How do NSAIDs alter blood flow to the kidneys?

Nonsteroidal Anti-inflammatory Drugs

Renal perfusion is reduced in heart failure, and prostaglandins become increasingly important in controlling renal plasma flow and fluid homeostasis. NSAIDs, however, reduce prostaglandin synthesis, thus decreasing glomerular filtration and resulting in salt and water retention.214,228 NSAIDs act by inhibiting both COX-1 and COX-2. It was long thought that the analgesic aspect was generated by COX-2 inhibition and that the adverse gastrointestinal effects were mediated by COX-1. This led to the development of selective COX-2 inhibitors, such as celecoxib and valdecoxib. COX-2 inhibitors still have some of the adverse effects observed with NSAIDs: namely, the ability to increase blood pressure and to exacerbate heart failure through salt and water retention.214,228 Gastrointestinal complications are less common with COX-2 inhibitors,229 and these drugs were initially thought to be successful. However, soon after their release on the market, it became evident that some COX-2 inhibitors increase the risk of myocardial infarction and stroke.229-231 A comparison of celecoxib and placebo in adenoma prevention did reveal higher rates of a composite endpoint of myocardial infarction, stroke, and heart failure in patients treated with celecoxib.232

Through a number of mechanisms, COX-2 inhibition may increase the risk of cardiovascular events. COX-2 inhibitors can increase systemic blood pressure slightly233 but may accelerate atherosclerosis through effects on mitochondrial oxidative phosphorylation or monocyte chemotaxis.234 There is probably also a prothrombotic effect of COX-2 inhibition.235 Thromboxane is a prothrombotic prostanoid that depends on COX-1 for its production, whereas the production of prostacyclin (epoprostenol), an antithrombotic agent, depends on COX-2. Preferential COX-2 inhibition leads to reduced levels of prostacyclin, with a lesser effect on thromboxane, thereby potentially leading to a prothrombotic state.

Thus, it appears that both NSAIDs and COX-2 inhibitors are associated with a higher risk of cardiovascular events, including heart failure, myocardial infarction, and stroke. Although some COX-2 inhibitors have been withdrawn from the market, NSAIDs have been available for many years, both by prescription and over the counter. A large number of patients depend on these analgesics to control pain; in the absence of alternative effective treatments, the removal of these drugs from circulation is not a feasible option. In clinical practice, physicians must be aware of the adverse effects of all the medicines they prescribe and, in investigating ill health, must always consider drugs as a cause, particularly when no alternative cause is apparent. On the other hand, a drug with a strong association with a particular cardiovascular adverse effect could be entirely blameless, and alternative causes should not be discounted.

Pathophysiology and Etiology of Prerenal Azotemia

Impaired renal perfusion with a resultant fall in glomerular capillary filtration pressure is a common cause of AKI. In this setting, tubular function is typically normal, renal reabsorption of sodium and water is increased, and consequently urine chemistries reveal a low urine sodium (<10 mmol/l) and a concentrated urine (urine osmolality >500 mOsm/kg).

A marked reduction in renal perfusion may overwhelm autoregulation and precipitate an acute fall in GFR. With lesser degrees of renal hypoperfusion, glomerular filtration pressures and GFR are maintained by afferent arteriolar vasodilation (mediated by vasodilatory eicosanoids) and efferent arteriolar vasoconstriction (mediated by angiotensin II). In this setting, AKI may be precipitated by agents that impair afferent arteriolar dilation (nonsteroidal anti-inflammatory drugs [NSAIDs]) or efferent vasoconstriction (angiotensin-converting enzyme [ACE] inhibitors and angiotensin receptor blockers [ARBs]).

Prerenal azotemia is commonly secondary to extracellular fluid volume depletion due to gastrointestinal losses (diarrhea, vomiting, prolonged nasogastric drainage), renal losses (diuretics, osmotic diuresis in hyperglycemia), dermal losses (burns, extensive sweating), or possibly sequestration of fluid, so-called third spacing (e.g., acute pancreatitis, muscle trauma). Renal perfusion may be impaired even in the setting of normal or even increased extracellular fluid. For example, renal perfusion may be reduced by a decreased cardiac output (heart failure) or by systemic arterial vasodilation with redistribution of cardiac output to extrarenal vascular beds (e.g., sepsis, liver cirrhosis). The presence of AKI in the setting of severe heart failure has been termed the cardiorenal syndrome and is often exacerbated by the use of ACE inhibitors and diuretics.

An unusual cause of prerenal AKI is the hyperoncotic state. Infusion of large quantities of osmotically active substances, such as mannitol, dextran, and protein, can increase the glomerular oncotic pressure enough to exceed the glomerular capillary hydrostatic pressure, which stops glomerular filtration, leading to an anuric form of AKI.

Prerenal azotemia can be corrected if the extrarenal factors causing the renal hypoperfusion are rapidly reversed. Failure to restore renal blood flow during the functional prerenal stage will ultimately lead to ischemic ATN and tubular cell injury.

RENIN-RELEASE, HYPERTENSION, AND KIDNEY ISCHEMIA

Reduced renal perfusion pressure initiates several compensatory mechanisms that sustain blood flow. Initial responses include a rise in systemic arterial pressure that restores poststenotic pressure and flow in the kidneys. When present, the contralateral kidney without vascular occlusion responds to elevated arterial pressure with suppression of renin release and exaggerated sodium excretion (termed pressure natriuresis) that tends to counteract the rise in pressure. It should be emphasized that this phase may have normal renal blood flow to both kidneys, enhanced renin release from the poststenotic kidney, and elevated systemic pressure. Renal vein renin levels are elevated only on the side of the stenotic kidney, while measured levels of venous oxygen do not differ, indicating adequate blood flow to both kidneys.7 An abundant literature during the era of surgical revascularization indicates that subjects with lateralization of renal vein renin values were most likely to lower arterial pressures after removing the stenotic lesion.

SUMMARY

When renal perfusion pressure is reduced in conscious Brattleboro homozygotes by constricting the aorta, urine osmolality is raised above that of plasma even though the GFR is reduced very little or not at all. This ability to concentrate urine in the absence of vasopressin cannot be accounted for by an increase in filtration fraction and consequent increased proximal fractional reabsorption, nor (almost certainly) by a non-ADH-mediated increase in water permeability of the distal nephron. It is possible that the capacity to render urine hyperosmotic to plasma in the absence of vasopressin and without a decrease in GFR could result from decreased peritubular hydrostatic pressure and a resultant increase in proximal fractional reabsorption and/or a rise in the cortico-papillary interstitial osmotic gradient. These possibilities still need to be examined. We wish to stress that our work does not necessarily challenge the so-called Berliner-Davidson hypothesis [6], which may account for the concentration of urine in the absence of vasopressin when the GFR is decreased.

Worsening Objective Measures of Cardiac Performance

•

Diminished renal perfusion (prerenal azotemia/rising serum creatinine)

Hepatic congestion (elevated liver function tests)

Decreased end-organ perfusion (metabolic acidosis/elevated serum lactate)

Deteriorating left ventricular function by echocardiogram

Decreased left ventricular ejection fraction by radionuclide ventriculography

Worsened cardiomegaly/pulmonary edema on chest radiograph

Diminished maximal oxygen consumption VO2 on exercise testing

Abnormal parameters on right heart catheterization

Elevated central venous pressure

Worsening pulmonary arterial hypertension/pulmonary vascular resistance

Declining cardiac output/cardiac index

Increasing arteriovenous oxygen difference (A – VO2)

Urinary Output and Clinical Signs of Hypovolemia

A reduction in renal perfusion normally results in dilatation of the afferent glomerular arteriole and constriction of the efferent arteriole so that glomerular filtration rate (GFR) is kept constant. However, if mean arterial pressure falls below 70 mm Hg (kidney autoregulatory threshold), renal perfusion pressure and glomerular filtration rate fall, leading to oliguria. However, the kidney is affected by many factors including cardiac function, osmotic load, intrathoracic pressure, intraabdominal pressure, and chronic renal insufficiency which make urine output an unreliable predictor of volume status.32 Other signs of inadequate intravascular volume are peripheral cyanosis, skin mottling, tachycardia, hypotension, and cold extremities. All these signs are nonspecific and unreliable indicators of adequate resuscitation.

Hypoxic or Ischemic Injury (Tubulorrhexis).

Notably reduced renal perfusion from any cause can result in tubular necrosis. Severe hypotension associated with shock results in preglomerular vasoconstriction and reduced glomerular filtration. The resulting renal ischemia can produce sublethal tubular cell injury and dysfunction or cause cell death by necrosis or apoptosis. Following less severe insults and within different portions of the renal tubule, apoptosis may occur in lieu of necrosis. The apoptotic pathway can be triggered by the following:

Binding of ligands to the tumor necrosis factor (TNF) superfamily

Deficiency of cellular growth factors

Imbalance between proapoptotic and antiapoptotic oncogenes

Alteration of other mediators of apoptotic signaling pathways such as reactive oxygen metabolites, caspases, and ceramide

Proximal tubular epithelium has a microvillous border, which amplifies absorptive surface area and cellular junctional complexes that structurally polarize the cell so that membrane phospholipids and specialized proteins remain in the appropriate domains. The integrity of these cellular structures is critical to absorption and secretion. Early structural changes after ischemic insult include formation of apical blebs, loss of brush border, loss of cellular polarity, disruption of tight junctions, and sloughing of cells, which result in intratubular cast formation (E-Fig. 11-1).

E-Figure 11-1. Effect of Ischemia on Cell Structure and Function.

A polarized renal proximal tubule cell with a well-developed actin cortical cytoskeleton is shown on the left. Also shown is attachment to the extracellular matrix (ECM) via integrins. Following ischemic injury there is extensive disruption, redistribution, and aggregation of the actin cytoskeleton resulting in loss of microvilli structure, blebbing of microvilli into the lumen, detachment of cells from the ECM, and opening of junctional complexes (JC). Injured proximal tubule cells can undergo primary repair and recover directly into a polarized epithelial cell. Cells can also go through an undifferentiated phase followed by redifferentiation, or cells can die either rapidly via necrosis or in a much slower programmed manner known as apoptosis. The primary route of cellular repair involves direct recovery. The percentage of cells reverting to an undifferentiated state or dying depends on the severity of the injury and the location within the kidney. FA, Focal adhesions; TW, terminal web.

Damage to the cellular cytoskeleton modifies cell polarity, cell-to-cell interactions, and cell-matrix interactions. Initially, ischemic damage modifies cell polarity by disruption of the terminal web and disassembly of the microvillar actin cores. This is followed by conversion of G actin to F actin and its redistribution from the apical cell component to form diffuse aggregates throughout the cytoplasm (E-Figs. 11-2 and 11-3). Cells are attached to each other by junctional complexes, tight junctions, and adherens junctions and to the ECM by integrins. Several mechanisms contribute to tight junction disruption, which is manifested as alteration in cellular permeability and cell polarity. The contributing mechanisms include redistribution of membrane lipids and proteins, such as Na+/K+-ATPase, to the apical membrane after alteration of the actin cytoskeleton and redistribution of integrins to the apical cell surface so that cell desquamation occurs. The former results in deranged sodium handling by the proximal tubular cell.

E-Figure 11-2. Effect of Ischemia on the Actin Cytoskeleton and the Cytoskeletal-Surface Membrane Interactions in Proximal Tubule Cells.

During ischemia, alterations in the actin cytoskeleton involve disruption of the actin cytoskeleton with redistribution and aggregation of actin throughout the cytoplasm. Consequently, notable alterations occur in cytoskeletal-surface membrane interactions. Loss of cell-cell adhesion, cell-matrix adhesion, and polarity of surface membrane proteins during ischemia play a role in the diminished glomerular filtration rate that is the hallmark of ischemic acute renal failure. See Fig. 11-14 for more detail about the actin cytoskeleton and the cytoskeletal-surface membrane.

Animals with severe tubular necrosis have accompanying functional derangements of vascular, tubular, and/or glomerular origin. Vascular derangements include the following:

Afferent arteriolar constriction

Efferent arteriolar dilation

Loss of autoregulation of renal blood flow

Prolonged ischemia can produce a paradoxic response of the autoregulatory system, where increased glomerular capillary resistance from tubular fluid stasis results in activation of afferent arteriolar vasoconstriction. Decreased production of or response to vasodilative factors, such as prostaglandin and atrial natriuretic peptide, also contribute. Afferent arteriole vasoconstriction, back leak of fluid, and tubular obstruction account for decreased glomerular filtration rate (GFR) (Fig. 11-9).

Tubuloglomerular feedback is the mechanism by which GFR is matched to the solute load and the solute handling characteristics of the tubules. Because of altered sodium handling, increased concentrations reach the macula densa, and activation of the renin-angiotensin system occurs. This is followed by intrarenal vasoconstriction, particularly affecting outer cortical nephrons, and results in decreased glomerular blood flow, decreased filtration, and reduced formation of urine.

B. Decreased Distal Delivery of Sodium

Mild to moderate reductions in renal perfusion do not typically cause distal delivery of Na+ to fall to a level that impairs K+ secretion sufficiently to result in clinically significant hyperkalemia. In untreated congestive heart failure S[K+] is typically normal or high normal despite the reduction in distal Na+ delivery as long as the impairment in cardiac function and renal perfusion is not severe. When such patients are treated with ACEIs or ARBs the fall in circulating aldosterone concentration is typically counterbalanced by increased distal Na+ delivery so that the S[K+] remains stable. The increase in distal Na+ is due to the afterload-reducing effects of these drugs, causing an improvement in cardiac output and renal perfusion.

When renal perfusion becomes more severely reduced, as in patients with intractable congestive heart failure, proximal reabsorption can become so intense that very little Na+ escapes into the distal nephron. A lack of Na+ availability can begin to impair renal K+ secretion, particularly in the setting of CKD, where baseline aldosterone levels are often reduced and the capacity for increased production is limited.

Elderly subjects are prone to intravascular volume depletion due to poor intake and impaired renal Na+ conservation. The resultant decrease in distal Na+ delivery puts these patients at risk for hyperkalemia, since age is also associated with impaired release of renin and aldosterone in response to volume depletion.49 This risk increases further with concurrent use of RAAS blockers.

Other Types of Kidney Failure in Cirrhosis

Renal Function Imaging

At the end of the renal perfusion sequence, imaging for renal function begins. Dynamic or sequential static, 3- to 5-minute 99mTc-DTPA or 99mTc-MAG3 (Fig. 9-2) images are then obtained over 20 to 30 minutes. Evaluation of the images includes attention to renal anatomy and position, symmetry and adequacy of function, and collecting system patency. With 99mTc-MAG3, the maximal parenchymal activity is seen at 3 to 5 minutes, with activity usually appearing in the collecting system and bladder by about 4 to 8 minutes. Some laboratories routinely use furosemide to clear activity from the renal collecting systems. However, post-void or post-ambulation images to enhance collecting system drainage may be obtained as needed. Time-activity (renogram) curves for each kidney, reflective of relative renal function, are also usually created from regions of interest over the renal parenchyma, as discussed below.