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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 -
Kidney Diseases (Basel, Switzerland) Apr 2023Diabetic kidney disease (DKD) is a major source of chronic kidney disease and end-stage renal disease. The injury of glomerulus in DKD is the primary focus; however,...
INTRODUCTION
Diabetic kidney disease (DKD) is a major source of chronic kidney disease and end-stage renal disease. The injury of glomerulus in DKD is the primary focus; however, proximal tubulopathy also is an indispensable factor in the progression of DKD. Interleukin-37 (IL-37), an anti-inflammatory cytokine of IL-1 family member, has been demonstrated to be associated with diabetes and its relative complications in recent years, but the effect of IL-37 on renal fibrosis in DKD is unclear.
METHODS
We established streptozotocin plus high fat diet-induced DKD mice model with wild type or IL-37 transgenic mice. Masson and HE staining, immunostaining, and Western blot were used to observe renal fibrosis. In addition, RNA-sequencing was applied to explore the potential mechanisms of IL-37. In vitro, treatment of human proximal tubular (HK-2) cells with 30 mmol/L high glucose or 300 ng/mL recombinant IL-37 further elucidated the possible mechanism of IL-37 inhibition of DKD renal fibrosis.
RESULTS
In this work, we first verified the decreased expression of IL-37 in kidney of DKD patient and its correlation with clinical features of renal impairment. Moreover, IL-37 expression markedly attenuated proteinuria and renal fibrosis in DKD mice. Using RNA-sequencing, we found and confirmed a novel role of IL-37 in ameliorating fatty acid oxidation (FAO) reduction of renal tubular epithelial cells both in vivo and in intro. In addition, further mechanistic studies showed that IL-37 alleviated the FAO reduction in HK-2 cells and renal fibrosis in DKD mice through upregulating carnitine palmitoyl-transferase 1A (CPT1A), an important catalyzer for FAO pathway.
CONCLUSION
These data suggest that IL-37 attenuates renal fibrosis via regulating FAO in renal epithelial cells. Upregulation of IL-37 levels might be an effective therapeutic avenue for DKD.
PubMed: 37065609
DOI: 10.1159/000529460 -
Renal Failure Dec 2023Crystal-storing histiocytosis (CSH), light chain proximal tubulopathy (LCPT), and light chain crystalline podocytopathy (LCCP) are rare complications of multiple myeloma... (Review)
Review
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.
Topics: Humans; Female; Aged; Multiple Myeloma; Fanconi Syndrome; Pronase; Kidney Diseases; Immunoglobulin kappa-Chains; Antibodies, Monoclonal; Histiocytosis
PubMed: 36632756
DOI: 10.1080/0886022X.2022.2145970 -
Critical Reviews in Oncology/hematology May 2020Monoclonal gammopathy of renal significance (MGRS) is characterized by the nephrotoxic monoclonal immunoglobulin (MIg) secreted by an otherwise asymptomatic or indolent... (Review)
Review
Monoclonal gammopathy of renal significance (MGRS) is characterized by the nephrotoxic monoclonal immunoglobulin (MIg) secreted by an otherwise asymptomatic or indolent B-cell or plasma cell clone, without hematologic criteria for treatment. The spectrum of MGRS-associated disorders is wide, including non-organized deposits or inclusions such as C3 glomerulopathy with monoclonal glomerulopathy (MIg-C3G), monoclonal immunoglobulin deposition disease, proliferative glomerulonephritis with monoclonal immunoglobulin deposits and organized deposits like immunoglobulin related amyloidosis, type I and type II cryoglobulinaemic glomerulonephritis, light chain proximal tubulopathy, and so on. Kidney biopsy should be conducted to identify the exact disease associated with MGRS. These MGRS-associated diseases can involve one or more renal compartments, including glomeruli, tubules and vessels. Hydrophobic residues replacement, N-glycosylated, increase in isoelectric point in MIg causes it to transform from soluble form to tissue deposition, causing glomerular damage. Complement deposition is found in MIg-C3G, which is caused by an abnormality of the alternative pathway and may involve multiple factors including complement component 3 nephritic factor, anti-complement factor auto-antibodies or MIg which directly cleaves C3. The effect of transforming growth factor beta and platelet-derived growth factor-β on mesangial extracellular matrix is associated with glomerular and tubular basement membrane thickening, nodular glomerulosclerosis, and interstitial fibrosis. Furthermore, inflammatory factors, growth factors and virus infection may play an important role in the development of the diseases. In this review, for the first time, we discussed current highlights in the mechanism of MGRS-related lesions.
Topics: Glomerulonephritis; Humans; Kidney; Kidney Diseases; Kidney Glomerulus; Paraproteinemias
PubMed: 32199132
DOI: 10.1016/j.critrevonc.2020.102926 -
Metabolites Mar 2020Vitamin D is tightly linked with renal tubular homeostasis: the mitochondria of proximal convoluted tubule cells are the production site of 1α,25-dihydroxyvitamin D3.... (Review)
Review
Vitamin D is tightly linked with renal tubular homeostasis: the mitochondria of proximal convoluted tubule cells are the production site of 1α,25-dihydroxyvitamin D3. Patients with renal impairment or tubular injury often suffer from chronic inflammation. This alteration comes from oxidative stress, acidosis, decreased clearance of inflammatory cytokines and stimulation of inflammatory factors. The challenge is to find the right formula for each patient to correctly modulate the landscape of treatment and preserve the essential functions of the organism without perturbating its homeostasis. The complexity of the counter-regulation mechanisms and the different axis involved in the Vitamin D equilibrium pose a major issue on Vitamin D as a potential effective anti-inflammatory drug. The therapeutic use of this compound should be able to inhibit the development of inflammation without interfering with normal homeostasis. Megalin-Cubilin-Amnionless and the FGF23-Klotho axis represent two Vitamin D-linked mechanisms that could modulate and ameliorate the damage response at the renal tubular level, balancing Vitamin D therapy with an effect potent enough to contrast the inflammatory cascades, but which avoids potential severe side effects.
PubMed: 32204545
DOI: 10.3390/metabo10030115 -
Therapie 2021
Topics: Acyclovir; Humans; Kidney Diseases; Polyuria
PubMed: 32919761
DOI: 10.1016/j.therap.2020.08.001 -
EMBO Molecular Medicine Jul 2021Nephropathic cystinosis is a severe monogenic kidney disorder caused by mutations in CTNS, encoding the lysosomal transporter cystinosin, resulting in lysosomal cystine...
Nephropathic cystinosis is a severe monogenic kidney disorder caused by mutations in CTNS, encoding the lysosomal transporter cystinosin, resulting in lysosomal cystine accumulation. The sole treatment, cysteamine, slows down the disease progression, but does not correct the established renal proximal tubulopathy. Here, we developed a new therapeutic strategy by applying omics to expand our knowledge on the complexity of the disease and prioritize drug targets in cystinosis. We identified alpha-ketoglutarate as a potential metabolite to bridge cystinosin loss to autophagy, apoptosis and kidney proximal tubule impairment in cystinosis. This insight combined with a drug screen revealed a bicalutamide-cysteamine combination treatment as a novel dual-target pharmacological approach for the phenotypical correction of cystinotic kidney proximal tubule cells, patient-derived kidney tubuloids and cystinotic zebrafish.
Topics: Amino Acid Transport Systems, Neutral; Anilides; Animals; Cysteamine; Cystinosis; Humans; Nitriles; Phenotype; Tosyl Compounds; Zebrafish
PubMed: 34165243
DOI: 10.15252/emmm.202013067 -
Pediatric Nephrology (Berlin, Germany) Feb 2020Acid-base homeostasis is one of the most tightly regulated systems in the body. Maintaining the acid-base balance is particularly challenging for preterm infants and... (Review)
Review
Acid-base homeostasis is one of the most tightly regulated systems in the body. Maintaining the acid-base balance is particularly challenging for preterm infants and growing neonates. The kidney, which represents the crucial ultimate line of defense against disturbances of acid-base balance, undergoes a complex maturation process during the transition from a fetal to an extra-uterine environment. This review article summarizes the physiology of acid-base regulation by the immature human kidney and discusses disorders of acid-base balance, such as metabolic acidosis, respiratory acidosis, metabolic alkalosis, and respiratory alkalosis. In conditions of metabolic acidosis, the serum anion gap and the urinary anion gap can be useful tools to define the nature of the acidosis. Metabolic acidosis can reflect a decrease in glomerular filtration rate, or be the consequence of selective disorders of proximal or distal tubular function. Most tubulopathies associated with metabolic acidosis observed in neonates are primary, hereditary, isolated tubulopathies. Proximal renal tubular acidosis is characterized by bicarbonate wasting, while the distal types of renal tubular acidosis are secondary to distal acidification defects. All tubulopathies are associated with hypokalemia, with the exception of type 4 hyperkalemic distal renal tubular acidosis. The transporter defects in the various acid-base tubulopathies are now well defined. Treatment of the acidosis varies according to the site and mechanism of the defect. Chronic renal tubular acidosis or alkalosis severely impair growth and calcium metabolism. Early rational therapeutic intervention can prevent some of the consequences of the disorders and improves the prognosis.
Topics: Acid-Base Imbalance; Female; Humans; Infant, Newborn; Kidney; Male
PubMed: 30456666
DOI: 10.1007/s00467-018-4142-9 -
Current Opinion in Nephrology and... Jul 2024Renal tubules have robust active transport and mitochondrial metabolism, which are functionally coupled to maintain energy homeostasis. Here, I review the current... (Review)
Review
PURPOSE OF REVIEW
Renal tubules have robust active transport and mitochondrial metabolism, which are functionally coupled to maintain energy homeostasis. Here, I review the current literature and our recent efforts to examine mitochondrial adaptation to different transport activities in renal tubules.
RECENT FINDINGS
The advance of extracellular flux analysis (EFA) allows real-time assessments of mitochondrial respiration, glycolysis, and oxidation of energy substrates. We applied EFA assays to freshly isolated mouse proximal tubules, thick ascending limbs (TALs), and distal convoluted tubules (DCTs) and successfully differentiated their unique metabolic features. We found that TALs and DCTs adjusted their mitochondrial bioenergetics and biogenesis in response to acute and chronic alterations of transport activity. Based on the literature and our recent findings, I discuss working models and mechanisms underlying acute and chronic tubular adaptations to transport activity. The potential roles of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), AMP-activated protein kinase (AMPK), and uncoupling protein 2 (UCP2) are discussed.
SUMMARY
Mitochondria in renal tubules are highly plastic to accommodate different transport activities. Understanding the mechanisms may improve the treatment of renal tubulopathies.
Topics: Animals; Energy Metabolism; Mitochondria; Humans; Kidney Tubules; AMP-Activated Protein Kinases; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Biological Transport
PubMed: 38573234
DOI: 10.1097/MNH.0000000000000986 -
Annals of the New York Academy of... Mar 2023Magnesium is the fourth most abundant cation in the body. It plays a critical role in many biological processes, including the process of energy release. Paracellular... (Review)
Review
Magnesium is the fourth most abundant cation in the body. It plays a critical role in many biological processes, including the process of energy release. Paracellular transport of magnesium is mandatory for magnesium homeostasis. In addition to intestinal absorption that occurs in part across the paracellular pathway, magnesium is reabsorbed by the kidney tubule. The bulk of magnesium is reabsorbed through the paracellular pathway in the proximal tubule and the thick ascending limb of the loop of Henle. The finding that rare genetic diseases due to pathogenic variants in genes encoding specific claudins (CLDNs), proteins located at the tight junction that determine the selectivity and the permeability of the paracellular pathway, led to an awareness of their importance in magnesium homeostasis. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is caused by a loss of function of CLDN16 or CLDN19. Pathogenic CLDN10 variants cause HELIX syndrome, which is associated with a severe renal loss of sodium chloride and hypermagnesemia. The present review summarizes the current knowledge of the mechanisms and factors involved in paracellular magnesium permeability. The review also highlights some of the unresolved questions that need to be addressed.
Topics: Humans; Magnesium; Nephrocalcinosis; Hypercalciuria; Homeostasis; Membrane Proteins; Claudins
PubMed: 36622354
DOI: 10.1111/nyas.14953