Electrolyte and Acid-Base Disorders Triggered by Aminoglycoside or Colistin Therapy: A Systematic Review

Aminoglycoside or colistin therapy may alter the renal tubular function without decreasing the glomerular filtration rate. This association has never been extensively investigated. We conducted a systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations. Databases searched included United States National Library of Medicine, Excerpta Medica, and Web of Science. For the final analysis, we evaluated 46 reports, published after 1960, describing 82 cases. A total of 286 electrolyte and acid-base disorders were reported. Hypomagnesemia, hypokalemia, and hypocalcemia were reported in more than three quarter of cases. Further disorders were, in decreasing order of frequency, metabolic alkalosis, hyponatremia, hypophosphatemia, hypouricemia, hypernatremia, and metabolic acidosis. Six electrolyte and acid-base disorders were reported in seven cases, five in 12 cases, four in 16 cases, three in 31 cases, two in 11 cases, and one in five cases. Laboratory features consistent with a loop of Henle/distal tubular dysfunction were noted in 56 (68%), with a proximal tubular dysfunction in three (3.7%), and with a mixed dysfunction in five (6.1%) cases. The laboratory abnormality was unclassified in the remaining 18 (22%) cases. Treatment with aminoglycosides or colistin may trigger a proximal tubular or, more frequently, a loop of Henle/distal tubular dysfunction.

Urinary miRNA Biomarkers of Drug-Induced Kidney Injury and Their Site Specificity Within the Nephron

Drug-induced kidney injury (DIKI) is a major concern in both drug development and clinical practice. There is an unmet need for biomarkers of glomerular damage and more distal renal injury in the loop of Henle and the collecting duct (CD). A cross-laboratory program to identify and characterize urinary microRNA (miRNA) patterns reflecting tissue- or pathology-specific DIKI was conducted. The overall goal was to propose miRNA biomarker candidates for DIKI that could supplement information provided by protein kidney biomarkers in urine. Rats were treated with nephrotoxicants causing injury to distinct nephron segments: the glomerulus, proximal tubule, thick ascending limb (TAL) of the loop of Henle and CD. Meta-analysis identified miR-192-5p as a potential proximal tubule-specific urinary miRNA candidate. This result was supported by data obtained in laser capture microdissection nephron segments showing that miR-192-5p expression was enriched in the proximal tubule. Discriminative miRNAs including miR-221-3p and -222-3p were increased in urine from rats treated with TAL versus proximal tubule toxicants in accordance with their expression localization in the kidney. Urinary miR-210-3p increased up to 40-fold upon treatment with TAL toxicants and was also enriched in laser capture microdissection samples containing TAL and/or CD versus proximal tubule. miR-23a-3p was enriched in the glomerulus and was increased in urine from rats treated with doxorubicin, a glomerular toxicant, but not with toxicants affecting other nephron segments. Taken together these results suggest that urinary miRNA panels sourced from specific nephron regions may be useful to discriminate the pathology of toxicant-induced lesions in the kidney, thereby contributing to DIKI biomarker development needs for industry, clinical, and regulatory use.

Antihypertensive and Renal Mechanisms of SGLT2 (Sodium-Glucose Linked Transporter 2) Inhibitors

Empaglifolzin, canagliflozin, and dapagliflozin are SGLT2 (sodium-glucose linked transporter type 2) inhibitors for treatment of type 2 diabetes mellitus that also reduce blood pressure, mortality, and cardiovascular disease and slow the loss of glomerular filtration rate. SGLT2 inhibitors inhibit the coupled reabsorption of sodium and glucose from the proximal tubules, thereby increasing renal glucose and sodium excretion, but they have more widespread renal effects, including inhibition of the sodium:proton exchanger. They increase the delivery of sodium to the loop of Henle and can thereby activate the tubuloglomerular feedback response to correct glomerular hyperfiltration. There are multiple potential mechanisms whereby these drugs lower blood pressure and preserve kidney function that are the focus of this review.

Uromodulin and kidneys

Uromodulin (UMO) is a multifunctional glycoprotein expressed in the epithelial cells of the thick ascending part of the loop of Henle. Currently a lot of data about mechanisms of biosynthesis, apical and basolateral transport of UMO, changes in urine and blood concentrations in different kidney compartments damage, roles of UMO in protecting kidneys from infections, maintaining mineral homeostasis, development of arterial hypertension and the participation of this glycoprotein in other physiological and pathological processes has been accumulated. The article discusses the clinical significance of UMO in the development and progression of chronic kidney disease, prognostic value of UMO urine and blood concentrations in terms of the risk of cardiovascular diseases and probability of acute kidney damage in patients with cardiovascular pathology. Briefly highlights issues of UMO gene mutation and development of autosomal dominant tubulointerstitial kidney disease.

Renal medicine

The kidneys are of fundamental importance in the regu­lation of fluid and electrolytes, maintaining permissive extracellular fluid composition (salts and water), pH, and volume, while also mediating the removal of waste prod­ucts. Based on the anatomy of the nephron, three main processes occur in order to deliver this balance: glom­erular filtration, tubular secretion, and tubular resorption. Drugs can act at different sites within this system, so that functional equilibrium can be restored in various disease states (e.g. hypertension, heart failure, liver failure, neph­rotic syndrome). CKD is a long- term condition that lasts more than 3 months and affects the function of both kidneys. It results from any pathology that reduces renal functional capacity and produces a decrease in GFR to less than 60 mL/ min/ 1.73 m². Prevalence within the UK is high, particularly in the elderly and affects 6– 8% of the population. The most common cause of CKD is idiopathic (unknown, usually with small kidneys), then diabetes mellitus. In both, glom­erular damage and mesangial injury (causing metabolic and haemodynamic effects) occur. Mild- moderate essen­tial hypertension does not cause CKD. Knowledge of the functional anatomy of the proximal tubule and loop of Henle is essential in understanding therapeutic targets and treatment of pathologies, as each region and transporter system has a key role. In brief, the journey of solutes from the blood to the production of urine occurs at five main anatomical sites— the glom­erulus, the proximal tubule, the loop of Henle, the distal tubule (proximal part and distal part), and the collecting ducts (Figures 5.1 and 5.2). The glomerulus is a network of capillaries (like a ball of string), which merge with the nephron via Bowman’s cap­sule. It is the first site of filtration and the place where solutes, toxins, and small proteins are removed from the wider circulatory system, after delivery by the renal ar­teries (via an afferent arteriole). Blood and larger proteins remain in the arteriole and leave via an efferent branch, while the filtrate enters the proximal convoluted tubule. The afferent:efferent system ensures that a constant filtration pressure is maintained irrespective of variations in arterial pressure. The capillary bed is very large, so that permeability and filtration rates are high. A normal glomerular filtration rate (GFR) i.e. 90– 120 mL/ min/ 1.73 m², depends on hydrostatic pressure, the colloid osmotic pressure and hydraulic per¬meability.

Bartter and Gitelman syndromes: Questions of class

Bartter and Gitelman syndromes are rare inherited tubulopathies characterized by hypokalaemic, hypochloraemic metabolic alkalosis. They are caused by mutations in at least 7 genes involved in the reabsorption of sodium in the thick ascending limb (TAL) of the loop of Henle and/or the distal convoluted tubule (DCT). Different subtypes can be distinguished and various classifications have been proposed based on clinical symptoms and/or the underlying genetic cause. Yet, the clinical phenotype can show remarkable variability, leading to potential divergences between classifications. These problems mostly relate to uncertainties over the role of the basolateral chloride exit channel CLCNKB, expressed in both TAL and DCT and to what degree the closely related paralogue CLCNKA can compensate for the loss of CLCNKB function. Here, we review what is known about the physiology of the transport proteins involved in these disorders. We also review the various proposed classifications and explain why a gene-based classification constitutes a pragmatic solution.

Histogenesis of human fetal kidney from 14 weeks to 36 weeks: a study

Background: The knowledge of fetal human Kidney morphology and developmental anatomy is very important for prenatal diagnosis of disorders such as Wilm’s tumor, hydronephroses and congenital malformation etc.Methods: The study was carried out on 40 kidneys procured from 20 spontaneously aborted fetuses (11males and 9 females) ranging from 14wks-36wks of gestation, after confirming their age through CRL they were grouped and then processed to form slides and stained with haemtoxylin and eosin and seen under light microscope.Results: All kidneys were lobulated at early gestational age and became fused by 36 wks. Corticomedullary junction and preformed collecting tubules were seen clearly by 18wks. Well differentiated PCT and DCT were formed by 19-23 wks. Well-formed pyramids by 28 wks and medullary rays by 29 weeks were clearly distinguished. Loop of Henle developed and distinguished by 28 wks. Increased vascularity was seen by 32-36 wks. Nephrogenic zone and undifferentiated mesenchyme decreased and matured glomeruli increased by 36 wks.Conclusions: The present study gave emphasis to the development of each component in medulla and cortex of kidney.