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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 -
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 -
Nephrology, Dialysis, Transplantation :... Apr 2020The incidence of chronic kidney disease (CKD) is 10 times higher in human immunodeficiency virus (HIV)-infected patients than in the general population. We explored the...
BACKGROUND
The incidence of chronic kidney disease (CKD) is 10 times higher in human immunodeficiency virus (HIV)-infected patients than in the general population. We explored the prevalence and determinants of proximal tubular dysfunction (PTD) in HIV-infected individuals, and assessed the impact of the tubulopathy on the estimated glomerular filtration rate (eGFR) outcome.
METHODS
A cohort study was performed on 694 outpatients followed in a French centre to analyse the prevalence of PTD, the diagnosis performance of screening tools and the associated factors. eGFR was prospectively evaluated to analyse the predictive value of the tubulopathy on eGFR decrease.
RESULTS
At inclusion, 14% of the patients presented with PTD and 5% with CKD. No individual tubular marker, including non-glomerular proteinuria, glycosuria dipstick or hypophosphataemia, registered sufficient performance to identify PTD. We found a significant interaction between tenofovir disoproxil fumarate exposure and ethnicity (P = 0.03) for tubulopathy risk. Tenofovir disoproxil fumarate exposure was associated with PTD in non-Africans [adjusted odds ratio (aOR) = 4.71, P < 10-3], but not in patients of sub-Saharan African origin (aOR = 1.17, P = 0.73). Among the 601 patients followed during a median of 4.3 years, 13% experienced an accelerated eGFR decline. Unlike microalbuminuria and glomerular proteinuria, tubulopathy was not associated with accelerated eGFR decline.
CONCLUSION
PTD is not rare in HIV-infected individuals but is less frequent in sub-Saharan African patients and is associated with tenofovir disoproxil fumarate exposure only in non-Africans. Its diagnosis requires multiple biochemical testing and it is not associated with an accelerated eGFR decline.
Topics: Adult; Anti-HIV Agents; Biomarkers; Ethnicity; Female; France; Glomerular Filtration Rate; HIV; HIV Infections; Humans; Kidney Tubules; Male; Middle Aged; Prevalence; Prospective Studies; Renal Insufficiency, Chronic; Tenofovir
PubMed: 31071216
DOI: 10.1093/ndt/gfz081 -
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 -
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 -
European Journal of Case Reports in... 2019Acquired causes of Fanconi syndrome in adults are usually due to drugs, toxins or paraproteinaemias. Infectious causes are rarely described. We report a case of invasive...
UNLABELLED
Acquired causes of Fanconi syndrome in adults are usually due to drugs, toxins or paraproteinaemias. Infectious causes are rarely described. We report a case of invasive pneumococcal disease in a patient who developed a Fanconi-like syndrome during the course of her illness. This patient presented with multiple electrolyte derangements consisting predominantly of hypokalaemia, hypomagnesaemia and hypophosphataemia during hospitalization for invasive pneumococcal disease with possible Austrian syndrome. Further evaluation revealed significant urinary losses of these electrolytes, uric acid and β2-microglobulin. Together with evidence of hypouricaemia, this is suggestive of proximal renal tubulopathy, and hence a Fanconi-like syndrome. The patient's clinical condition and biochemical anomalies improved following pneumococcus treatment.
LEARNING POINTS
Suspect Fanconi syndrome when there are multiple electrolyte derangements consisting of hypokalaemia, hypomagnesaemia and hypophosphataemia.Recognise the common causes of Fanconi syndrome and appreciate that infections such as legionellosis, leptospirosis and pneumococcal disease can potentially result in Fanconi syndrome.The management of Fanconi syndrome is generally supportive and involves treating the underlying cause.
PubMed: 31742198
DOI: 10.12890/2019_001230 -
American Journal of Kidney Diseases :... Feb 2016
Review
Topics: Animals; Atlases as Topic; Humans; Immunoglobulin Light Chains; Kidney Diseases; Kidney Glomerulus; Kidney Tubules, Proximal
PubMed: 26802336
DOI: 10.1053/j.ajkd.2015.12.006 -
Journal of Tropical Pediatrics Feb 2023Sickle cell disease causes microvascular occlusion in different vascular beds. In kidneys, it leads to occult glomerular dysfunction causing asymptomatic...
BACKGROUND
Sickle cell disease causes microvascular occlusion in different vascular beds. In kidneys, it leads to occult glomerular dysfunction causing asymptomatic microalbuminuria, proximal tubulopathy causing hyposthenuria and increased free water loss and distal tubulopathy causing poor urine acidification. We studied the prevalence of various types of renal dysfunction, the ability of different tests to detect it at an early stage and the correlation of these parameters in children receiving hydroxyurea (HU).
PROCEDURE
Fifty-six children (sample size calculated using SAS9.2 package) attending paediatric clinical services in a tertiary care hospital between 2 and 12 years of age diagnosed by high-performance liquid chromatography (HPLC) were enrolled. Their demographic and laboratory data including renal and urine parameters were collected. Parameters like fractional excretion of sodium (FeNa), trans tubular potassium gradient (TtKg) and free water clearance (TcH2O) were derived by calculations. Data were analysed using IBM SPSS Version 21.0 and Microsoft Office Excel 2007.
RESULTS
We found a significant number of children to have microalbuminuria (17.8%), hyposthenuria (30.4%) and impaired renal tubular potassium excretion (TtKg) (81.3%). A significant correlation was found between the dose of HU with urine osmolality (p < 0.0005) and free water clearance (p = 0.002), while all parameters showed a significant correlation with compliance with HU. Derangement in urine microalbumin and TcH2O correlated significantly with low mean haemoglobin levels (<9 g/dl).
CONCLUSION
Renal dysfunction is common in children with SCD and can be detected early using simple urine parameters and can be prevented with an early and appropriate dosage of HU with good compliance.
Topics: Child; Humans; Kidney Diseases; Kidney; Anemia, Sickle Cell; Albuminuria; Hydroxyurea; India; Water
PubMed: 37004730
DOI: 10.1093/tropej/fmad019