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Scientific Reports Oct 2023Megalin/LRP2 is a major receptor supporting apical endocytosis in kidney proximal tubular cells. We have previously reported that kidney-specific perinatal ablation of...
Megalin/LRP2 is a major receptor supporting apical endocytosis in kidney proximal tubular cells. We have previously reported that kidney-specific perinatal ablation of the megalin gene in cystinotic mice, a model of nephropathic cystinosis, essentially blocks renal cystine accumulation and partially preserves kidney tissue integrity. Here, we examined whether inhibition of the megalin pathway in adult cystinotic mice by dietary supplementation (5x-fold vs control regular diet) with the dibasic amino-acids (dAAs), lysine or arginine, both of which are used to treat patients with other rare metabolic disorders, could also decrease renal cystine accumulation and protect cystinotic kidneys. Using surface plasmon resonance, we first showed that both dAAs compete for protein ligand binding to immobilized megalin in a concentration-dependent manner, with identical inhibition curves by L- and D-stereoisomers. In cystinotic mice, 2-month diets with 5x-L-lysine and 5x-L-arginine were overall well tolerated, while 5x-D-lysine induced strong polyuria but no weight loss. All diets induced a marked increase of dAA urinary excretion, most prominent under 5x-D-lysine, without sign of kidney insufficiency. Renal cystine accumulation was slowed down approx. twofold by L-dAAs, and totally suppressed by D-lysine. We conclude that prolonged dietary manipulation of the megalin pathway in kidneys is feasible, tolerable and can be effective in vivo.
Topics: Adult; Humans; Animals; Mice; Cystine; Cystinosis; Lysine; Low Density Lipoprotein Receptor-Related Protein-2; Kidney; Dietary Supplements
PubMed: 37828038
DOI: 10.1038/s41598-023-43105-x -
Archives of Medical Research Sep 2023Bartter's syndrome (BS) is a group of salt-wasting tubulopathies characterized by hypokalemia, metabolic alkalosis, hypercalciuria, secondary hyperaldosteronism, and low...
BACKGROUND
Bartter's syndrome (BS) is a group of salt-wasting tubulopathies characterized by hypokalemia, metabolic alkalosis, hypercalciuria, secondary hyperaldosteronism, and low or normal blood pressure. Loss-of-function variants in genes encoding for five proteins expressed in the thick ascending limb of Henle in the nephron, produced different genetic types of BS.
AIM
Clinical and genetic analysis of families with Antenatal Bartter syndrome (ABS) and with Classic Bartter syndrome (CBS).
METHODS
Nine patients from unrelated non-consanguineous Mexican families were studied. Massive parallel sequencing of a gene panel or whole-exome sequencing was used to identify the causative gene.
RESULTS
Proband 1 was homozygous for the pathogenic variant p.Arg302Gln in the SLC12A1 gene encoding for the sodium-potassium-chloride NKCC2 cotransporter. Proband 3 was homozygous for the nonsense variant p.Cys308* in the KCNJ1 gene encoding for the ROMK potassium channel. Probands 7, 8, and 9 showed variants in the CLCKNB gene encoding the chloride channel ClC-Kb: proband 7 was compound heterozygous for the deletion of the entire gene and the missense change p.Arg438Cys; proband 8 presented a homozygous deletion of the whole gene and proband 9 was homozygous for the nonsense mutation p.Arg595*. A heterozygous variant of unknown significance was detected in the SLC12A1 gene in proband 2, and no variants were found in SLC12A1, KCNJ1, BSND, CLCNKA, CLCNKB, and MAGED2 genes in probands 4, 5, and 6.
CONCLUSIONS
Genetic analysis identified loss-of-function variants in the SLC12A1, KCNJ1, and CLCNKB genes in four patients with ABS and in the CLCNKB gene in two patients with CBS.
Topics: Humans; Female; Pregnancy; Bartter Syndrome; Homozygote; Sequence Deletion; Heterozygote; Mutation; Antigens, Neoplasm; Adaptor Proteins, Signal Transducing; Chloride Channels
PubMed: 37516009
DOI: 10.1016/j.arcmed.2023.102859 -
Birth Defects Research Oct 2023Bartter syndrome (BS) is a rare congenital salt-losing renal tubular transport disorder, characterized by salt wasting, polyuria, biochemical abnormalities, and...
BACKGROUND
Bartter syndrome (BS) is a rare congenital salt-losing renal tubular transport disorder, characterized by salt wasting, polyuria, biochemical abnormalities, and acid-base homeostasis imbalance. The syndrome has five different genetic forms, and novel mutations of CLCNKB gene lead to type 3 BS also known as classic BS. In this case, we report clinical and molecular findings from a newborn baby with BS.
CASE
A 10-day-old male infant born at 37 weeks of gestation by cesarean section following a pregnancy complicated with polyhydramnios, and fetal distress to a 30-year-old gravida 3, para 3 mother, with a 2500 g birth weight was brought to the pediatric emergency department due to weight loss and jaundice. The neonate was referred to the neonatal intensive care unit (NICU) with a preliminary diagnosis of hyponatremic dehydration (Na: 122 mmol/L, 10% dehydration) and hypokalemic hypochloremic metabolic alkalosis (K: 2.13 mmol/L, Cl: 63 mmol/L, pH: 7.62, pCO : 39 mmHg, HCO : 40.8 mmol/L, BE: 16.9 mmol/L), and hypocalcemia (ionized Ca: 0.72 mmol/L). On arrival to the NICU, symptomatic focal seizures, and polyuria complicated his course. Spot urine biochemistry revealed a renal salt wasting and hypercalciuria: Creatine 11.4 mg/dL Na: 51 mmol/L (54-150), K: 26 mmol/L (20-80), Cl: 164 mmol/L, fractional excretion of sodium (FENa): 3% (0.9-1.6), fractional excretion of chloride (FECl): 17% (<0.5%) and Ca/Cr: 0.33 (<0.2). Biochemical abnormalities disappeared through intravenous fluid and electrolyte therapy, but he could not achieve adequate weight gain, and polyuric urine output (6.5 cc/kg/h), and metabolic alkalosis continued as the enteral feedings advance. Patient's serum renin: 184 pg/mL (5-27 pg/mL) and aldosterone: 1670 pg/mL (1-180 ng/dL) were elevated. Polyuria, renal salt wasting, electrolyte and acid-base disturbances, and hyperreninemic hyperaldosteronism established the diagnosis as Bartter syndrome. An oral indomethacin (1 mg/kg/day) treatment, on the 8th day. ensured the weight gain, and normalized daily urine output. He achieved the goal of birth weight on the 30th day and he was 3520 g weight at discharge on day 42. The genetic tests of the patient as KCNJ1 SLC12A1 gene sequence analysis revealed a novel homozygous mutation in the 14th exon of the CLCNKB gene, the c.1334_1338del CTTTT (p. Ser445fs*4) variant was identified.
DISCUSSION
The diagnosis of BS should be considered in the presence of a medical history of severe polyhydramnios of fetal origin. Postnatally, polyuria, signs of dehydration, renal salt wasting, and hypokalemic-metabolic alkalosis should prompt the clinician to request genetic testing for BS in the neonatal period. This case is presented to emphasize that early diagnosis of BS should be considered in newborns presenting with electrolyte abnormalities and metabolic alkalosis accompanying dehydration and favorable growth results can be achieved by starting indomethacin treatment in the early neonatal period. The clinical exome sequencing illustrated a novel missense variant in the CLCNKB gene leading to the molecular diagnosis of BS type 3.
PubMed: 37587715
DOI: 10.1002/bdr2.2235 -
Annals of Clinical Biochemistry Jan 2024Diabetes insipidus (DI) is a group of disorders that lead to inappropriate production of large volumes of dilute urine. The three main forms are central DI (CDI),... (Review)
Review
Diabetes insipidus (DI) is a group of disorders that lead to inappropriate production of large volumes of dilute urine. The three main forms are central DI (CDI), nephrogenic DI (NDI) and primary polydipsia (PP). Differentiating CDI/NDI from PP is important as patients with true DI are at risk of severe dehydration without treatment. Biochemical testing is key in the diagnosis of DI. The indirect water deprivation test (WDT) is commonly used in the investigation of DI but has drawbacks including being cumbersome and sometimes producing equivocal results. Direct measurement of AVP has theoretical advantages but has generally only been used in specialist centres. Disadvantages include the requirement to measure AVP under hypertonic stimulation and pre-analytical/analytical challenges. Copeptin (CT-proAVP) is a proxy marker for AVP that is more stable, easier to measure and has been studied more widely in recent years. Historically, the evidence supporting the diagnostic performance of these tests has been relatively poor, being based on a few small, usually single-centre studies. However more recent, well-designed prospective studies are improving the evidence base for investigation of DI. These studies have focused on the utility of copeptin measurements during stimulation tests. There is evidence that measurement of copeptin under stimulation offers improved diagnostic performance compared to the WDT. There is currently a lack of systematic, evidence-based guidelines on the diagnosis of DI, but as the quality of the evidence defining the diagnostic performance of tests for DI continues to improve, a clearer consensus on the optimal approach should become achievable.
Topics: Humans; Prospective Studies; Polyuria; Glycopeptides; Diagnosis, Differential; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diabetes Mellitus
PubMed: 36650746
DOI: 10.1177/00045632231154391 -
Frontiers in Endocrinology 2023MIRAGE syndrome is a rare disease characterized by myelodysplasia, infection, growth restriction, adrenal hypoplasia, genital phenotypes, and enteropathy. Herein, we...
Case report: a premature infant with severe intrauterine growth restriction, adrenal insufficiency, and inflammatory diarrhea: a genetically confirmed case of MIRAGE syndrome.
INTRODUCTION
MIRAGE syndrome is a rare disease characterized by myelodysplasia, infection, growth restriction, adrenal hypoplasia, genital phenotypes, and enteropathy. Herein, we report the case of a girl with MIRAGE syndrome who presented with adrenal insufficiency and chronic diarrhea.
CASE PRESENTATION
The patient was born at 29 + 6 weeks of gestational age with a birth weight of 656 g (<3p). Her height and head circumference were also <3p. At birth, she presented with respiratory distress, meconium staining, and pneumomediastinum, which were managed with high-frequency ventilation and empirical antibiotics. Physical examination showed generalized hyperpigmentation and normal female genitalia. A few days after birth, polyuria and hypotension developed, and laboratory findings revealed hypoglycemia, hyponatremia, and hyperkalemia. Plasma adrenocorticotropic hormone levels were elevated with low serum cortisol levels and high plasma renin activity, which were suggestive of adrenal insufficiency. Hydrocortisone and fludrocortisone were introduced and maintained, and hyperpigmentation attenuated with time. Both kidneys looked dysplastic, and adrenal glands could not be traced on abdominal ultrasound. From the early days of life, thrombocytopenia and anemia were detected, but not to life-threatening level and slowly recovered up to the normal range. Despite aggressive nutritional support, weight gain and growth spurt were severely retarded during the hospital stay. Additionally, after introducing enteral feeding, she experienced severe diarrhea and subsequent perineal skin rashes and ulcerations. Fecal calprotectin level was highly elevated; however, a small bowel biopsy resulted in non-specific submucosal congestion. The patient was diagnosed with MIRAGE syndrome with SAMD9 gene mutation. She was discharged with tube feeding and elemental formula feeding continued, but chronic diarrhea persisted. By the time of the last follow-up at 15 months of corrected age, she was fortunately not subjected to severe invasive infection and myelodysplastic syndrome. However, she was dependent on tube feeding and demonstrated a severe developmental delay equivalent to approximately 5-6 months of age.
CONCLUSION
The early diagnosis of adrenal crisis and hormone replacement therapy can save the life of -patients with MIRAGE syndrome; however, chronic intractable diarrhea and growth and developmental delay continue to impede the patient's well-being.
Topics: Humans; Infant, Newborn; Infant; Female; Fetal Growth Retardation; Intracellular Signaling Peptides and Proteins; Adrenal Insufficiency; Infant, Premature; Diarrhea; Myelodysplastic Syndromes; Hyperpigmentation
PubMed: 37745698
DOI: 10.3389/fendo.2023.1242387 -
Neurourology and Urodynamics Aug 2024The link between nocturia and cardiovascular disease (CVD) is frequently discussed in literature, yet the precise nature of this relationship remains poorly... (Review)
Review
AIMS
The link between nocturia and cardiovascular disease (CVD) is frequently discussed in literature, yet the precise nature of this relationship remains poorly characterized. The existing literature was reviewed in order to address issues concerning the origin, diagnosis, management, and implications of the co-occurrence of CVD and nocturia.
METHODS
This review summarizes literature and recommendations regarding the link between CVD and nocturia discussed during a think-tank meeting held at the 2023 International Consultation on Incontinence-Research Society.
RESULTS
Cardiovascular disorders are often underestimated contributors to nocturia, with various potential mechanisms influencing nighttime urination, such as impact on fluid retention, atrial natriuretic peptide, and glomerular filtration rate. The redistribution of fluid from leg edema in supine position can lead nocturnal polyuria (NP). Additionally, sleep disturbances due to nocturia in itself may lead to CVD through an increase in blood pressure, insulin resistance, and inflammation. Disrupted circadian rhythms (e.g., in sleep pattern and urine production) were identified as critical factors in most etiologies of nocturia, and their contribution is deemed imperative in future research and treatment approaches, particularly in the aging population. NP can be detected through a simple bladder diary and can even be used to distinguish cardiac from noncardiac causes of nocturia. For the treatment of NP, desmopressin can be effective in select patients, however, caution and close monitoring is warranted for those with CVD due to increased risk of side effects.
CONCLUSIONS
Gaps were identified in the available evidence and clear cut recommendations were put forth for future research. It is essential to gain a deeper understanding of the mechanisms linking nocturia and CVD to develop optimal management strategies.
Topics: Nocturia; Humans; Cardiovascular Diseases; Cardiovascular System
PubMed: 37942826
DOI: 10.1002/nau.25331 -
American Journal of Physiology. Renal... Oct 2023Nocturia (waking to void) is prevalent among older adults. Disruption of the well-described circadian rhythm in urine production with higher nighttime urine output is...
Nocturia (waking to void) is prevalent among older adults. Disruption of the well-described circadian rhythm in urine production with higher nighttime urine output is its most common cause. In young adults, their circadian rhythm is modulated by the 24-h secretory pattern of hormones that regulate salt and water excretion, including antidiuretic hormone (ADH), renin, angiotensin, aldosterone, and atrial natriuretic peptide (ANP). The pattern of hormone secretion is less clear in older adults. We investigated the effect of sleep on the 24-h secretion of these hormones in healthy older adults. Thirteen participants aged ≥65 yr old underwent two 24-h protocols at a clinical research center 6 wk apart. The first used a habitual wake-sleep protocol, and the second used a constant routine protocol that removed the influence of sleep, posture, and diet. To assess hormonal rhythms, plasma was collected at 8:00 am, 12:00 pm, 4:00 pm, and every 30 min from 7:00 pm to 7:00 am. A mixed-effects regression model was used to compare subject-specific and mean trajectories of hormone secretion under the two conditions. ADH, aldosterone, and ANP showed a diurnal rhythm that peaked during sleep in the wake-sleep protocol. These nighttime elevations were significantly attenuated within subjects during the constant routine. We conclude that sleep has a masking effect on circadian rhythm amplitude of ADH, aldosterone, and ANP: the amplitude of each is increased in the presence of sleep and reduced in the absence of sleep. Disrupted sleep could potentially alter nighttime urine output in healthy older adults via this mechanism. Nocturia (waking to void) is the most common cause of sleep interruption among older adults, and increased nighttime urine production is its primary etiology. We showed that in healthy older adults sleep affects the 24-h secretory rhythm of hormones that regulate salt-water balance, which potentially alters nighttime urine output. Further studies are needed to elucidate the impact of chronic insomnia on the secretory rhythms of these hormones.
Topics: Young Adult; Humans; Aged; Aldosterone; Nocturia; Urination; Sleep; Circadian Rhythm; Polyuria
PubMed: 37560770
DOI: 10.1152/ajprenal.00025.2023 -
Clinical Therapeutics Dec 2023This is a case report of a patient experiencing hyponatremia who was ultimately diagnosed with pituitary apoplexy-associated cerebral salt wasting syndrome (CSWS). (Review)
Review
PURPOSE
This is a case report of a patient experiencing hyponatremia who was ultimately diagnosed with pituitary apoplexy-associated cerebral salt wasting syndrome (CSWS).
METHODS
Laboratory tests, clinical evaluations, and magnetic resonance imaging were performed by specialists.
FINDINGS
The patient presented with severe headache, thirst, and polyuria. Results of laboratory tests indicated hyponatremia, decreased plasma osmolality, and elevated urine osmolality. Fluid restriction worsened the situation, and normal saline treatment helped return serum sodium and chloride levels to normal. Pituitary apoplexy-associated CSWS was finally considered.
IMPLICATIONS
Pituitary apoplexy is a rare but reasonable etiology for CSWS with hyponatremia. Saline therapy is usually effective.
Topics: Humans; Hyponatremia; Pituitary Apoplexy; Inappropriate ADH Syndrome
PubMed: 37778916
DOI: 10.1016/j.clinthera.2023.09.012 -
Frontiers in Microbiology 2024Hemorrhagic fever with renal syndrome (HFRS) is an acute infectious disease comprising five stages: fever, hypotension, oliguria, diuresis (polyuria), and convalescence....
INTRODUCTION
Hemorrhagic fever with renal syndrome (HFRS) is an acute infectious disease comprising five stages: fever, hypotension, oliguria, diuresis (polyuria), and convalescence. Increased vascular permeability, coagulopathy, and renal injury are typical clinical features of HFRS, which has a case fatality rate of 1-15%. Despite this, a comprehensive meta-analyses of the clinical characteristics of patients who died from HFRS is lacking.
METHODS
Eleven Chinese- and English-language research databases were searched, including the China National Knowledge Infrastructure Database, Wanfang Database, SinoMed, VIP Database, PubMed, Embase, Scopus, Cochrane Library, Web of Science, Proquest, and Ovid, up to October 5, 2023. The search focused on clinical features of patients who died from HFRS. The extracted data were analyzed using STATA 14.0.
RESULTS
A total of 37 articles on 140,295 patients with laboratory-confirmed HFRS were included. Categorizing patients into those who died and those who survived, it was found that patients who died were older and more likely to smoke, have hypertension, and have diabetes. Significant differences were also observed in the clinical manifestations of multiple organ dysfunction syndrome, shock, occurrence of overlapping disease courses, cerebral edema, cerebral hemorrhage, toxic encephalopathy, convulsions, arrhythmias, heart failure, dyspnea, acute respiratory distress syndrome, pulmonary infection, liver damage, gastrointestinal bleeding, acute kidney injury, and urine protein levels. Compared to patients who survived, those who died were more likely to demonstrate elevated leukocyte count; decreased platelet count; increased lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase levels; prolonged activated partial thromboplastin time and prothrombin time; and low albumin and chloride levels and were more likely to use continuous renal therapy. Interestingly, patients who died received less dialysis and had shorter average length of hospital stay than those who survived.
CONCLUSION
Older patients and those with histories of smoking, hypertension, diabetes, central nervous system damage, heart damage, liver damage, kidney damage, or multiorgan dysfunction were at a high risk of death. The results can be used to assess patients' clinical presentations and assist with prognostication.https://www.crd.york.ac.uk/prospero/, (CRD42023454553).
PubMed: 38638893
DOI: 10.3389/fmicb.2024.1329683 -
American Journal of Physiology. Cell... May 2024Acute pyelonephritis (APN) is most frequently caused by uropathogenic (UPEC), which ascends from the bladder to the kidneys during a urinary tract infection. Patients...
Acute pyelonephritis (APN) is most frequently caused by uropathogenic (UPEC), which ascends from the bladder to the kidneys during a urinary tract infection. Patients with APN have been reported to have reduced renal concentration capacity under challenged conditions, polyuria, and increased aquaporin-2 (AQP2) excretion in the urine. We have recently shown increased AQP2 accumulation in the plasma membrane in cell cultures exposed to lysates and in the apical plasma membrane of inner medullary collecting ducts in a 5-day APN mouse model. This study aimed to investigate if AQP2 expression in host cells increases UPEC infection efficiency and to identify specific bacterial components that mediate AQP2 plasma membrane insertion. As the transepithelial water permeability in the collecting duct is codetermined by AQP3 and AQP4, we also investigated whether AQP3 and AQP4 localization is altered in the APN mouse model. We show that AQP2 expression does not increase UPEC infection efficiency and that AQP2 was targeted to the plasma membrane in AQP2-expressing cells in response to the two pathogen-associated molecular patterns (PAMPs), lipopolysaccharide and peptidoglycan. In contrast to AQP2, the subcellular localizations of AQP1, AQP3, and AQP4 were unaffected both in lysate-incubated cell cultures and in the APN mouse model. Our finding demonstrated that cellular exposure to lipopolysaccharide and peptidoglycan can trigger the insertion of AQP2 in the plasma membrane revealing a new regulatory pathway for AQP2 plasma membrane translocation, which may potentially be exploited in intervention strategies. Acute pyelonephritis (APN) is associated with reduced renal concentration capacity and increased aquaporin-2 (AQP2) excretion. Uropathogenic (UPEC) mediates changes in the subcellular localization of AQP2 and we show that in vitro, these changes could be elicited by two pathogen-associated molecular patterns (PAMPs), namely, lipopolysaccharide and peptidoglycan. UPEC infection was unaltered by AQP2 expression and the other renal AQPs (AQP1, AQP3, and AQP4) were unaltered in APN.
Topics: Pyelonephritis; Animals; Aquaporin 2; Mice; Uropathogenic Escherichia coli; Aquaporin 3; Acute Disease; Escherichia coli Infections; Lipopolysaccharides; Cell Membrane; Humans; Aquaporin 4; Peptidoglycan; Kidney; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 38525539
DOI: 10.1152/ajpcell.00308.2023