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Clinical Kidney Journal Apr 2012Light chain proximal tubulopathy is a paraproteinemic-related kidney disease most commonly seen in patients with a plasma cell dyscrasia. The classic description is that...
Light chain proximal tubulopathy is a paraproteinemic-related kidney disease most commonly seen in patients with a plasma cell dyscrasia. The classic description is that of proximal tubules with kappa-restricted intracytoplasmic crystals in a patient with a clinical Fanconi's syndrome. Recently, other variants of light chain proximal tubulopathy have been described including those without crystal formation. We expand the morphologic spectrum in this report of a patient who presented with acute renal failure, proteinuria and hematuria. Biopsy revealed proximal tubulopathy in which the proximal tubules show intracytoplasmic amyloid formation. This is the first description, to our knowledge, of amyloid proximal tubulopathy.
PubMed: 29497513
DOI: 10.1093/ckj/sfs004 -
Frontiers in Medicine 2022Monoclonal gammopathy (MG) causes various nephropathies, which may suffice for cytoreductive therapy even in the absence of diagnostic criteria for multiple myeloma or...
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.
PubMed: 35419374
DOI: 10.3389/fmed.2022.723758 -
Kidney International Reports May 2021Plasma and B cells dyscrasias that overproduce monoclonal immunoglobulin free light chains (FLCs) affect the kidney frequently in various ways. The hematologic dyscrasia... (Review)
Review
Plasma and B cells dyscrasias that overproduce monoclonal immunoglobulin free light chains (FLCs) affect the kidney frequently in various ways. The hematologic dyscrasia responsible for the production of FLCs may or may not meet the criteria for cancer, such as multiple myeloma (MM) or lymphoma, or may remain subclinical. If there is overt malignancy, the accompanying kidney disorder is called myeloma- or lymphoma-associated. If the dyscrasia is subclinical, the associated kidney disorders are grouped as monoclonal gammopathy of renal significance. Glomeruli and tubules may both be involved. The proximal tubule disorders comprise a spectrum of interesting syndromes, which range in severity. This review focuses on the recent insights gained into the patterns and the mechanisms of proximal tubule toxicity of FLCs, including subtle transport disorders, such as proximal tubule acidosis, partial or complete Fanconi syndrome, or severe acute or chronic renal failure. Histologically, there may be crystal deposition in the proximal tubule cells, acute tubule injury, interstitial inflammation, fibrosis, and tubule atrophy. Specific structural alterations in the V domain of FLCs caused by somatic hypermutations are responsible for crystal formation as well as partial or complete Fanconi syndrome. Besides crystal formation, tubulointerstitial inflammation and proximal tubulopathy can be mediated by direct activation of inflammatory pathways through cytokines and Toll-like receptors due to cell stress responses induced by excessive FLC endocytosis into the proximal tubule cells. Therapy directed against the clonal source of the toxic light chain can prevent progression to more severe lesions and may help preserve kidney function.
PubMed: 34013100
DOI: 10.1016/j.ekir.2021.02.026 -
Clinical Nephrology Apr 2020Plasma cell dyscrasias, including multiple myeloma (MM), are associated with diverse forms of pathology in the kidney. Some pathologic lesions, including light chain... (Review)
Review
Plasma cell dyscrasias, including multiple myeloma (MM), are associated with diverse forms of pathology in the kidney. Some pathologic lesions, including light chain (myeloma) cast nephropathy (LCCN), are relatively common, while others, such as light chain proximal tubulopathy (LCPT), are less so. Both LCCN and LCPT are associated with clinical manifestations of acute kidney injury. Rare instances of coincidental LCPT and LCCN have been reported, but none to our knowledge of coincidental crystalline forms of these diseases, with similar forms appearing in the urine. While LCPT is usually associated with intracytoplasmic deposition of crystallized light chains, the intraluminal light chain casts in LCCN are typically amorphous and do not form crystals. We report here the co-occurrence of these two monoclonal crystalline forms of acute kidney injury in a 66-year-old woman with known history of κ-restricted multiple myeloma. Additionally, forms suggestive of a crystalline morphology were observed in the urine sediment. Clinicians who observe similar crystalline structures on renal biopsy or in urine sediment should have a high index of suspicion for underlying multiple myeloma as a unifying diagnosis.
Topics: Acute Kidney Injury; Aged; Crystallization; Female; Humans; Immunoglobulin Light Chains; Kidney Diseases; Kidney Tubules, Proximal; Multiple Myeloma; Urine
PubMed: 31907143
DOI: 10.5414/CN109770 -
World Journal of Hepatology Dec 2020The recommended monitoring tools for evaluating nucleot(s)ide analogue renal toxicity, such as estimated glomerular filtration rate (eGFR) and phosphatemia, are late...
BACKGROUND
The recommended monitoring tools for evaluating nucleot(s)ide analogue renal toxicity, such as estimated glomerular filtration rate (eGFR) and phosphatemia, are late markers of proximal tubulopathy. Multiple early markers are available, but no consensus exists on their use.
AIM
To determine the 24 mo prevalence of subclinical proximal tubulopathy (SPT), as defined with early biomarkers, in treated untreated hepatitis B virus (HBV)-monoinfected patients.
METHODS
A prospective, non-randomized, multicenter study of HBV-monoinfected patients with a low number of renal comorbidities was conducted. The patients were separated into three groups: Naïve, starting entecavir (ETV) treatment, or starting tenofovir disoproxil (TDF) treatment. Data on the early markers of SPT, the eGFR and phosphatemia, were collected quarterly. SPT was defined as a maximal tubular reabsorption of phosphate/eGFR below 0.8 mmoL/L and/or uric acid fractional excretion above 10%. The prevalence and cumulative incidence of SPT at month 24 (M24) were calculated. Quantitative data were analyzed using analyses of variance or Kruskal-Wallis tests, whereas chi-squared or Fisher's exact tests were used to analyze qualitative data. Multivariate analyses were used to adjust for any potential confounding factors.
RESULTS
Of the 196 patients analyzed, 138 (84 naïve, 28 starting ETV, and 26 starting TDF) had no SPT at inclusion. At M24, the prevalence of SPT was not statistically different between naïve and either treated group (21.1% 30.7%, 0.42 and 50.0% 30.7%, = 0.32 for ETV and TDF, respectively); no patient had an eGFR lower than 50 mL/min/1.73 m² or phosphatemia less than 0.48 mmoL/L. In the multivariate analysis, no explanatory variables were identified after adjustment. The cumulative incidence of SPT over 24 mo (25.5%, 13.3%, and 52.9% in the naïve, ETV, and TDF groups, respectively) tended to be higher in the TDF group the naïve group (hazard ratio: 2.283, = 0.05). SPT-free survival at M24 was 57.6%, 68.8%, and 23.5% for the naïve, ETV, and TDF groups, respectively. The median survival time without SPT, evaluated only in the TDF group, was 5.9 mo.
CONCLUSION
The prevalence and incidence of SPT was higher in TDF-treated patients compared to naïve patients. SPT in the naïve population suggests that HBV can induce renal tubular toxicity.
PubMed: 33442458
DOI: 10.4254/wjh.v12.i12.1326 -
Journal of the American Society of... Mar 2015Crystalline nephropathy refers to renal parenchymal deposition of crystals leading to kidney damage. The most common forms of crystalline nephropathy encountered in...
Crystalline nephropathy refers to renal parenchymal deposition of crystals leading to kidney damage. The most common forms of crystalline nephropathy encountered in renal pathology are nephrocalcinosis and oxalate nephropathy. Less frequent types include urate nephropathy, cystinosis, dihydroxyadeninuria, and drug-induced crystalline nephropathy (e.g., caused by indinavir or triamterene). Monoclonal proteins can also deposit in the kidney as crystals and cause tissue damage. This occurs in conditions such as light chain proximal tubulopathy, crystal-storing histiocytosis, and crystalglobulinemia. The latter is a rare complication of multiple myeloma that results from crystallization of monoclonal proteins in the systemic vasculature, leading to vascular injury, thrombosis, and occlusion. In this report, we describe a case of crystalglobulin-induced nephropathy and discuss its pathophysiology and the differential diagnosis of paraprotein-induced crystalline nephropathy.
Topics: Biopsy; Crystallization; Female; Humans; Kidney; Kidney Diseases; Middle Aged; Multiple Myeloma; Serum Globulins
PubMed: 25190731
DOI: 10.1681/ASN.2014050509 -
International Journal of Hematology Sep 2021
Topics: Aged, 80 and over; Biomarkers; Biopsy; Female; Humans; Immunoglobulin Light Chains; Kidney Diseases; Kidney Tubules, Proximal; Monoclonal Gammopathy of Undetermined Significance; Symptom Assessment
PubMed: 34275065
DOI: 10.1007/s12185-021-03193-9 -
Cells Dec 2022Tubulopathy plays a central role in the pathophysiology of diabetic kidney disease (DKD). Under diabetic conditions, the kidney proximal tubule cells (KPTCs) are exposed... (Review)
Review
Tubulopathy plays a central role in the pathophysiology of diabetic kidney disease (DKD). Under diabetic conditions, the kidney proximal tubule cells (KPTCs) are exposed to an extensive amount of nutrients, most notably glucose; these nutrients deteriorate KPTCs function and promote the development and progression of DKD. Recently, the facilitative glucose transporter 2 (GLUT2) in KPTCs has emerged as a central regulator in the pathogenesis of DKD. This has been demonstrated by identifying its specific role in enhancing glucose reabsorption and glucotoxicity, and by deciphering its effect in regulating the expression of the sodium-glucose transporter 2 (SGLT2) in KPTCs. Moreover, reduction/deletion of KPTC-GLUT2 has been recently found to ameliorate DKD, raising the plausible idea of considering it as a therapeutic target against DKD. However, the underlying molecular mechanisms by which GLUT2 exerts its deleterious effects in KPTCs remain vague. Herein, we review the current findings on the proximal tubule GLUT2 biology and function under physiologic conditions, and its involvement in the pathophysiology of DKD. Furthermore, we shed new light on its cellular regulation during diabetic conditions.
Topics: Humans; Kidney; Kidney Tubules, Proximal; Glucose; Diabetic Nephropathies; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 36611887
DOI: 10.3390/cells12010094 -
Advances in Chronic Kidney Disease Mar 2022Monoclonal gammopathies occur secondary to a broad range of clonal B lymphocyte or plasma cell disorders, producing either whole or truncated monoclonal immunoglobulins.... (Review)
Review
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.
Topics: Glomerulonephritis; Hematologic Neoplasms; Humans; Kidney; Kidney Diseases; Kidney Glomerulus; Paraproteinemias
PubMed: 35817530
DOI: 10.1053/j.ackd.2022.01.004 -
Kidney International Oct 2009
Topics: Fanconi Syndrome; Female; Humans; Immunoglobulin Light Chains; Kidney Tubules, Proximal; Lymphoma, Large B-Cell, Diffuse; Middle Aged; Spleen
PubMed: 19165173
DOI: 10.1038/ki.2008.666