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International Journal of Molecular... May 2021Lowe syndrome and Dent II disease are X-linked monogenetic diseases characterised by a renal reabsorption defect in the proximal tubules and caused by mutations in the...
Lowe syndrome and Dent II disease are X-linked monogenetic diseases characterised by a renal reabsorption defect in the proximal tubules and caused by mutations in the OCRL gene, which codes for an inositol-5-phosphatase. The life expectancy of patients suffering from Lowe syndrome is largely reduced because of the development of chronic kidney disease and related complications. There is a need for physiological human in vitro models for Lowe syndrome/Dent II disease to study the underpinning disease mechanisms and to identify and characterise potential drugs and drug targets. Here, we describe a proximal tubule organ on chip model combining a 3D tubule architecture with fluid flow shear stress that phenocopies hallmarks of Lowe syndrome/Dent II disease. We demonstrate the high suitability of our in vitro model for drug target validation. Furthermore, using this model, we demonstrate that proximal tubule cells lacking OCRL expression upregulate markers typical for epithelial-mesenchymal transition (EMT), including the transcription factor SNAI2/Slug, and show increased collagen expression and deposition, which potentially contributes to interstitial fibrosis and disease progression as observed in Lowe syndrome and Dent II disease.
Topics: Genetic Diseases, X-Linked; Humans; Kidney Tubules, Proximal; Lab-On-A-Chip Devices; Models, Biological; Mutation; Nephrolithiasis; Oculocerebrorenal Syndrome; Phenotype; Phosphoric Monoester Hydrolases
PubMed: 34069732
DOI: 10.3390/ijms22105361 -
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 -
Human Molecular Genetics Jul 2021Dent disease 1 (DD1) is a rare X-linked renal proximal tubulopathy characterized by low molecular weight proteinuria and variable degree of hypercalciuria,...
Dent disease 1 (DD1) is a rare X-linked renal proximal tubulopathy characterized by low molecular weight proteinuria and variable degree of hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressing to chronic kidney disease. Although mutations in the electrogenic Cl-/H+ antiporter ClC-5, which impair endocytic uptake in proximal tubule cells, cause the disease, there is poor genotype-phenotype correlation and their contribution to proximal tubule dysfunction remains unclear. To further discover the mechanisms linking ClC-5 loss-of-function to proximal tubule dysfunction, we have generated novel DD1 cellular models depleted of ClC-5 and carrying ClC-5 mutants p.(Val523del), p.(Glu527Asp) and p.(Ile524Lys) using the human proximal tubule-derived RPTEC/TERT1 cell line. Our DD1 cellular models exhibit impaired albumin endocytosis, increased substrate adhesion and decreased collective migration, correlating with a less differentiated epithelial phenotype. Despite sharing functional features, these DD1 cell models exhibit different gene expression profiles, being p.(Val523del) ClC-5 the mutation showing the largest differences. Gene set enrichment analysis pointed to kidney development, anion homeostasis, organic acid transport, extracellular matrix organization and cell-migration biological processes as the most likely involved in DD1 pathophysiology. In conclusion, our results revealed the pathways linking ClC-5 mutations with tubular dysfunction and, importantly, provide new cellular models to further study DD1 pathophysiology.
Topics: Animals; Biological Phenomena; Cell Line; Chloride Channels; Dent Disease; Endocytosis; Genetic Association Studies; Genetic Diseases, X-Linked; Humans; Hypercalciuria; Kidney Tubules, Proximal; Mutation; Nephrocalcinosis; Nephrolithiasis; Proteinuria
PubMed: 33987651
DOI: 10.1093/hmg/ddab131 -
Orphanet Journal of Rare Diseases May 2021Chronic kidney disease (CKD) is one of the main long-term prognosis factors in methylmalonic acidemia (MMA), a rare disease of propionate catabolism. Our objective was...
BACKGROUND
Chronic kidney disease (CKD) is one of the main long-term prognosis factors in methylmalonic acidemia (MMA), a rare disease of propionate catabolism. Our objective was to precisely address the clinical and biological characteristics of long-term CKD in MMA adolescent and adult patients.
PATIENTS AND METHODS
In this retrospective study, we included MMA patients older than 13 years who had not received kidney and/or liver transplantation. We explored tubular functions, with special attention to proximal tubular function. We measured glomerular filtration rate (mGFR) by iohexol clearance and compared it to estimated glomerular filtration rate (eGFR) by Schwartz formula and CKD-EPI.
RESULTS
Thirteen patients were included (M/F = 5/8). Median age was 24 years (13 to 32). Median mGFR was 57 mL/min/1.73 m (23.3 to 105 mL/min/1.73 m). Ten out of 13 patients had mGFR below 90 mL/min/1.73 m. No patient had significant glomerular proteinuria. No patient had complete Fanconi syndrome. Only one patient had biological signs suggestive of incomplete proximal tubulopathy. Four out of 13 patients had isolated potassium loss, related to a non-reabsorbable anion effect of urinary methylmalonate. Both Schwartz formula and CKD-EPI significantly overestimated GFR. Bias were respectively 16 ± 15 mL/min/1.73 m and 37 ± 22 mL/min/1.73 m.
CONCLUSION
CKD is a common complication of the MMA. Usual equations overestimate GFR. Therefore, mGFR should be performed to inform therapeutic decisions such as dialysis and/or transplantation. Mild evidence of proximal tubular dysfunction was found in only one patient, suggesting that other mechanisms are involved.
Topics: Adolescent; Adult; Amino Acid Metabolism, Inborn Errors; Creatinine; Glomerular Filtration Rate; Humans; Kidney; Renal Insufficiency, Chronic; Retrospective Studies; Young Adult
PubMed: 33985557
DOI: 10.1186/s13023-021-01851-z -
Kidney Medicine 2021Myeloma-related kidney disease has several manifestations; the 2 most common histologic diagnoses are myeloma cast nephropathy and acute tubular necrosis. We describe a...
Myeloma-related kidney disease has several manifestations; the 2 most common histologic diagnoses are myeloma cast nephropathy and acute tubular necrosis. We describe a case of different kidney pathologies occurring concomitantly in a patient found to have immunoglobulin A κ multiple myeloma. A White woman in her 70s presented with an 8-month history of back pain and was found to have nephrotic-range proteinuria and acute kidney injury. Serum calcium level was 12.6 mg/dL. Kidney biopsy showed κ light chain only proliferative glomerulonephritis with monoclonal immunoglobulin deposits, crystalglobulinemia, light chain proximal tubulopathy with κ light chain deposits, mild tubular atrophy, and interstitial fibrosis. Free κ light chain ratio was >1,000 mg/dL and free κ light chain level was 4,670 mg/dL. Within a week following treatment of hypercalcemia and initiation of chemotherapy, her acute kidney injury and hypercalcemia resolved. This case highlights the many kidney manifestations of multiple myeloma and that prompt management targeting these manifestations, including hypercalcemia, can improve clinical outcomes.
PubMed: 33851128
DOI: 10.1016/j.xkme.2020.10.013 -
BMC Nephrology Apr 2021Plasma cell dyscrasias (PCD) are characterized by an abnormal production of intact monoclonal immunoglobulins or parts such as heavy or light chains. In most cases, the...
BACKGROUND
Plasma cell dyscrasias (PCD) are characterized by an abnormal production of intact monoclonal immunoglobulins or parts such as heavy or light chains. In most cases, the monoclonal protein (also termed paraprotein) is produced by a clonal plasma cell population. The production of monoclonal proteins can result in deposits of various types and localization depending on the type, amount, and electrochemical properties of the paraprotein. One histopathologic presentation, albeit rare, are crystalline deposits. They can form in various organs and hence cause a wide spectrum of symptoms.
CASE PRESENTATION
A 49-year-old man presented to the emergency department with eyestrain and foreign body sensation after overhead drilling. Examination of the eyes revealed crystalline deposits in the cornea of both eyes. After additional diagnostic testing, deposits were attributed to free light chains. Monoclonal gammopathy of undetermined significance (MGUS) was diagnosed according to serum electrophoresis and immunofixation. Four years later, new onset of proteinuria was detected. A percutaneous biopsy of the kidney showed severe light chain podocytopathy with secondary focal segmental glomerulosclerosis (FSGS) and light chain proximal tubulopathy (LCPT). In these lesions, crystalline deposits identical to the corneal deposits were found in ultrastructural and immunofluorescent analysis. The patient was diagnosed with monoclonal gammopathy of renal significance (MGRS), and a plasma cell directed therapy was initiated.
CONCLUSIONS
PCD can present with a wide array of symptoms and are notoriously difficult to diagnose. Extrarenal manifestations such as crystalline deposits in the cornea are one possible manifestation. The case presented herein emphasizes the notion that extrarenal paraprotein deposits warrant a thorough search for the underlying clonal disease.
Topics: Biopsy; Cornea; Diagnostic Errors; Humans; Kidney; Male; Middle Aged; Monoclonal Gammopathy of Undetermined Significance; Paraproteinemias
PubMed: 33823814
DOI: 10.1186/s12882-021-02309-x -
Journal of the American Society of... Jun 2021The transepithelial transport of electrolytes, solutes, and water in the kidney is a well-orchestrated process involving numerous membrane transport systems. Basolateral...
BACKGROUND
The transepithelial transport of electrolytes, solutes, and water in the kidney is a well-orchestrated process involving numerous membrane transport systems. Basolateral potassium channels in tubular cells not only mediate potassium recycling for proper Na,K-ATPase function but are also involved in potassium and pH sensing. Genetic defects in cause EAST/SeSAME syndrome, characterized by renal salt wasting with hypokalemic alkalosis associated with epilepsy, ataxia, and sensorineural deafness.
METHODS
A candidate gene approach and whole-exome sequencing determined the underlying genetic defect in eight patients with a novel disease phenotype comprising a hypokalemic tubulopathy with renal salt wasting, disturbed acid-base homeostasis, and sensorineural deafness. Electrophysiologic studies and surface expression experiments investigated the functional consequences of newly identified gene variants.
RESULTS
We identified mutations in the gene encoding KCNJ16, which along with KCNJ15 and KCNJ10, constitutes the major basolateral potassium channel of the proximal and distal tubules, respectively. Coexpression of mutant KCNJ16 together with KCNJ15 or KCNJ10 in oocytes significantly reduced currents.
CONCLUSIONS
Biallelic variants in were identified in patients with a novel disease phenotype comprising a variable proximal and distal tubulopathy associated with deafness. Variants affect the function of heteromeric potassium channels, disturbing proximal tubular bicarbonate handling as well as distal tubular salt reabsorption.
Topics: Acid-Base Imbalance; Adolescent; Adult; Alleles; Animals; Child, Preschool; Female; Hearing Loss, Sensorineural; Humans; Hypokalemia; Infant; Infant, Newborn; Kidney Diseases; Kidney Tubules; Loss of Function Mutation; Male; Mice; Nephrons; Oocytes; Pedigree; Phenotype; Potassium Channels, Inwardly Rectifying; RNA, Messenger; Renal Reabsorption; Salts; Exome Sequencing; Xenopus laevis; Young Adult
PubMed: 33811157
DOI: 10.1681/ASN.2020111587 -
CEN Case Reports Aug 2021We herein report a case of a combined crystalline light chain tubulopathy, podocytopathy, histiocytosis, and cast nephropathy in a patient with monoclonal gammopathy of...
We herein report a case of a combined crystalline light chain tubulopathy, podocytopathy, histiocytosis, and cast nephropathy in a patient with monoclonal gammopathy of renal significance (MGRS). A 66-year-old female with impaired renal function was referred to our department. Despite intravenous fluid resuscitation, the kidney function worsened progressively; thus, a kidney biopsy was performed. The kidney biopsy revealed light chain proximal tubulopathy (LCPT) with crystals, light chain crystal podocytopathy (LCCP), crystal-storing histiocytosis (CSH), and light chain cast nephropathy (LCCN). Of note, LCCP and CSH were diagnosed via electron microscopy. Serum and urine immunoelectrophoresis (IEP) revealed the presence of monoclonal Bence-Jones protein and free κ light chains. Bone marrow aspiration showed < 10% plasma cell proliferation. Thus, we had encountered a rare case in which a variety of kidney lesions were combined with MGRS. Most of the LCPT, LCCP, and CSH cases show monoclonal IgG κ, while our case showed Bence-Jones protein κ.
Topics: Aged; Bence Jones Protein; Female; Histiocytosis; Humans; Immunoglobulin kappa-Chains; Kidney Diseases; Kidney Tubules, Proximal; Microscopy, Immunoelectron; Podocytes
PubMed: 33675012
DOI: 10.1007/s13730-021-00588-9 -
Human Mutation May 2021Mutations in the CLCN5 gene encoding the 2Cl /1H exchanger ClC-5 are associated with Dent disease 1, an inherited renal disorder characterized by low-molecular-weight...
Mutations in the CLCN5 gene encoding the 2Cl /1H exchanger ClC-5 are associated with Dent disease 1, an inherited renal disorder characterized by low-molecular-weight (LMW) proteinuria and hypercalciuria. In the kidney, ClC-5 is mostly localized in proximal tubule cells, where it is thought to play a key role in the endocytosis of LMW proteins. Here, we investigated the consequences of eight previously reported pathogenic missense mutations of ClC-5 surrounding the "proton glutamate" that serves as a crucial H -binding site for the exchanger. A complete loss of function was observed for a group of mutants that were either retained in the endoplasmic reticulum of HEK293T cells or unstainable at plasma membrane due to proteasomal degradation. In contrast, the currents measured for the second group of mutations in Xenopus laevis oocytes were reduced. Molecular dynamics simulations performed on a ClC-5 homology model demonstrated that such mutations might alter ClC-5 protonation by interfering with the water pathway. Analysis of clinical data from patients harboring these mutations demonstrated no phenotype/genotype correlation. This study reveals that mutations clustered in a crucial region of ClC-5 have diverse molecular consequences in patients with Dent disease 1, ranging from altered expression to defects in transport.
Topics: Chloride Channels; Dent Disease; Genetic Diseases, X-Linked; Glutamic Acid; HEK293 Cells; Humans; Nephrolithiasis; Protons
PubMed: 33600050
DOI: 10.1002/humu.24184 -
Frontiers in Medicine 2020Overproduction of human light chains (LCs) and immunoglobulins can result in various forms of renal disease such as cast nephropathy, monoclonal immunoglobulin...
Overproduction of human light chains (LCs) and immunoglobulins can result in various forms of renal disease such as cast nephropathy, monoclonal immunoglobulin deposition disease, LC proximal tubulopathy, AL amyloidosis, and crystal storing histiocytosis. This is caused by cellular uptake of LCs and overwhelmed intracellular transport and degradation in patients with high urine LC concentrations. LC kappa and lambda purification was evaluated by sodium dodecyl sulfate gel electrophoresis. LC and myeloma protein binding to immobilized renal proteins was measured by enzyme-linked immunosorbent assay (ELISA). The human protein microarray (HuProt™) was screened with purified kappa and lambda LC. Identified LC partners were subsequently analyzed for renal expression sites using protein databases, Human Protein Atlas, UniProt, and Bgee. Binding of urinary LCs and immunoglobulins to immobilized whole renal proteins from 22 patients with myeloma or plasma cell dyscrasia was shown by ELISA. Forty lambda and 23 kappa interaction partners were identified from HuProt™ array screens, of which 21 were shared interactors. Among the total of 42 interactors, 12 represented cell surface proteins. Lambda binding signals were approximately 40% higher than kappa signals. LC interaction with renal cells and disease-causing pathologies are more complex than previously thought. It involves an extended spectrum of proteins expressed throughout the nephron, and their identification has been enabled by recently developed methods of protein analysis such as protein microarray screening. Further biochemical studies on interacting proteins are warranted to elucidate their clinical relevance.
PubMed: 33521021
DOI: 10.3389/fmed.2020.609582