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Bulletin Du Cancer May 2023Electrolyte disorders (ED) are common in patients with cancer and in most cases, the etiologies do not differ from the general population. They may also be induced by... (Review)
Review
Electrolyte disorders (ED) are common in patients with cancer and in most cases, the etiologies do not differ from the general population. They may also be induced by the cancer, its therapy or paraneoplastic syndromes. ED are associated with poor outcomes, increased morbidity and mortality in this population. Hyponatremia is the most common disorder, often multifactorial, iatrogenic or secondary to the syndrome of inappropriate antidiuretic hormone secretion, usually due to small cell lung cancer. More rarely, hyponatremia may reveal adrenal insufficiency. Hypokalemia is generally multifactorial and associated with other ED. Cisplatin and ifosfamide induce proximal tubulopathies with hypokalemia and/or hypophosphatemia. Hypomagnesemia is often iatrogenic, related to cisplatin or cetuximab, but can be prevented by supplementation. Hypercalcemia can impair life quality and be life-threatening in the most severe cases. Hypocalcemia is less common and often of iatrogenic origin. Finally, the tumor lysis syndrome is a diagnostic and therapeutic emergency that affects the prognosis of patients. Its incidence tends to increase in solid oncology, related to the improvement of therapies. Prevention and early diagnosis of ED are essential to optimize the overall management of patients with underlying cancer and cancer therapy. The aim of this review is to synthesize most frequent ED and their management.
PubMed: 37208250
DOI: 10.1016/j.bulcan.2023.04.014 -
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 -
Kidney International Mar 2022
Topics: Humans; Kidney Diseases; Kidney Tubules, Proximal; Valproic Acid
PubMed: 35190045
DOI: 10.1016/j.kint.2021.08.005 -
Diabetes Apr 2017The current view of diabetic kidney disease, based on meticulously acquired ultrastructural morphometry and the utility of measuring plasma creatinine and urinary... (Review)
Review
The current view of diabetic kidney disease, based on meticulously acquired ultrastructural morphometry and the utility of measuring plasma creatinine and urinary albumin, has been almost entirely focused on the glomerulus. While clearly of great importance, changes in the glomerulus are not the major determinant of renal prognosis in diabetes and may not be the primary event in the development of diabetic kidney disease either. Indeed, advances in biomarker discovery and a greater appreciation of tubulointerstitial histopathology and the role of tubular hypoxia in the pathogenesis of chronic kidney disease have given us pause to reconsider the current "glomerulocentric" paradigm and focus attention on the proximal tubule that by virtue of the high energy requirements and reliance on aerobic metabolism render it particularly susceptible to the derangements of the diabetic state. Such findings raise important issues for therapeutic advances specifically targeting the pathophysiological perturbations that develop in this part of the nephron.
Topics: Apoptosis; Diabetic Nephropathies; Disease Progression; Fibrosis; Humans; Hypoxia; Ischemia; Kidney Glomerulus; Kidney Tubules, Proximal; Mitochondria; Oxygen Consumption; Renal Insufficiency, Chronic
PubMed: 28325740
DOI: 10.2337/db16-0796 -
The Journal of Clinical Endocrinology... Dec 2022Biallelic pathogenic variants in the NEUROG3 gene cause malabsorptive diarrhea, insulin-dependent diabetes mellitus (IDDM), and rarely hypogonadotropic hypogonadism....
CONTEXT
Biallelic pathogenic variants in the NEUROG3 gene cause malabsorptive diarrhea, insulin-dependent diabetes mellitus (IDDM), and rarely hypogonadotropic hypogonadism. With only 17 reported cases, the clinical and mutational spectra of this disease are far from complete.
OBJECTIVE
To identify the underlying genetic etiology in 3 unrelated Thai patients who presented with early-onset malabsorptive diarrhea, endocrine abnormalities, and renal defects and to determine the pathogenicity of the newly identified pathogenic variants using luciferase reporter assays and western blot.
METHODS
Three unrelated patients with congenital diarrhea were recruited. Detailed clinical and endocrinological features were obtained. Exome sequencing was performed to identify mutations and in vitro functional experiments including luciferase reporter assay were studied to validate their pathogenicity.
RESULTS
In addition to malabsorptive diarrhea due to enteric anendocrinosis, IDDM, short stature, and delayed puberty, our patients also exhibited pituitary gland hypoplasia with multiple pituitary hormone deficiencies (Patient 1, 2, 3) and proximal renal tubulopathy (Patient 2, 3) that have not previously reported. Exome sequencing revealed that Patient 1 was homozygous for c.371C > G (p.Thr124Arg) while the other 2 patients were homozygous for c.284G > C (p.Arg95Pro) in NEUROG3. Both variants have never been previously reported. Luciferase reporter assay demonstrated that these 2 variants impaired transcriptional activity of NEUROG3.
CONCLUSIONS
This study reported pituitary gland hypoplasia with multiple pituitary hormone deficiencies and proximal renal tubulopathy and 2 newly identified NEUROG3 loss-of-function variants in the patients with NEUROG3-associated syndrome.
Topics: Humans; Basic Helix-Loop-Helix Transcription Factors; Diabetes Mellitus, Type 1; Nerve Tissue Proteins; Mutation; Diarrhea; Phenotype; Pituitary Hormones
PubMed: 36149814
DOI: 10.1210/clinem/dgac554 -
Nephrologie & Therapeutique Aug 2021COVID-19 is a disease caused by the RNA virus SARS-CoV-2. It is characterised by an attack mainly affecting the respiratory system. There is renal involvement which is...
COVID-19 is a disease caused by the RNA virus SARS-CoV-2. It is characterised by an attack mainly affecting the respiratory system. There is renal involvement which is characterised by three main types of damage, acute tubular necrosis occurring in the most severe cases, proximal tubulopathy which is a prognostic marker of the disease and segmental and focal hyalinosis occurring in a genetically predisposed terrain. The pathophysiology of SARS-CoV-2 renal involvement is not yet defined. The direct role of the virus is debated, whereas the cytokine storm and the hypoxic and thrombotic complications seem more important. The long-term outcome of the renal damage appears to be quite good. Long-term follow-up will allow us to say whether the renal damage is part of the long COVID.
Topics: Acute Kidney Injury; Biopsy; COVID-19; COVID-19 Vaccines; Glomerulosclerosis, Focal Segmental; Humans; Kidney; Kidney Tubular Necrosis, Acute
PubMed: 34266783
DOI: 10.1016/j.nephro.2021.06.002 -
Frontiers in Genetics 2024Nephrolithiasis (NL) is a common condition worldwide. The incidence of NL and nephrocalcinosis (NC) has been increasing, along with their associated morbidity and... (Review)
Review
Nephrolithiasis (NL) is a common condition worldwide. The incidence of NL and nephrocalcinosis (NC) has been increasing, along with their associated morbidity and economic burden. The etiology of NL and NC is multifactorial and includes both environmental components and genetic components, with multiple studies showing high heritability. Causative gene variants have been detected in up to 32% of children with NL and NC. Children with NL and NC are genotypically heterogenous, but often phenotypically relatively homogenous, and there are subsequently little data on the predictors of genetic childhood NL and NC. Most genetic diseases associated with NL and NC are secondary to hypercalciuria, including those secondary to hypercalcemia, renal phosphate wasting, renal magnesium wasting, distal renal tubular acidosis (RTA), proximal tubulopathies, mixed or variable tubulopathies, Bartter syndrome, hyperaldosteronism and pseudohyperaldosteronism, and hyperparathyroidism and hypoparathyroidism. The remaining minority of genetic diseases associated with NL and NC are secondary to hyperoxaluria, cystinuria, hyperuricosuria, xanthinuria, other metabolic disorders, and multifactorial etiologies. Genome-wide association studies (GWAS) in adults have identified multiple polygenic traits associated with NL and NC, often involving genes that are involved in calcium, phosphorus, magnesium, and vitamin D homeostasis. Compared to adults, there is a relative paucity of studies in children with NL and NC. This review aims to focus on the genetic component of NL and NC in children.
PubMed: 38606357
DOI: 10.3389/fgene.2024.1381174 -
Nephrology, Dialysis, Transplantation :... Oct 2023Light chain proximal tubulopathy (LCPT) is a rare form of paraprotein-related disease, occurring in two main histopathological forms: crystalline and non-crystalline....
BACKGROUND
Light chain proximal tubulopathy (LCPT) is a rare form of paraprotein-related disease, occurring in two main histopathological forms: crystalline and non-crystalline. The clinicopathological features, treatment strategies and outcomes, especially of the non-crystalline form, are not well described.
METHODS
We conducted a single-centre retrospective case series of 12 LCPT patients, 5 crystalline and 7 non-crystalline, between 2005 and 2021.
RESULTS
The median age was 69.5 years (range 47-80). Ten patients presented with CKD and significant proteinuria (median estimated glomerular filtration rate of 43.5 ml/min/1.73 m2; urine protein:creatinine ratio 328 mg/mmol). Only six patients had known haematological disease at the time of renal biopsy. Multiple myeloma (MM) was diagnosed in seven patients cases and monoclonal gammopathy of renal significance (MGRS) in five patients. A clone was detected in all cases combining serum/urine electrophoresis and free light chain (LC) assays. Crystalline and non-crystalline variants had similar clinical presentations. For the non-crystalline variant, a diagnosis was reached based on a combination of CKD without another cause, haematological workup, LC restriction on immunofluorescence and abnormalities on electron microscopy (EM). Nine of 12 patients received clone-directed treatment. Patients who achieved haematological response (including all non-crystalline LCPT) had improved renal outcomes over a median follow-up of 79 months.
CONCLUSIONS
The non-crystalline variant may go unrecognised because of its subtle histopathological features and requires EM to distinguish it from 'excessive LC resorption without tubular injury'. Clone-directed treatment with good haematological response improves renal outcomes in both variants but limited data exist in MGRS. Multicentre prospective studies are needed to better define the clinicopathological characteristics associated with poor outcomes and optimize treatment strategies in patients with MGRS.
Topics: Humans; Middle Aged; Aged; Aged, 80 and over; Retrospective Studies; Kidney Diseases; Kidney; Multiple Myeloma; Immunoglobulin Light Chains; Renal Insufficiency, Chronic; Paraproteinemias
PubMed: 37120733
DOI: 10.1093/ndt/gfad085 -
Current Opinion in Nephrology and... Sep 2022Kir5.1 interacts with Kir4.2 in proximal tubule and with Kir4.1 in distal convoluted tubule (DCT), connecting tubule (CNT) and cortical collecting duct (CCD) to form... (Review)
Review
PURPOSE OF REVIEW
Kir5.1 interacts with Kir4.2 in proximal tubule and with Kir4.1 in distal convoluted tubule (DCT), connecting tubule (CNT) and cortical collecting duct (CCD) to form basolateral-K+-channels. Kir4.2/Kir5.1 and Kir4.1/Kir5.1 play an important role in regulating Na+/HCO3--transport of the proximal tubule and Na+/K+ -transport in the DCT/CNT/CCD. The main focus of this review is to provide an overview of the recent development in the field regarding the role of Kir5.1 regulating renal electrolyte transport in the proximal tubule and DCT.
RECENT FINDINGS
Loss-of-function-mutations of KCNJ16 cause a new form of tubulopathy, characterized by hypokalaemia, Na+-wasting, acid-base-imbalance and metabolic-acidosis. Abnormal bicarbonate transport induced by loss-of-function of KCNJ16-mutants is recapitulated in Kir4.2-knockout-(Kir4.2 KO) mice. Deletion of Kir5.1 also abolishes the effect of dietary Na+ and K+-intakes on the basolateral membrane voltage and NCC expression/activity. Long-term high-salt intake or high-K+-intake causes hyperkalaemic in Kir5.1-deficient mice.
SUMMARY
Kir4.2/Kir5.1 activity in the proximal tubule plays a key role in regulating Na+, K+ and bicarbonate-transport through regulating electrogenic-Na+-bicarbonate-cotransporter-(NBCe1) and type 3-Na+/H+-exchanger-(NHE3). Kir4.1/Kir5.1 activity of the DCT plays a critical role in mediating the effect of dietary-K+ and Na+-intakes on NCC activity/expression. As NCC determines the Na+ delivery rate to the aldosterone-sensitive distal nephron (ASDN), defective regulation of NCC during high-salt and high-K+ compromises renal K+ excretion and K+ homeostasis.
Topics: Animals; Bicarbonates; Humans; Ion Transport; Kidney Tubules; Kidney Tubules, Distal; Mice; Potassium Channels, Inwardly Rectifying; Sodium
PubMed: 35894283
DOI: 10.1097/MNH.0000000000000817 -
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