Acute-on-Chronic Renal Failure in the Rat: Functional Compensation and Hypoxia Tolerance

Abstract

Background: We hypothesized that chronic renal parenchymal disease may predispose to acute renal failure (ARF), facilitating the induction of hypoxic medullary tubular injury. Methods: To induce chronic renal parenchymal injury, rats underwent sham operation (control) or bilateral 50-min clamping of the renal artery [ischemia-reperfusion (IR)]. One or 3 months later, both groups were subjected to an ARF protocol, consisting of radiocontrast and the inhibition of prostaglandin and nitric oxide synthesis. Renal function and morphology were determined 24 h later. Results: Chronic tubulointerstitial changes (fibrosis, atrophy and hypertrophy) in the IR group correlated with baseline tubular function, but glomerular function was preserved. Functional deterioration after the ARF protocol was only marginally more pronounced in the IR group, and the degree of medullary acute tubular necrosis (ATN) was unaffected by prior IR. The extent of both tubular necrosis and chronic tubulointerstitial changes independently predicted the acute decline in renal function. Immunostaining of IR kidneys disclosed critically low medullary pO₂ (determined by pimonidazole adducts), regional hypoxic cell response (hypoxia-inducible factors) and upregulation of endothelin-B receptors. Conclusions: Compensatory changes result in normal plasma creatinine 1 and 3 months after IR, despite diminished tubular function. Preexisting renal disease only marginally predisposes to ARF, and the extent of ATN is not significantly enhanced. These findings illustrate the complex interaction between chronic and acute renal injury and dysfunction and parallel the difficulty of their assessment in the clinical practice. Adaptive cellular responses to chronic hypoxia in conjunction with parenchymal loss and decreased oxygen demand might alleviate acute hypoxic injury.

Hypoxia-inducible Factors and the Prevention of Acute Organ Injury

“…We also found that HIF-α isoforms are stabilized in acute hypoxic stress, predominantly in the cortex in rhabdomyolysis-induced kidney injury [26], in the outer stripe of the outer medulla following ischemia and reperfusion [27,28], or in the inner stripe and inner medulla following the induction of distal tubular hypoxic injury by radiocontrast agent, or after the inhibition of prostaglandin or NO synthesis or with their combinations [23]. Outer medullary HIF stabilization is also noted in chronic tubulointerstitial disease [29] and in experi mental diabetes [30], again spatially distributed in areas with proven hypoxia. HIF was also detected in biopsies from transplanted kidneys [31].…”

Renal Parenchymal Hypoxia, Hypoxia Adaptation, and the Pathogenesis of Radiocontrast Nephropathy

“…In such models, despite a more prominent reduction of GFR after the injection of the radiocontrast, the extent of ATN was not intensified as compared with control animals that were subjected to similar radiocontrastmediated hypoxic insults (43,54). Conceivably, chronic HIFmediated hypoxia adaptation provides acute hypoxia tolerance.…”

“…Conceivably, chronic HIFmediated hypoxia adaptation provides acute hypoxia tolerance. Importantly, in an acute-on-chronic renal failure model of CIN, declining GFR was mostly predicted by the extent of chronic tubulointerstitial disease, whereas medullary hypoxic tubular injury could be correlated with evolving tubular dysfunction, such as defects in urine concentrating capacity and sodium transport, assays not routinely used in clinical practice (54).…”

“…By contrast, HIF-mediated adaptive processes occur in clinical conditions characterized by chronic hypoxia, such as diabetes or chronic tubulointerstitial disease (left arm). Conceivably, under such settings, acute dye-induced hypoxic tubular injury is prevented or attenuated, and renal dysfunction reflects dysregulation of compensatory mechanisms that preserve glomerular filtration (54). The extent and severity of acute tubular damage also largely depends on the severity of the dye-induced acute hypoxic stress (in part related to the presence or absence of predisposing factors).…”

Perspective in Chronic Kidney Disease: Targeting Hypoxia-Inducible Factor (HIF) as Potential Therapeutic Approach

“…Many hypoxiatriggered HIF-dependent protective effectors such as EPO and VEGF rise, which counteracts the effect of the harmful pathways, promoting angiogenesis, improving tissue oxygenation and cell survival, and facilitating homing of progenitor cells. 121 In fact, rats with chronic tubulointerstitial disease 122 or diabetes 123 have shown unpredicted resistance to acute hypoxic insults, possibly through hypoxia tolerance, induced by HIFmediated pathways. However, diabetic kidneys subjected to extreme hypoxic conditions, such as warm ischemia reflow 124 or ex vivo perfusion with red cellfree perfusate, 123 are highly exposed to hypoxic damage, which suggests that HIF-mediated renoprotection is ineffective beyond a "window of opportunity" of moderate acute hypoxic stress.…”