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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 -
The Journal of Antimicrobial... Mar 2022Data evaluating the risk of proximal tubular dysfunction in women receiving tenofovir disoproxil fumarate for the prevention of mother-to-child transmission (PMTCT) of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Data evaluating the risk of proximal tubular dysfunction in women receiving tenofovir disoproxil fumarate for the prevention of mother-to-child transmission (PMTCT) of HBV are scarce.
OBJECTIVES
To assess the risk of proximal tubulopathy in pregnant women receiving tenofovir disoproxil fumarate for PMTCT of HBV.
PATIENTS AND METHODS
We used urine samples collected from HBV monoinfected pregnant women who participated in a Phase III, multicentre, randomized, double-blind, placebo-controlled clinical trial assessing a tenofovir disoproxil fumarate short course from 28 weeks gestational age (28-wk-GA) to 2 months post-partum (2-months-PP) for PMTCT of HBV in Thailand. Markers of tubular dysfunction, including retinol binding protein, kidney injury molecule-1, α1-microglobuin and β2-microglobulin, were assayed at 28- and 32-wk-GA and 2-months-PP visits. Proximal tubulopathy was defined as the presence of ≥2 of the following: tubular proteinuria, euglycaemic glycosuria and increased urinary phosphate.
RESULTS
A total of 291 women participated in the study. No kidney-related adverse events were severe, and none led to tenofovir disoproxil fumarate discontinuation. At 2-months-PP, 3 of the 120 (3%) evaluated women in the tenofovir disoproxil fumarate group experienced proximal tubulopathy versus 3 of 125 (2%) in the placebo group (P = 1.00). None of the six women met the criteria for proximal tubulopathy at 12-months-PP but proteinuria persisted in three of them. No growth abnormalities were found at 1 year of age in infants born to mothers with proximal tubulopathy at 2-months-PP.
CONCLUSIONS
In these HBV-infected pregnant and breastfeeding women, tenofovir disoproxil fumarate administered from 28-wk-GA to 2-months-PP was not associated with a higher risk of proximal tubulopathy.
Topics: Antiviral Agents; Child, Preschool; Female; Hepatitis B virus; Humans; Infant; Infectious Disease Transmission, Vertical; Pregnancy; Pregnancy Complications, Infectious; Pregnant Women; Tenofovir
PubMed: 35045168
DOI: 10.1093/jac/dkab490 -
International Journal of Molecular... Jan 2023Cadmium (Cd) is a toxic metal that accumulates in kidneys, especially in the proximal tubular epithelial cells, where virtually all proteins in the glomerular...
Cadmium (Cd) is a toxic metal that accumulates in kidneys, especially in the proximal tubular epithelial cells, where virtually all proteins in the glomerular ultrafiltrate are reabsorbed. Here, we analyzed archived data on the estimated glomerular filtration rate (eGFR) and excretion rates of Cd (E), total protein (E), albumin (E), β-microglobulin (E), and α1-microglobulin (E), which were recorded for residents of a Cd contamination area and a low-exposure control area of Thailand. Excretion of Cd and all proteins were normalized to creatinine clearance (C) as E/C and E/C to correct for differences among subjects in the number of surviving nephrons. Low eGFR was defined as eGFR ≤ 60 mL/min/1.73 m, while proteinuria was indicted by E/C ≥ 20 mg/L of filtrate. E/C varied directly with E/C (β = 0.263, < 0.001) and age (β = 0.252, < 0.001). In contrast, eGFR values were inversely associated with E/C (β = -0.266, < 0.001) and age (β = -0.558, < 0.001). At E/C > 8.28 ng/L of filtrate, the prevalence odds ratios for proteinuria and low eGFR were increased 4.6- and 5.1-fold, respectively ( < 0.001 for both parameters). Thus, the eGFR and tubular protein retrieval were both simultaneously diminished by Cd exposure. Of interest, E/C was more closely correlated with E/C ( = 0.507), E ( = 0.430), and E/C ( = 0.364) than with E/C ( = 0.152). These data suggest that Cd may differentially reduce the ability of tubular epithelial cells to reclaim proteins, resulting in preferential reabsorption of albumin.
Topics: Humans; Cadmium; Proteinuria; Kidney; Kidney Glomerulus; Glomerular Filtration Rate; beta 2-Microglobulin; Albumins; Creatinine
PubMed: 36768208
DOI: 10.3390/ijms24031893 -
Nefrologia 2022Gout is recurrent inflammatory arthritis caused by the deposition of monosodium urate crystals in the joints. The risk factors that predispose to suffering from gout... (Review)
Review
Gout is recurrent inflammatory arthritis caused by the deposition of monosodium urate crystals in the joints. The risk factors that predispose to suffering from gout include non-modifiable factors such as gender, age, ethnicity and genetics, and modifiable factors such as diet and lifestyle. It has been shown that the heritability of uric acid levels in the blood is greater than 30%, which indicates that genetics play a key role in these levels. Hyperuricaemia is often a consequence of reduced renal urate excretion since more than 70% is excreted by the kidneys, mainly through the proximal tubule. The mechanisms that explain that hyperuricaemia associated with reduced renal urate excretion is, to a large extent, a proximal renal tubular disorder, have begun to be understood following the identification of two genes that encode the URAT1 and GLUT9 transporters. When they are carriers of loss-of-function mutations, they explain the two known variants of renal tubular hypouricaemia. Some polymorphisms in these genes may have an opposite gain-of-function effect, with a consequent increase in urate reabsorption. Conversely, loss-of-function polymorphisms in other genes that encode transporters involved in urate excretion (ABCG2, ABCC4) can lead to hyperuricaemia. Genome-wide association study (GWAS) methods have made it possible to locate new gout-related loci associated with reduced renal urate excretion (NIPAL1, FAM35A).
Topics: Genome-Wide Association Study; Gout; Humans; Hyperuricemia; Kidney Diseases; Nephrologists; Renal Elimination; Uric Acid
PubMed: 36210617
DOI: 10.1016/j.nefroe.2022.05.007 -
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 -
American Journal of Physiology. Renal... Feb 2021The various forms of Fanconi renotubular syndromes (FRTS) offer significant challenges for clinicians and present unique opportunities for scientists who study proximal... (Review)
Review
The various forms of Fanconi renotubular syndromes (FRTS) offer significant challenges for clinicians and present unique opportunities for scientists who study proximal tubule physiology. This review will describe the clinical characteristics, genetic underpinnings, and underlying pathophysiology of the major forms of FRST. Although the classic forms of FRTS will be presented (e.g., Dent disease or Lowe syndrome), particular attention will be paid to five of the most recently discovered FRTS subtypes caused by mutations in the genes encoding for L-arginine:glycine amidinotransferase (), solute carrier family 34 (type Ii sodium/phosphate cotransporter), member 1 (), enoyl-CoAhydratase/3-hydroxyacyl CoA dehydrogenase (), hepatocyte nuclear factor 4A (), or NADH dehydrogenase complex I, assembly factor 6 (). We will explore how mutations in these genes revealed unexpected mechanisms that led to compromised proximal tubule functions. We will also describe the inherent challenges associated with gene discovery studies based on findings derived from small, single-family studies by focusing the story of FRTS type 2 (). Finally, we will explain how extensive alternative splicing of HNF4A has resulted in confusion with mutation nomenclature for FRTS type 4.
Topics: Fanconi Syndrome; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; Kidney Tubules, Proximal; Mutation
PubMed: 33283647
DOI: 10.1152/ajprenal.00214.2020 -
Indian Journal of Pediatrics Sep 2014Ifosfamide is commonly used as a chemotherapeutic agent in children. The authors report a 4-y-old boy who developed proximal renal tubulopathy with florid rickets a year...
Ifosfamide is commonly used as a chemotherapeutic agent in children. The authors report a 4-y-old boy who developed proximal renal tubulopathy with florid rickets a year after completion of ifosfamide therapy for Ewing's sarcoma. After initiation of treatment, there was complete healing of rickets and he did not need supplements beyond 18 mo. Growth monitoring and musculoskeletal system examination is important in all children who have received ifosfamide therapy. Routine monitoring for nephrotoxicity during and after ifosfamide therapy helps in early identification and intervention.
Topics: Antineoplastic Agents, Alkylating; Bone Neoplasms; Child, Preschool; Chronic Kidney Disease-Mineral and Bone Disorder; Humans; Ifosfamide; Male; Sarcoma, Ewing
PubMed: 23912821
DOI: 10.1007/s12098-013-1112-x -
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 -
Diabetologia Jan 2023Senescent renal tubular cells may be linked to diabetic kidney disease (DKD)-related tubulopathy. We studied mice with or without diabetes in which hedgehog interacting...
Hedgehog interacting protein activates sodium-glucose cotransporter 2 expression and promotes renal tubular epithelial cell senescence in a mouse model of type 1 diabetes.
AIMS/HYPOTHESIS
Senescent renal tubular cells may be linked to diabetic kidney disease (DKD)-related tubulopathy. We studied mice with or without diabetes in which hedgehog interacting protein (HHIP) was present or specifically knocked out in renal tubules (Hhip-KO), hypothesising that local deficiency of HHIP in the renal tubules would attenuate tubular cell senescence, thereby preventing DKD tubulopathy.
METHODS
Low-dose streptozotocin was employed to induce diabetes in both Hhip-KO and control (Hhip) mice. Transgenic mice overexpressing Hhip in renal proximal tubular cells (RPTC) (Hhip-Tg) were used for validation, and primary RPTCs and human RPTCs (HK2) were used for in vitro studies. Kidney morphology/function, tubular senescence and the relevant molecular measurements were assessed.
RESULTS
Compared with Hhip mice with diabetes, Hhip-KO mice with diabetes displayed lower blood glucose levels, normalised GFR, ameliorated urinary albumin/creatinine ratio and less severe DKD, including tubulopathy. Sodium-glucose cotransporter 2 (SGLT2) expression was attenuated in RPTCs of Hhip-KO mice with diabetes compared with Hhip mice with diabetes. In parallel, an increased tubular senescence-associated secretory phenotype involving release of inflammatory cytokines (IL-1β, IL-6 and monocyte chemoattractant protein-1) and activation of senescence markers (p16, p21, p53) in Hhip mice with diabetes was attenuated in Hhip-KO mice with diabetes. In contrast, Hhip-Tg mice had increased tubular senescence, which was inhibited by canagliflozin in primary RPTCs. In HK2 cells, HHIP overexpression or recombinant HHIP increased SGLT2 protein expression and promoted cellular senescence by targeting both ataxia-telangiectasia mutated and ataxia-telangiectasia and Rad3-related-mediated cell arrest.
CONCLUSIONS/INTERPRETATION
Tubular HHIP deficiency prevented DKD-related tubulopathy, possibly via the inhibition of SGLT2 expression and cellular senescence.
Topics: Animals; Humans; Mice; Diabetes Mellitus, Type 1; Epithelial Cells; Hedgehog Proteins; Sodium-Glucose Transporter 2; Carrier Proteins; Membrane Glycoproteins; Mice, Transgenic; Diabetes Mellitus, Experimental; Kidney Tubules; Cellular Senescence
PubMed: 36260124
DOI: 10.1007/s00125-022-05810-6 -
Nefrologia Sep 2021Gout is recurrent inflammatory arthritis caused by the deposition of monosodium urate crystals in the joints. The risk factors that predispose to suffering from gout... (Review)
Review
Gout is recurrent inflammatory arthritis caused by the deposition of monosodium urate crystals in the joints. The risk factors that predispose to suffering from gout include non-modifiable factors such as gender, age, ethnicity and genetics, and modifiable factors such as diet and lifestyle. It has been shown that the heritability of uric acid levels in the blood is greater than 30%, which indicates that genetics play a key role in these levels. Hyperuricaemia is often a consequence of reduced renal urate excretion since more than 70% is excreted by the kidneys, mainly through the proximal tubule. The mechanisms that explain that hyperuricaemia associated with reduced renal urate excretion is, to a large extent, a proximal renal tubular disorder, have begun to be understood following the identification of two genes that encode the URAT1 and GLUT9 transporters. When they are carriers of loss-of-function mutations, they explain the two known variants of renal tubular hypouricaemia. Some polymorphisms in these genes may have an opposite gain-of-function effect, with a consequent increase in urate reabsorption. Conversely, loss-of-function polymorphisms in other genes that encode transporters involved in urate excretion (ABCG2, ABCC4) can lead to hyperuricaemia. Genome-wide association study (GWAS) methods have made it possible to locate new gout-related loci associated with reduced renal urate excretion (NIPAL1, FAM35A).
PubMed: 34503865
DOI: 10.1016/j.nefro.2021.03.013