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World Journal of Clinical Pediatrics Dec 2023Renal tubular acidosis (RTA) can lead to renal calcification in children, which can cause various complications and impair renal function. This review provides... (Review)
Review
Renal tubular acidosis (RTA) can lead to renal calcification in children, which can cause various complications and impair renal function. This review provides pediatricians with a comprehensive understanding of the relationship between RTA and renal calcification, highlighting essential aspects for clinical management. The article analyzed relevant studies to explore the prevalence, risk factors, underlying mechanisms, and clinical implications of renal calcification in children with RTA. Results show that distal RTA (type 1) is particularly associated with nephrocalcinosis, which presents a higher risk of renal calcification. However, there are limitations to the existing literature, including a small number of studies, heterogeneity in methodologies, and potential publication bias. Longitudinal data and control groups are also lacking, which limits our understanding of long-term outcomes and optimal management strategies for children with RTA and renal calcification. Pediatricians play a crucial role in the early diagnosis and management of RTA to mitigate the risk of renal calcification and associated complications. In addition, alkaline therapy remains a cornerstone in the treatment of RTA, aimed at correcting the acid-base imbalance and reducing the formation of kidney stones. Therefore, early diagnosis and appropriate therapeutic interventions are paramount in preventing and managing renal calcification to preserve renal function and improve long-term outcomes for affected children. Further research with larger sample sizes and rigorous methodologies is needed to optimize the clinical approach to renal calcification in the context of RTA in the pediatric population.
PubMed: 38178934
DOI: 10.5409/wjcp.v12.i5.295 -
The Journal of the Royal College of... Sep 2020Tenofovir disoproxil fumarate (TDF) is the foundation nucleotide reverse-transcriptase inhibitor in the recommended first-line regimen for all naive human...
Tenofovir disoproxil fumarate (TDF) is the foundation nucleotide reverse-transcriptase inhibitor in the recommended first-line regimen for all naive human immunodeficciency virus-1 (HIV-1) patients whose age is more than 10 years and body weight is more than 30 kg. Although it has a good safety profile overall, nephrotoxicity is a concern and its overall incidence is 1-6% with a long period of clinical latency. Nephrotoxicity may manifest as either proximal renal tubule dysfunction in the form of a partial or complete Fanconi syndrome or as decreased renal function leading to acute or chronic kidney injury. Osteomalacia can also develop secondary to complicating hypophosphataemia and low calcitriol levels. Here we report a 50-year-old HIV-positive male on tenofovir who presented with proximal renal tubular acidosis and fracture of left neck of femur four years after initiation of the drug.
Topics: Child; Fanconi Syndrome; HIV Infections; Humans; Incidence; Male; Middle Aged; Osteomalacia; Tenofovir
PubMed: 32936106
DOI: 10.4997/JRCPE.2020.316 -
American Journal of Nephrology 2022In metabolic acidosis, a negative calcium balance is induced by decreased renal tubular calcium reabsorption. This occurs independently of the action of parathyroid... (Review)
Review
BACKGROUND
In metabolic acidosis, a negative calcium balance is induced by decreased renal tubular calcium reabsorption. This occurs independently of the action of parathyroid hormone or vitamin D and was attributed to a direct action of metabolic acidosis on the renal tubular cells. The latter has been verified by recent studies on the molecular levels in the kidney.
SUMMARY
Whereas the regulatory role of urinary calcium excretion was traditionally assigned to the transcellular calcium transport in the distal convoluted tubule (DCT) and connecting tubule (CNT), most of the calcium reabsorption from the glomerular filtrate paracellularly occurs through the tight junctions in the proximal tubule (PT) and the thick ascending limb (TAL) of Henle's loop. Interestingly, all these nephron segments participate in producing hypercalciuria caused by metabolic acidosis. Claudin-2 is the major route of paracellular calcium transport in the PT and was downregulated in rats with 5 days' NH4Cl loading. In the TAL, the lumen-positive voltage produced by apical K+ recycling drives paracellular reabsorption of Ca2+ and Mg2+ via the claudin-16/19 complex. Activation of calcium-sensing receptor (CaSR) by extracellular calcium upregulates claudin-14, which in turn interacts with the claudin-16/19 complex and inhibits its cation permeability. This TAL CaSR-claudins axis was activated by chronic NH4Cl loading in rats. Finally, the major transcellular calcium transporters TRPV5 and 28K calcium-binding protein in the DCT-CNT were also downregulated by NH4Cl or acetazolamide administration in mice.
KEY MESSAGES
Both paracellular and transcellular calcium transport pathways in the kidney are regulated by metabolic acidosis and lead to renal calcium wasting. In the PT, claudin-2 is downregulated by acidic pH. In the TAL of Henle's loop, CaSR is stimulated by the ionized calcium released from bone and upregulates claudin-14, which in turn inhibits the claudin-16/19 complex and leads to calcium and magnesium wasting. Finally, the transcellular calcium transporters, TRPV5 and calbindin-D28K, are downregulated by metabolic acidosis in the DCT and CNT.
Topics: Mice; Rats; Animals; Calcium; Hypercalciuria; Claudin-2; Claudins; Kidney; Acidosis
PubMed: 36450225
DOI: 10.1159/000528089 -
Nephrologie & Therapeutique Apr 2021Kidney stone disease comprising nephrolithiasis and nephrocalcinosis is a clinical syndrome of increasing prevalence with remarkable heterogeneity. Stone composition,... (Review)
Review
Kidney stone disease comprising nephrolithiasis and nephrocalcinosis is a clinical syndrome of increasing prevalence with remarkable heterogeneity. Stone composition, age of manifestation, rate of recurrence, and impairment of kidney function varies with underlying etiologies. While calcium-based kidney stones account for the vast majority their etiology is still poorly understood. Recent studies underline the notion that genetic susceptibility together with dietary habits constitutes the major driver of kidney stone formation. In addition to single gene (Mendelian) disorders, which are most likely underestimated in the adult population, common risk alleles explain part of the observed heritability. Interestingly, identified GWAS loci often match those of Mendelian disease genes and vice versa (CASR, SLC34A1, CYP24A1). These findings provide mechanistic links related to renal calcium homeostasis, vitamin D metabolism, and CaSR-signaling regulated by the CaSR-CLDN14-CLDN16/19 axis (paracellular Ca reabsorption) and TRPV5 (transcellular Ca reabsorption). Recent identification of new single gene disorders of calcium-oxalate-nephrolithiasis (SLC26A1, CLDN2) and distal renal tubular acidosis with nephrocalcinosis (FOXI1, WDR72, ATP6V1C2) enabled additional insights into the kidney-gut axis and molecular prerequisites of proper urinary acidification. Implementation of centralized patient registries on hereditary kidney stone diseases are necessary to build up well characterized cohorts for urgently needed clinical studies.
Topics: Adult; Alleles; Forkhead Transcription Factors; Genetic Predisposition to Disease; Humans; Kidney Calculi; Nephrocalcinosis
PubMed: 33910705
DOI: 10.1016/j.nephro.2020.02.003 -
Current Opinion in Nephrology and... Mar 2023The present review summarizes findings of recent studies examining the epidemiology, pathophysiology, and treatment of type 4 renal tubular acidosis (RTA) and uric acid... (Review)
Review
PURPOSE OF REVIEW
The present review summarizes findings of recent studies examining the epidemiology, pathophysiology, and treatment of type 4 renal tubular acidosis (RTA) and uric acid nephrolithiasis, two conditions characterized by an abnormally acidic urine.
RECENT FINDINGS
Both type 4 RTA and uric acid nephrolithiasis disproportionately occur in patients with type 2 diabetes and/or chronic kidney disease. Biochemically, both conditions are associated with reduced renal ammonium excretion resulting in impaired urinary buffering and low urine pH. Reduced ammoniagenesis is postulated to result from hyperkalemia in type 4 RTA and from insulin resistance and fat accumulation in the renal proximal tubule in uric acid nephrolithiasis. The typical biochemical findings of hyperkalemia and systemic acidosis of type 4 RTA are rarely reported in uric acid stone formers. Additional clinical differences between the two conditions include findings of higher urinary uric acid excretion and consequent urinary uric acid supersaturation in uric acid stone formers but not in type 4 RTA.
SUMMARY
Type 4 RTA and uric acid nephrolithiasis share several epidemiological, clinical, and biochemical features. Although both conditions may be manifestations of diabetes mellitus and thus have a large at-risk population, the means to the shared biochemical finding of overly acidic urine are different. This difference in pathophysiology may explain the dissimilarity in the prevalence of kidney stone formation.
Topics: Humans; Uric Acid; Diabetes Mellitus, Type 2; Acidosis, Renal Tubular; Hyperkalemia; Hydrogen-Ion Concentration; Kidney Calculi; Nephrolithiasis
PubMed: 36683539
DOI: 10.1097/MNH.0000000000000859 -
Indian Journal of Pediatrics Sep 2020Although kidney stones are less common in children than in adults, incidence in children is rising. Kidney stones may lead to significant morbidity in addition to... (Review)
Review
Although kidney stones are less common in children than in adults, incidence in children is rising. Kidney stones may lead to significant morbidity in addition to escalating medical costs. Clinical presentation is variable. Bilateral kidney stones in a younger child should prompt work-up for primary hyperoxaluria. Metabolic abnormalities are more frequent in children and can result in frequent stone recurrence. Whole exome sequencing data shows genetic defects in about 30% of stone formers. 24 h urine collection should be conducted when patient receives his usual diet and fluid intake with normal activity. Infrared spectroscopy and X-ray diffraction are used for stone analysis. Urine studies should be delayed by 4-6 wk after stone fragmentation or treatment of any stone related complications. The goal of evaluation is to identify modifiable risk factors for which targeted therapy may be instituted. Primary indications for surgical intervention include pain, infection and obstruction. Extracorporeal shockwave lithotripsy (ESWL), ureteroscopy, and percutaneous nephrolithotomy (PCNL) are most commonly used, and selection is based on stone size, anatomy, composition and anatomy. Advances in technology have allowed a shift to minimally invasive surgeries. Comprehensive management requires multidisciplinary team. Children with kidney stones require long term follow-up with periodic assessment of stone forming activity and ascertaining stone burden. High index of suspicion should be there to diagnose diseases like primary hyperoxaluria, Dent's disease, renal tubular acidosis (RTA) etc. as these diseases have ramifications on kidney function and growth.
Topics: Adult; Child; Humans; Kidney Calculi; Lithotripsy; Recurrence; Risk Factors; Ureteroscopy
PubMed: 32794099
DOI: 10.1007/s12098-020-03424-7 -
Kidney360 Oct 2021
Topics: Acidosis, Renal Tubular; Humans; Hypokalemia; Lupus Nephritis
PubMed: 35372981
DOI: 10.34067/KID.0005302021 -
Nephron 2023Serum creatinine and albuminuria are primary markers of glomerular function and injury, respectively. Tubular secretion, acid-base homeostasis, protein reabsorption,... (Review)
Review
BACKGROUND
Serum creatinine and albuminuria are primary markers of glomerular function and injury, respectively. Tubular secretion, acid-base homeostasis, protein reabsorption, among other tubular functions, are largely ignored. This mini-review aimed to discuss how two tubular functions, secretion, and acid-base homeostasis are associated with major adverse kidney events (MAKEs).
SUMMARY
Proximal tubular secretion is an essential function that allows the elimination of endogenous substances and drugs. Recently discovered endogenous markers in urine and plasma allow a noninvasive way of assessing tubular secretion markers. Several studies have found an association between these markers and a higher risk of chronic kidney disease (CKD) progression and mortality. In a study we recently performed among patients with CKD and at risk of cardiovascular events, lower tubular secretion was associated with an increased risk of acute kidney injury and metabolic acidosis, independent of baseline eGFR and albuminuria. The kidney tubules also play a crucial role in acid-base homeostasis. Although the standard clinical assessment of acidosis consists of measuring serum bicarbonate, urinary ammonium excretion decreases before over metabolic acidosis. Urinary ammonium excretion is associated with CKD progression, a higher risk of kidney failure, and an increased mortality risk, independent of baseline eGFR and albuminuria.
KEY MESSAGES
Novel biomarkers of kidney tubular health consistently associate with MAKEs, above and beyond baseline eGFR, albuminuria, and other CKD risk factors. Tubular markers may provide new opportunities to improve kidney prognosis, drug dosing, and monitoring for adverse events.
Topics: Humans; Albuminuria; Kidney Tubules; Renal Insufficiency, Chronic; Biomarkers; Acidosis; Ammonium Compounds; Glomerular Filtration Rate
PubMed: 37524063
DOI: 10.1159/000531946 -
Best Practice & Research. Clinical... Mar 2024Phosphate is an integral part of human cellular structure and function. Though most recognised disorders of phosphaturia are genetic in origin, phosphate loss due to... (Review)
Review
Phosphate is an integral part of human cellular structure and function. Though most recognised disorders of phosphaturia are genetic in origin, phosphate loss due to acquired conditions is commonly encountered in clinical practice. Acquired hypophosphatemia is most commonly due to renal phosphate wasting and can produce significant morbidity. It also heralds future kidney damage, and continued exposure can lead to progressive kidney injury and potentially renal failure. These conditions are a diverse group of disorders with common shared mechanisms causing loss of phosphate in the urine. Renal phosphate loss can occur as an isolated entity or as a part of generalised proximal tubular dysfunction, i.e., Fanconi's syndrome. An insight into the pathophysiological mechanisms of acquired phosphaturia can help clinicians monitor their patients better and avoid potential harms.
Topics: Humans; Fanconi Syndrome; Hypophosphatemia, Familial; Kidney Diseases; Osteomalacia; Phosphates; Paraneoplastic Syndromes
PubMed: 38007379
DOI: 10.1016/j.beem.2023.101839