scholarly journals Tubulopathy meets Sherlock Holmes: biochemical fingerprinting of disorders of altered kidney tubular salt handling

2021 ◽  
Author(s):  
Detlef Bockenhauer ◽  
Robert Kleta
Keyword(s):  
Urine Volume ◽  
Transport Proteins ◽  
Tubular Reabsorption ◽  
Environmental Stressors ◽  
Transport Pathway ◽  
Waste Products ◽  
Tubular Transport ◽  
Glomerular Filtrate ◽  
Sodium Handling ◽  
Biochemical Abnormalities

AbstractEvolution moves in mysterious ways. Excretion of waste products by glomerular filtration made perfect sense when life evolved in the ocean. Yet, the associated loss of water and solutes became a problem when life moved onto land: a serious design change was needed and this occurred in the form of ever more powerful tubules that attached to the glomerulus. By reabsorbing typically more than 99% of the glomerular filtrate, the tubules not only minimise urinary losses, but, crucially, also maintain homeostasis: tubular reabsorption and secretion are adjusted so as to maintain an overall balance, in which urine volume and composition matches intake and environmental stressors. A whole orchestra of highly specialised tubular transport proteins is involved in this process and dysfunction of one or more of these results in the so-called kidney tubulopathies, characterised by specific patterns of clinical and biochemical abnormalities. In turn, recognition of these patterns helps establish a specific diagnosis and pinpoints the defective transport pathway. In this review, we will discuss these clinical and biochemical “fingerprints” of tubular disorders of salt-handling and how sodium handling affects volume homeostasis but also handling of other solutes.

Renal excretion of radiofluoride in the dog

1960 ◽  
Vol 198 (4) ◽  
pp. 829-832 ◽  
Author(s):  
Curtis H. Carlson ◽  
W. D. Armstrong ◽  
Leon Singer ◽  
Lerner B. Hinshaw
Keyword(s):  
Plasma Concentration ◽  
Glomerular Filtration ◽  
Renal Excretion ◽  
Urine Volume ◽  
Urine Concentration ◽  
Tubular Reabsorption ◽  
Carrier Free ◽  
Renal Clearances ◽  
Concentration Ratios

Renal clearances of continuously infused radiofluoride were measured in 10 dogs in which a large part of the skeleton had been excluded from the system in order to produce a more constant plasma radiofluoride concentration. The results were evaluated to describe the factors of glomerular filtration and tubular reabsorption of fluoride under several conditions. The animals that received carrier-free radiofluoride infusions excreted urine with a mean radiofluoride concentration 3.4–14.5 times that of the plasma. The urine-to-plasma concentration ratios obtained with animals given a load of stable fluoride was 13.5–29.6. An increased urine volume resulted in a decreased tubular reabsorption of fluoride and the clearance was increased. Chlorothiazide increased radiofluoride excretion but decreased the urine concentration. The radiofluoride clearances were always less than the creatinine clearances but were 7.8–179 times the chloride clearances. The effect of chlorothiazide was to decrease the ratio of fluoride to chloride clearance by increasing chloride clearance more than fluoride clearance.

Adaptive changes to moderate seasonal heat in human subjects

1959 ◽  
Vol 14 (6) ◽  
pp. 995-996 ◽  
Author(s):  
Roy B. Mefferd
Keyword(s):  
Human Subjects ◽  
Economic Status ◽  
Urine Volume ◽  
South Texas ◽  
Moderate Increase ◽  
Waste Products ◽  
Average Temperature ◽  
Adaptive Mechanisms ◽  
Seasonal Heat ◽  
Excretion Rates

The excretion patterns of 29 members (including children) of 7 south Texas Caucasian families of varying economic status were determined each November (neutral-cool, averaging 68.7°F) and May (warm, averaging 81.6°F) for 3 consecutive years, to determine whether heat-adaptive mechanisms were stimulated by a moderate increase in average temperature as contrasted to intense heat. Four timed overnight samples from each person were analyzed in each period for five electrolytes, five nitrogenous waste products and thirteen amino acids. Excretion rates of most substances were lower in November than in May. Creatinine and the magnesium/calcium ratio were elevated, however, and the urine volume, magnesium, urea, glutamic acid, arginine and the sodium/potassium and uric acid/creatinine ratios did not change significantly. The excretion patterns of the heat-adapted human subjects were strikingly similar to those seen in heat-adapted rats. Submitted on April 13, 1959

Renal clearance of glucose in hypothermic dogs

1959 ◽  
Vol 196 (4) ◽  
pp. 866-872 ◽  
Author(s):  
G. S. Kanter
Keyword(s):  
Renal Function ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Control Period ◽  
Urine Volume ◽  
Tubular Reabsorption ◽  
Arterial Blood ◽  
Glucose Reabsorption ◽  
Kinetics Of ◽  
Glucose Excretion

Quantitative alterations in both glomerular filtration (GFR) and tubular reabsorption of glucose, before, during and after onset of hypothermia were investigated. Urine was collected by direct cannulation of ureters and arterial blood obtained from a femoral cannula. Creatinine was used to measure GFR and glucose was analyzed by the glucose-oxidase method. During control period (rectal temp. 38°C) it was found that onlg a trace (17 ± 4 mg %) (.09 ± .02 mg/min.) of glucose spilled over into the urine. With the development of hypothermia a progressive fall in glomerular filtration rate was observed (78 ± 5 ml/min. at control rectal temp. (R.T.) to 30 ± 5 ml/min. at R.T. of 25°C). In spite of the fact that less fluid was filtered across the glomerulus, both urine volume and glucose excretion increased markedly (373 ± 122 mg %) (4.3 ± 1.9 mg/min.) at R.T. of 25°C. There is obviously a twofold effect of hypothermia on renal function, physically via the cardiovascular system resulting in a falling GFR and chemically on the tubular reabsorptive processes resulting in a decreased glucose reabsorption. To study the kinetics of this decreased glucose reabsorption, glucose Tm was investigated. It was found that control glucose Tm averaged 380 mg/min. (the E/F ratio being 52%). At 27°C R.T. the Tm was 103 mg/min. (E/F ratio being 73%).

Phosphorus Intake in Preterm Babies and Variation of Tubular Reabsorption for Phosphate per Liter Glomerular Filtrate

Neonatology ◽  
1992 ◽  
Vol 61 (6) ◽  
pp. 345-350 ◽  
Author(s):  
J.P. Langhendries ◽  
A. François ◽  
F. Chedid ◽  
O. Battisti ◽  
J.M. Bertrand ◽  
...  
Keyword(s):  
Tubular Reabsorption ◽  
Glomerular Filtrate ◽  
Preterm Babies ◽  
Phosphorus Intake

Effect of urea loading on urine osmolality during osmotic diuresis in hydropenic rats

1963 ◽  
Vol 205 (5) ◽  
pp. 1053-1057 ◽  
Author(s):  
Thomas I. Koike ◽  
Ralph H. Kellogg
Keyword(s):  
Intravenous Infusion ◽  
Excretion Rate ◽  
Urine Osmolality ◽  
Tubular Reabsorption ◽  
Female Rats ◽  
Simultaneous Administration ◽  
Osmotic Diuresis ◽  
Tubular Transport ◽  
Solute Excretion ◽  
The Relationship

Osmotic diuresis was induced in hydropenic female rats by intravenous infusion of urea with and without vasopressin. The relationship between urine osmolality and total solute excretion rate was qualitatively similar to that observed during mannitol loading, but the maximal urine osmolalities achieved were markedly higher during urea loading and were unaffected by the simultaneous administration of probenecid or para-aminohippurate. Simultaneous inulin and urea clearances indicated net tubular reabsorption of 23–55% of the urea filtered. The results do not support the view that enhancement of concentrating ability by urea depends upon its active tubular transport.

Contribution of leaked load to solute transport by renal tubules

1978 ◽  
Vol 234 (6) ◽  
pp. F480-F484 ◽  
Author(s):  
D. G. Warnock ◽  
C. S. Patlak ◽  
M. B. Burg
Keyword(s):  
Substantial Part ◽  
Renal Tubules ◽  
In Vitro Perfusion ◽  
Tubule Lumen ◽  
Tubular Transport ◽  
Glomerular Filtrate ◽  
The Relationship ◽  
Convoluted Tubules ◽  
Filtered Load

Renal tubules reabsorb solutes from the glomerular filtrate. The relationship between "filtered load" and reabsorption has been previously discussed and analyzed in detail. One aspect which has not been emphasized, however, is that, when reabsorption of a solute causes its concentration (or activity) in the tubule lumen to decrease below the level in the blood, solute may enter the tubule down this concentration gradient adding a "leaked load" to the filtered load. The leaked load should be taken into account when quantifying tubular transport. In the present study we derived equations for estimating the leaked load and its contribution to transport. The importance of the leaked load of glucose in the rabbit proximal convoluted tubules is evaluated with parameters derived from in vitro perfusion and by solving the equations numerically. It is shown that, depending on the conditions, the leaked load of glucose may account for a substantial part of the glucose present in the tubule lumen and reabsorbed from the tubule. Also, the leaked load could conceivably be an important factor in the transport of other solutes such as lactase and bicarbonate in proximal tubules.

Transport of Xenobiotics Across the Blood-Brain Barrier

Physiology ◽  
2002 ◽  
Vol 17 (6) ◽  
pp. 231-234 ◽  
Author(s):  
Bruno Hagenbuch ◽  
Bo Gao ◽  
Peter. J. Meier
Keyword(s):  
Blood Brain Barrier ◽  
Transport Proteins ◽  
Brain Barrier ◽  
Drug Transporter ◽  
Detailed Characterization ◽  
Waste Products ◽  
Blood Brain ◽  
The Brain

Distinct transport proteins regulate the movement of waste products and xenobiotics across the blood-brain barrier (BBB). Members of the drug transporter families MDR, MRP, and OATP have been identified in the BBB, and a detailed characterization of the involved proteins is now required to target drugs more efficiently to the brain.

scholarly journals Novel GALNT3 Mutations Causing Hyperostosis-Hyperphosphatemia Syndrome Result in Low Intact Fibroblast Growth Factor 23 Concentrations

2007 ◽  
Vol 92 (5) ◽  
pp. 1943-1947 ◽  
Author(s):  
Shoji Ichikawa ◽  
Vincent Guigonis ◽  
Erik A. Imel ◽  
Mélanie Courouble ◽  
Sophie Heissat ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Fibrous Tissue ◽  
Old French ◽  
Fibroblast Growth ◽  
Dihydroxyvitamin D ◽  
Woven Bone ◽  
Glomerular Filtrate ◽  
Biochemical Abnormalities

Abstract Context: Hyperostosis-hyperphosphatemia syndrome (HHS) is a rare metabolic disorder characterized by hyperphosphatemia and localized hyperostosis. HHS is caused by mutations in GALNT3, which encodes UDP-N-acetyl-α-d-galactosamine:polypeptide N- acetylgalactosaminyltransferase 3. Familial tumoral calcinosis (TC), characterized by ectopic calcifications and hyperphosphatemia, is caused by mutations in the GALNT3 or fibroblast growth factor 23 (FGF23) genes. Objective: Our objective was to identify mutations in FGF23 or GALNT3 and determine serum FGF23 levels in an HHS patient. Design: Mutation detection in FGF23 and GALNT3 was performed by DNA sequencing, and serum FGF23 concentrations were measured by ELISA. Patients or Other Participants: A 5-year-old French boy with HHS and his family members participated. Results: The patient presented with painful cortical lesions in his leg. Radiographs of the affected bone showed diaphyseal hyperostosis. The lesional tissue comprised trabeculae of immature, woven bone surrounded by fibrous tissue. Biochemistry revealed elevated phosphate, tubular maximum rate for phosphate reabsorption per deciliter of glomerular filtrate, and 1,25-dihydroxyvitamin D levels. The patient was a compound heterozygote for two novel GALNT3 mutations. His parents and brother were heterozygous for one of the mutations and had no biochemical abnormalities. Intact FGF23 level in the patient was low normal, whereas C-terminal FGF23 was elevated, a pattern similar to TC. Conclusion: The presence of GALNT3 mutations and elevated C-terminal, but low intact serum FGF23, levels in HHS resemble those seen in TC, suggesting that HHS and TC are different manifestations of the same disorder. The absence of biochemical abnormalities in the heterozygous individuals suggests that one normal allele is sufficient for secretion of intact FGF23.

COX-2 inhibition prevents downregulation of key renal water and sodium transport proteins in response to bilateral ureteral obstruction

2005 ◽  
Vol 289 (2) ◽  
pp. F322-F333 ◽  
Author(s):  
Rikke Nørregaard ◽  
Boye L. Jensen ◽  
Chunling Li ◽  
Weidong Wang ◽  
Mark A. Knepper ◽  
...  
Keyword(s):  
Sodium Transport ◽  
Ureteral Obstruction ◽  
Transport Proteins ◽  
Outer Medulla ◽  
Fold Induction ◽  
Cox 2 ◽  
Type 3 ◽  
Sodium Handling ◽  
Cox 1

Bilateral ureteral obstruction (BUO) is associated with marked changes in the expression of renal aquaporins (AQPs) and sodium transport proteins. To examine the role of prostaglandin in this response, we investigated whether 24-h BUO changed the expression of cyclooxygenases (COX-1 and -2) in the kidney and tested the effect of the selective COX-2 inhibitor parecoxib (5 mg·kg−1·day−1 via osmotic minipumps) on AQPs and sodium transport. Sham and BUO kidneys were analyzed by semiquantitative immunoblotting, and a subset of kidneys was perfusion fixed for immunocytochemistry. BUO caused a significant 14-fold induction of inner medullary COX-2 (14.40 ± 1.8 vs. 1.0 ± 0.4, n = 6; P < 0.0001) and a reduction in medullary tissue osmolality, whereas COX-1 did not change. Immunohistochemistry confirmed increased COX-2 labeling associated with medullary interstitial cells. COX isoforms did not change in cortex/outer medulla after 24-h BUO. In BUO kidneys, inner medullary AQP2 expression was reduced, and this decrease was prevented by parecoxib. In the inner stripe of outer medulla, the type 3 Na+/H+ exchanger (NHE3) and apical Na+-K+-2Cl− cotransporter (BSC-1) were significantly reduced by BUO, and this decrease was significantly attenuated by parecoxib. Immunohistochemistry for AQP2, NHE3, and BSC-1 confirmed the effect of parecoxib. Parecoxib had no significant effect on the Na-K-ATPase α1-subunit, type II Na-Pi cotransporter, or AQP3. In conclusion, acute BUO leads to marked upregulation of COX-2 in inner medulla and selective COX-2 inhibition prevents dysregulation of AQP2, BSC-1, and NHE3 in response to BUO. These data indicate that COX-2 may be an important factor contributing to the impaired renal water and sodium handling in response to BUO.

scholarly journals Salt-Losing Tubulopathies in Children: What’s New, What’s Controversial?

2017 ◽  
Vol 29 (3) ◽  
pp. 727-739 ◽  
Author(s):  
Robert Kleta ◽  
Detlef Bockenhauer
Keyword(s):  
Clinical Evidence ◽  
Collecting Duct ◽  
Salt Transport ◽  
Renal Physiology ◽  
Thick Ascending Limb ◽  
Rare Disorders ◽  
Clinical Observations ◽  
Tubular Transport ◽  
Molecular Aspects ◽  
Sodium Handling

Renal tubulopathies provide insights into the inner workings of the kidney, yet also pose therapeutic challenges. Because of the central nature of sodium in tubular transport physiology, disorders of sodium handling may affect virtually all aspects of the homeostatic functions of the kidney. Yet, owing to the rarity of these disorders, little clinical evidence regarding treatment exists. Consequently, treatment can vary widely between individual physicians and centers and is based mainly on understanding of renal physiology, reported clinical observations, and individual experiences. Salt-losing tubulopathies can affect all tubular segments, from the proximal tubule to the collecting duct. But the more frequently observed disorders are Bartter and Gitelman syndrome, which affect salt transport in the thick ascending limb of Henle’s loop and/or the distal convoluted tubule, and these disorders generate the greatest controversies regarding management. Here, we review clinical and molecular aspects of salt-losing tubulopathies and discuss novel insights provided mainly by genetic investigations and retrospective clinical reviews. Additionally, we discuss controversial topics in the management of these disorders to highlight areas of importance for future clinical trials. International collaboration will be required to perform clinical studies to inform the treatment of these rare disorders.

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