Adenosine and Tubuloglomerular Feedback in the Pathophysiology of Acute Renal Failure

Adenosine and Tubuloglomerular Feedback TGF is a series of events where changes in the Na +, Cl −, and K + ion concentrations in the tubular fluid at the end of the thick ascending limb of the loop of Henle are sensed by the macula densa, which causes: 1.a change in single-nephron glomerular filtration rate (SNGFR) through an alteration of the vascular tone, predominantly in the afferent arteriole. 2.an alteration of renin secretion from granular cells. A rise in late proximal tubular flow rate, which in turn increases the respective electrolyte concentrations at the macula densa, lowers both SNGFR and renin secretion; a reduction in late proximal tubular flow rate causes the opposite effects.

TGF, which operates locally on the single-nephron level, adjusts afferent arteriolar resistance and SNGFR in response to changes in early distal tubular NaCl concentrations to keep the fluid and NaCl delivery to the distal nephron within certain limits. A relatively constant load to the distal nephron seems necessary in order for this part of the nephron to accomplish the fine adjustments in absolute reabsorption made to meet body needs. TGF establishes a balance between GFR and reabsorption in the proximal tubule and loop of Henle.

The importance of the symmetry between nephron filtration and reabsorption can be appreciated from the fact that a disparity of as little as 5% between filtered load and the reabsorption rate would lead to a net loss of about one third of the total extracellular fluid volume within 1 day. Because the amount of fluid and NaCl filtered in the glomeruli determines reabsorption and, thus, energy demand in the tubular and collecting duct system, TGF, by affecting GFR, contributes to the metabolic control of kidney function.

TGF can be divided into the following steps: 1.The luminal signal in the tubular fluid, which is sensed by the macula densa. 2.Signal transduction by the macula densa/extraglomerular mesangium to generate factors that act in step 3. 3.These factors ultimately exert effects at the afferent arterioles, including vascular smooth muscle cells and renin-containing cells.

The luminal signal is primarily recognized by the Na + - 2Cl − -K + cotransporter, which is located in the luminal membrane of macula densa cells. Adenosine contributes to signal transduction in TGF because – it reduces glomerular capillary pressure and SNGFR by predominant afferent arteriolar vasoconstriction – this response is rapid in onset and short in duration when the adenosine delivery is discontinued. Furthermore, adenosine inhibits renin release even at concentrations that are well below those inducing vasoconstriction.

Adenosine is a Mediator of Tubuloglomerular Feedback Adenosine couples energy metabolism with the control of GFR (and renin secretion) Transport-dependent hydrolysis of ATP in macula densa cells (or in the cells of the thick ascending limb in close proximity to the JGA) would lead to enhanced generation of AMP. Involved ATPases include basolateral Na + -K + - ATPase, which extrudes the Na + taken up across the apical membrane.

The AMP generated by these ATPases is dephosphorylated in the cell to adenosine by cytosolic 5′-nucleotidase and the generated adenosine could be released through a nucleoside transporter into the interstitium of the extraglomerular mesangium. Extracellular adenosine then binds to adenosine A 1 receptors at the surface of extraglomerular mesangial cells and increases cytosolic Ca 2+ concentrations. These signals could rapidly be transmitted to these target structures, inducing afferent arteriolar constriction (and inhibition of renin release).

Acute Renal Failure – Intrarenal Tubuloglomerular Feedback Dependent Mechanisms Ischemia and nephrotoxic substances damage kidney cells and impair cellular phosphorylation potential through a decrease in ATP synthesis and/or an increase in ATP hydrolysis. The immediate result of a reduced phosphorylation potential is impaired tubular reabsorption of electrolytes, which in turn leads to an increase in the NaCl concentration in the tubular fluid at the macula densa, followed by a TGF- mediated drop in GFR. Factors that can increase the activity of TGF are activation of the renin-angiotensin system, contraction of the extracellular volume as seen also in hemorrhage, nitric oxide synthase inhibition, and maneuvers that increase interstitial adenosine concentration.

Acute Renal Failure – Intrarenal Tubuloglomerular Feedback Independent Mechanisms Tubular cells in close proximity to the afferent arteriole could release vasoactive autacoids (adenosine, angiotensin II, prostaglandins, nitric oxide) at an enhanced rate independent of macula densa signal. Those autacoids can reduce GFR not only through vasoconstriction of the afferent arteriole or by decreasing glomerular ultrafiltration coefficient (K f ) but also through postglomerular vasodilation resulting in a drop in hydrostatic pressure of the glomerular capillaries.

Nephrotoxic substances and ischemia can lead to disintegration and formation of cellular debris such as detached brush-border membranes. This material leads to tubular obstruction, especially when tubular flow rate is low as in oliguric-anuric forms of ARF. The acute tubular obstruction can eventually stop glomerular filtration.

Constant tubular obstruction for 24 hours at the nephron and whole kidney level leads to sustained preglomerular vasoconstriction. Physical factors like cell swelling of tubule epithelial cells and vascular endothelium can interfere with the normal flow through renal tubules and blood vessels independent of TGF. Because the TGF mechanism serves to establish a relatively constant delivery to the early distal tubule, a reduction in filtration rate would be an appropriate response to a signal indicating failure of volume reabsorption.

This glomerular shutdown can be considered an intrarenal reflex to conserve volume. Without this reflex, an unchanged high GFR in the presence of a reduced capability of the tubular epithelium to reabsorb would lead to massive urinary volume loss. This advantage of the initial shutdown of GFR, however, if not reversible, would turn into the disadvantage of end-stage renal failure.