented with crystalline light chain proximal tubulopathy (LCPT). Fanconi syndrome (FS) may provide clinical clues in these patients. We report a case of a CLL patient who presented with hypokalemia in the setting of advanced kidney failure in which serum monoclonal IgG kappa was detected. The patient demonstrated typical signs and symptoms of FS. The urinary retinol binding protein was also extremely elevated (638 times upper normal limit). A kidney biopsy revealed non-crystalline LCPT with CLL infiltration. FS in CLL is an extremely rare presentation, as only four cases had been previously reported. Of these, only a single case had crystalline LCPT. Our case is the first report of non-crystalline LCPT in a CLL patient. Obinutuzumab and Venetoclax were started to address the CLL, and an improvement in kidney function was noted thereafter.

Monoclonal Gammopathy-Related Kidney Diseases.

Monoclonal gammopathies occur secondary to a broad range of clonal B lymphocyte or plasma cell disorders, producing either whole or truncated monoclonal immunoglobulins. The kidneys are often affected by these monoclonal proteins, and, although not mutually exclusive, can involve the glomeruli, tubules, interstitium, and vasculature. The nephrotoxic potential of these monoclonal proteins is dependent on a variety of physicochemical characteristics that are responsible for the diverse clinicopathologic manifestations, including glomerular diseases with organized deposits, glomerular diseases with granular deposits, and other lesions, such as C3 glomerulopathy and thrombotic microangiopathy with unique pathophysiologic features. The diseases that involve primarily the tubulointerstitial and vascular compartments are light chain cast nephropathy, light chain proximal tubulopathy, crystal-storing histiocytosis, and crystalglobulin-induced nephropathy with distinct acute and chronic clinicopathologic features. The diagnosis of a monoclonal gammopathy-related kidney disease is established by identification of an underlying active or more commonly, low-grade hematologic malignancy, serologic evidence of a monoclonal gammopathy when detectable, and most importantly, monoclonal protein-induced pathologic lesions seen in a kidney biopsy, confirming the association with the monoclonal protein. Establishing a diagnosis may be challenging at times, particularly in the absence of an overt hematologic malignancy, with or without monoclonal gammopathy, such as proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Overall, the treatment is directed against the underlying hematologic disorder and the potential source of the monoclonal protein.

Rare presentation of kappa light chain proximal tubulopathy with fibrillar aggregates

Abstract Introduction/Objective Patients with dysproteinemias may show a spectrum of renal alterations due to organized deposits of excess immunoglobulins, including primary amyloidosis, myeloma cast nephropathy, monoclonal immunoglobulin deposition disease, and light chain proximal tubulopathy (LCPT). Among the least common is LCPT, which shows ultrastructural cytoplasmic light chain inclusions with crystalline morphology or rarely fibrillar aggregates. We present the case of a patient with LCPT with fibrillar aggregates that is the only such case registered in our large academic surgical pathology electronic database. Our aim is to increase understanding and recognition of this rare variant. Methods/Case Report A 73-year-old man presented with 540 mg/day proteinuria, serum creatinine 5.73 mg/dL, platelets 178,000/cc, and 20% plasma cells in his bone marrow biopsy specimen. Kidney needle biopsy cores examined by light, fluorescent and transmission electron microscopy (EM) showed kappa light chain cast nephropathy and kappa LCPT with fibrillary aggregates, the latter requiring unmasking of kappa epitopes using pronase-treated paraffin sections. Congo red stain was negative. By EM, proximal tubules contained intracellular bundles of tightly aggregated fibrils with mean fibril diameter of 7.7 +/- 1.6 nm. Individual bundles were variably shaped as round, oval, spicular or irregular blobs. Fibrils were not seen in glomeruli. Results (if a Case Study enter NA) NA Conclusion This rare presentation of LCPT with fibrillar aggregates reinforces the utility of renal biopsy diagnosis that includes careful ultrastructural examination of renal tubules. In the absence of EM, the unique fibrillar organization of these cytoplasmic light chain aggregates would otherwise go unrecognized.

Simultaneous Light-Chain Proximal Tubulopathy (with Crystals), Myeloma Casts Nephropathy, and Intratubular Amyloidosis in a Patient with Monoclonal Gammopathy of Renal Significance

Simultaneous Light-Chain Proximal Tubulopathy (with Crystals), Myeloma Casts Nephropathy, and Intratubular Amyloidosis in a Patient with Monoclonal Gammopathy of Renal Significance

Coincidental light chain induced proximal tubulopathy with lupus nephritis: a\xa0case report and review of the\xa0literature

BackgroundWe report a case of light chain proximal tubulopathy associated with lupus nephritis in a patient known to have systemic lupus erythematosus. The kidney can be injured in several ways in any of these disorders. Light chain proximal tubulopathy is a rare form of renal tubular injury that may occur in and complicate plasma cell dyscrasia, characterized by cytoplasmic inclusions of the monoclonal light chain within proximal tubular cells. Lupus nephritis is a common form of renal injury as it occurs in about 25–50% of adult patients with systemic lupus erythematosus.Case presentationWe present a 57-year-old African patient known to have systemic lupus erythematosus and hypertension presented with a new complaint of microscopic hematuria. A renal biopsy was performed and revealed lupus nephritis class II concurrently associated with light chain induced proximal tubulopathy. A subsequent bone marrow biopsy was performed, which revealed multiple myeloma.ConclusionsWe report a case of coincidental lupus nephritis and proximal tubulopathy featuring a combined constellation of rare histopathological features that might add to the relationship between systemic lupus and paraproteinemia.