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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 -
AIDS (London, England) Jun 2024To evaluate the efficacy and safety of 96 weeks of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) treatment in participants switching from dolutegravir... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To evaluate the efficacy and safety of 96 weeks of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) treatment in participants switching from dolutegravir (DTG)-based therapy.
DESIGN
Studies 1489 (NCT02607930) and 1490 (NCT02607956) were phase 3 randomized, double-blind, active-controlled, first-line therapy trials in people with HIV-1. After 144 weeks of DTG-based or B/F/TAF treatment, participants could enter a 96-week open-label extension (OLE) of B/F/TAF.
METHODS
A pooled analysis evaluated viral suppression (HIV-1 RNA <50 copies/ml) and changes in CD4 + cell count at OLE Weeks 48 and 96, treatment-emergent resistance, safety, and tolerability after switch from a DTG-based regimen to B/F/TAF. Outcomes by prior treatment were summarized using descriptive statistics and compared by two-sided Wilcoxon rank sum test.
RESULTS
At OLE Week 96, participants who switched to B/F/TAF ( N = 519) maintained high levels of virologic suppression (99.5 and 99.1% in those switching from DTG/abacavir/lamivudine and DTG+F/TAF, respectively) and CD4 + cell count, with no treatment-emergent resistance to B/F/TAF. Twenty-one participants experienced drug-related adverse events after switching, with diarrhea, weight gain, and headache occurring most commonly. There were no cases of proximal renal tubulopathy, drug-related Grade 4 adverse events, or serious adverse events. Two participants discontinued B/F/TAF due to treatment-related adverse events. Participants who switched from DTG/abacavir/lamivudine experienced statistically significant greater weight gain than those who switched from DTG+F/TAF; however, median weight change from the blinded phase baseline to OLE Week 96 was numerically similar across treatment groups.
CONCLUSION
This medium-term analysis demonstrates the safety and efficacy of switching to B/F/TAF from a DTG-containing regimen in people with HIV-1.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Young Adult; Adenine; Alanine; Amides; Anti-HIV Agents; CD4 Lymphocyte Count; Double-Blind Method; Drug Substitution; Drug-Related Side Effects and Adverse Reactions; Emtricitabine; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV-1; Oxazines; Piperazines; Pyridones; Tenofovir; Treatment Outcome; Viral Load
PubMed: 38349226
DOI: 10.1097/QAD.0000000000003865 -
Journal of Medical Case Reports Aug 2021We 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... (Review)
Review
BACKGROUND
We 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 PRESENTATION
We 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.
CONCLUSIONS
We 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.
Topics: Adult; Biopsy; Humans; Kidney Diseases; Kidney Tubules, Proximal; Lupus Nephritis; Middle Aged; Multiple Myeloma; Paraproteinemias
PubMed: 34344460
DOI: 10.1186/s13256-021-02990-4 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Oct 2022Tubulointerstitial diseases is one of the common causes of renal dysfunction. Some rare pathological types are easy to be misdiagnosed and missedly diagnosed because of...
OBJECTIVES
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
Topics: Humans; Hematuria; Immunoglobulin Light Chains; Multiple Myeloma; Proteinuria; Nephritis, Interstitial; Acute Kidney Injury; Anemia; Renal Insufficiency, Chronic
PubMed: 36411687
DOI: 10.11817/j.issn.1672-7347.2022.220127 -
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 -
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 -
EJHaem Nov 2022Due to differences in the protein folding mechanisms, it is exceedingly rare for amyloid light chain (AL) amyloidosis and monoclonal gammopathy of renal significance...
Due to differences in the protein folding mechanisms, it is exceedingly rare for amyloid light chain (AL) amyloidosis and monoclonal gammopathy of renal significance (MGRS) to coexist. We herein report the first case of concurrent AL amyloidosis and a subclass of MGRS, light chain proximal tubulopathy (LCPT). The 53-year-old female was diagnosed with smoldering myeloma immunoglobulin G and AL amyloidosis with deposits in fat and gastrointestinal tissue. The kidney biopsy did not show amyloid deposits but electron microscopy revealed the presence of LCPT with crystal formation in proximal tubular epithelial cells. This case illustrates the complex pathophysiology of protein deposition in monoclonal gammopathies.
PubMed: 36467828
DOI: 10.1002/jha2.555 -
BMC Nephrology Aug 2020The nucleotide reverse transcriptase inhibitor Tenofovir Alafenamide (TAF) is a novel pro-drug of tenofovir (TFV) and possesses a superior renal safety profile compared...
BACKGROUND
The nucleotide reverse transcriptase inhibitor Tenofovir Alafenamide (TAF) is a novel pro-drug of tenofovir (TFV) and possesses a superior renal safety profile compared with tenofovir disoproxil fumerate (TDF). Due to unique pharmacokinetic characteristics, treatment with TAF is not associated with significant renal proximal tubular accumulation of TFV. TAF is associated with a lower risk of acute kidney injury, chronic kidney disease, proteinuria and renal proximal tubular dysfunction than treatment with TDF. No cases of Fanconi syndrome have been reported in clinical trials of TAF. It is unknown whether treatment with TAF can lead to accumulation of TFV in proximal tubular cells and cause nephrotoxicity under certain clinical circumstances.
CASE PRESENTATION
Here we report the case of a patient on stable TAF-based antiretroviral therapy with for HIV-1 infection who developed proximal tubulopathy when treated with gentamicin for febrile neutropenia in the context of relapsed Hodgkin lymphoma. Eighteen days after commencing chemotherapy for relapsed Hodgkin lymphoma the patient presented to hospital with fevers, hypotension and neutropenia. The patient was commenced on piperacillin, tazobactam and gentamicin. Within 24 h the patient developed marked hypokalaemia and hypophosphataemia requiring intravenous replacement therapy. There was proteinuria, glycosuria and evidence of marked urinary electrolyte wasting, consistent with acute proximal tubular dysfunction. Eleven days after the gentamicin was stopped the serum biochemistry normalised. The urinary electrolyte wasting and proteinuria had improved, and the glycosuria had resolved.
CONCLUSION
This is the first case report to describe acute renal proximal tubulopathy in an HIV-infected patient treated with TAF and gentamicin. As the number of patients prescribed TAF outside the clinical trial setting increases, so too does the potential for previously unreported drug interactions and adverse events. Clinicians need to be aware of potential unreported adverse drug reactions as the use of TAF becomes increasingly common in clinical practice.
Topics: Acute Disease; Alanine; Anti-Bacterial Agents; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Chemotherapy-Induced Febrile Neutropenia; Deprescriptions; Drug Interactions; Fanconi Syndrome; Gentamicins; Glycosuria; HIV Infections; Hodgkin Disease; Humans; Hypokalemia; Hypophosphatemia; Male; Middle Aged; Proteinuria; Tenofovir
PubMed: 32787843
DOI: 10.1186/s12882-020-01981-9 -
Clinical Journal of the American... Sep 2008Lowe syndrome is defined by congenital cataracts, mental retardation, and proximal tubulopathy and is due to mutations in OCRL. Recently, mutations in OCRL were found to...
BACKGROUND AND OBJECTIVES
Lowe syndrome is defined by congenital cataracts, mental retardation, and proximal tubulopathy and is due to mutations in OCRL. Recently, mutations in OCRL were found to underlie some patients with Dent disease, characterized by low molecular weight proteinuria, hypercalciuria, and nephrocalcinosis. This phenotypic heterogeneity is poorly understood.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
The renal phenotype of 16 patients with Lowe syndrome (10.9 +/- 7.0 yr) under care of the authors was characterized to define overlap of symptoms with Dent disease and infer clues about OCRL function. Medical charts of patients were reviewed for data regarding glomerular filtration rate and markers of proximal tubular function.
RESULTS
All patients had low molecular weight proteinuria and albuminuria. Lysosomal enzymuria was elevated in all 11 patients assessed. Fifteen patients had hypercalciuria, and 14 aminoaciduria. Seven patients required bicarbonate and three required phosphate replacement; all others maintained normal serum values without supplementation. None of the patients had detectable glycosuria, and none had clinically overt rickets. GFR was mildly to moderately impaired and highly variable, with a trend of deterioration with age.
CONCLUSIONS
Patients with Lowe syndrome do not have renal Fanconi syndrome but a selective proximal tubulopathy, variable in extent and dominated by low molecular weight proteinuria and hypercalciuria, the classical features of Dent disease. These findings suggest that OCRL and ClC-5, the chloride channel mutated in Dent disease, are involved in similar reabsorption pathways in the proximal tubule.
Topics: Acidosis, Renal Tubular; Adolescent; Adult; Albuminuria; Amino Acid Metabolism, Inborn Errors; Child; Child, Preschool; Europe; Fanconi Syndrome; Female; Glomerular Filtration Rate; Glycosuria; Humans; Hypercalciuria; Hypophosphatemia, Familial; Kidney Tubules, Proximal; Lysosomal Storage Diseases; Male; Mutation; Nephrocalcinosis; Oculocerebrorenal Syndrome; Phenotype; Phosphoric Monoester Hydrolases; Proteinuria; Renal Tubular Transport, Inborn Errors
PubMed: 18480301
DOI: 10.2215/CJN.00520108 -
Revista Do Instituto de Medicina... 2022Tenofovir Disoproxil Fumarate (TDF) is one of the drugs in the initial first-line antiretroviral regimen for the treatment of hepatitis B and HIV infections. Despite its... (Review)
Review
Tenofovir Disoproxil Fumarate (TDF) is one of the drugs in the initial first-line antiretroviral regimen for the treatment of hepatitis B and HIV infections. Despite its effectiveness and few adverse effects, it is related to renal and bone toxicity. We described two cases of HIV-positive middle-aged women who had been using TDF for two and four years (cases 1 and 2, respectively) and were admitted to the emergency room. Case 1 presented with metabolic ileum and diffuse bone pain while case 2 presented with bilateral coxo-femoral pain after a fall from standing height. Both cases had similar laboratory tests: hyperchloremic metabolic acidosis, hypophosphatemia, hypokalemia, hypouricemia and elevated plasma creatinine. In urinary exams, there was evidence of renal loss of electrolytes, justifying the serum alterations, in addition to glucosuria and proteinuria. The bone pain investigation identified bone fractures and reduced bone mineral density, together with increased levels of parathyroid hormone, alkaline phosphatase and vitamin D deficiency. These two cases illustrate the spectrum of adverse renal and bone effects associated with TDF use. TDF was discontinued and treatment was focused on correcting the electrolyte disturbances and acidosis, in addition to controlling the bone disease through vitamin D and calcium supplementation. The renal changes found in both cases characterized the Fanconi's syndrome, and occurred due to TDF toxicity to proximal tubule cells mitochondria. Bone toxicity occurred due to direct interference of TDF in bone homeostasis, in addition to vitamin D deficiency and phosphaturia resulting from tubulopathy. During the follow-up, both cases evolved with chronic kidney disease and in one of them, the Fanconi's syndrome did not revert. We emphasize the need to monitor markers of bone metabolism and glomerular and tubular functions in patients using TDF.
Topics: Anti-HIV Agents; Female; HIV Infections; Hepatitis B; Humans; Kidney; Kidney Diseases; Middle Aged; Tenofovir
PubMed: 35170711
DOI: 10.1590/S1678-9946202264010