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Embryology, Anatomy, and Physiology of the Kidneys and Ureters
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Paul Sturch, Sanjeev Madaan, Seshadri Sriprasad
Renin: released by granular cells of the juxtaglomerular apparatus in response to:Reduced renal blood pressure.Reduced sodium delivery to macula densa.Sympathetic stimulation.
Renal Blood Flow
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
In the juxtaglomerular apparatus, the macula densa lies in the wall of the ascending limb of the loop of Henle, close to the renal arterioles. The contraction of the smooth muscle of the afferent arteriole to the glomerulus is controlled by a vasoconstrictor, adenosine, from the macula densa (although the vasoconstrictor was previously thought to be renin). The macula densa releases more adenosine if the renal perfusion pressure rises and reduces production if the pressure falls. Adenosine production by the macula densa is determined by the composition of the fluid in the ascending loop of Henle.
Renal Pathophysiology
Published in Manit Arya, Taimur T. Shah, Jas S. Kalsi, Herman S. Fernando, Iqbal S. Shergill, Asif Muneer, Hashim U. Ahmed, MCQs for the FRCS(Urol) and Postgraduate Urology Examinations, 2020
Herman S. Fernando, Mohamed Yehia Abdallah, Iqbal S. Shergill
The glomerulus, which is about 200 μm in diameter, is formed by the invagination of a tuft of capillaries into the dilated, blind end of the nephron. In the distal convoluted tubule, while the predominant principle cells (P) are involved in Na+ reabsorption and vasopressin-stimulated water reabsorption, the intercalated cells (I) are associated with acid secretion and HCO3− transport. It is the wall of the afferent arteriole that contains renin-secreting juxtaglomerular cells. At this point the wall of the tubular epithelium is modified histologically to become the macula densa. The juxtaglomerular cells, the macula densa and the lacis cells near them are collectively known as juxtaglomerular apparatus. The kidney receives 25% of cardiac output.
The anti-hypertensive effects of sodium-glucose cotransporter-2 inhibitors
Published in Expert Review of Cardiovascular Therapy, 2023
Luxcia Kugathasan, Lisa Dubrofsky, Andrew Advani, David Z.I. Cherney
In contrast with a potential role for natriuresis, it is unlikely that the RAAS pathway contributes to the short-term antihypertensive effects of SGLT2 inhibitors, but it may help explain how BP reduction is maintained in certain patient groups. Although increased salt delivery to the macula densa should inhibit renin secretion, which would subsequently reduce BP, clinical studies demonstrate an increase in plasma renin activity and serum aldosterone following 12 weeks of dapagliflozin in patients with T2D [72]. The acute rise in systemic RAAS markers may be a compensatory mechanism in response to the transient diuretic action and subsequent volume depletion by SGLT2 inhibition [76,77]. However, this increase in renin activity and aldosterone concentration is reportedly lost after chronic intervention in patients with T2D, specifically after 6 months of SGLT2 inhibitor use [78]. It is postulated that other factors, including potassium and adrenocorticotropic hormone, may play a role in regulating aldosterone production, other than angiotensin II thereby limiting its rise long term [76]. This may perhaps implicate the RAAS in the prolonged reduction in BP with SGLT2 inhibitors but still does not explain how acute decreases in BP occur.
Euglycaemic diabetic ketoacidosis as a complication of SGLT-2 inhibitors: epidemiology, pathophysiology, and treatment
Published in Expert Opinion on Drug Safety, 2020
Erasmia Sampani, Pantelis Sarafidis, Aikaterini Papagianni
The mechanisms that enable the SGLT-2 inhibitor to offer nephroprotection are under investigation. Following an elegant human study in young hyperfiltrating patients with T1DM that showed empagliflozin to reduce GFR together with effective renal plasma flow and to increase renal vascular resistance [28], it was suggested that SGLT-2 inhibitors could modulate the afferent arteriole tone through interference with the tubuloglomerular feedback mechanism [23]. In particular, the inhibition of renal glucose and sodium reabsorption in the proximal renal tubules is expected to increase the distal availability of sodium-chloride. The macula densa functions by sensing the increased sodium-chloride availability and through this restores the tubuloglomerular feedback resulting in a reversal of the vasodilation of the afferent arteriole; this decreases glomerular hyperfiltration, intraglomerular pressure, and albumin excretion [23,28]. However, a recent randomized trial examining the effects of dapagliflozin on renal microcirculation in 44 patients with T2DM, did not confirm the above findings [29]. In particular, dapagliflozin also reduced GFR but did not increase renal vascular resistance, suggesting that the reduction in intraglomerular pressure with SGLT-2 inhibitors is not due to vasoconstriction of the afferent but to vasodilation of the efferent arteriole. Thus, the mechanistic details of the SGLT-2 inhibitor action on kidney vasculature possibly need to be further investigated by larger studies.
Efficacy and safety profile of SGLT2 inhibitors in patients with type 2 diabetes and chronic kidney disease
Published in Expert Opinion on Drug Safety, 2020
Sodium–glucose cotransporters type 2 (SGLT2), which are located in the proximal tubule of the kidney, are responsible for the reabsorption of >90% of filtered glucose. The SGLT2 expression is upregulated in the presence of hyperglycemia. The maximum reabsorptive capacity for glucose is increased by about 30% in patients with T2DM while the threshold for plasma glucose level at which glycosuria first occurs is also raised. The glucose-lowering efficacy of SGLT2is relies on the inhibition of glucose reabsorption that leads to increased urinary glucose excretion (UGE), an effect that is independent of insulin secretion and insulin action [18–20]. SGLT2is generally lead to the excretion of 60–100 g of glucose per day; this effect results in lowering hyperglycemia and subsequently could dampen glucose toxicity, thereby indirectly reducing insulin resistance and improving insulin secretion [21,22]. SGLT2is exert also osmotic diuresis and, at least transiently, natriuresis. Besides the glucose-lowering effect, SGLT2is exert pleiotropic effects [22,23], among which a reduction in body weight, a lowering of blood pressure, a diminution in serum uric acid, a reduction in inflammatory markers [24]. The increased sodium delivery at the macula densa contributes to activate the tubuloglomerular feedback, which increases afferent arteriolar tone. This effect contributes to reduce intraglomerular pressure, glomerular hyperfiltration, and albuminuria and may explain a transient reduction in eGFR after the initiation of SGLT2i therapy [23].