Contrast induced nephropathy pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]
Overview
The pathophysiology of CIN is not clearly understood; however, several attempts have been made to explain the underlying mechanism. It is generally agreed that CIN is due to a combination of several influences brought on by contrast-media infusion rather than a single process. The most important mechanism thought to be involved in CIN is a reduction in renal perfusion and subsequent hypoxia. This has been attributed to several alterations in the renal microenvironment including activation of the tubuloglomerular feeback, local vasoactive metabolites including adenosine, prostaglandin, NO, and endothelin as well as increased interstitial pressure.[1] Although sometimes considered controversial, studies have also proposed injury to renal tubular cells as another contributor both via a direct cytotoxic effect and via reactive oxygen species production.[2]
Pathophysiology
Several mechanisms have been put forth to explain the development of nephropathy following contrast administration. Broadly, the pathophysiology can be divided into renal vascular compromise and cytotoxic tubular cell injury.
Renal Vascular Compromise and Hypoxia
Vascular Resistance
The renal vascular bed is supplied by small capillaries known as the vasa recta. While these small vessels have a diameter similar to that of other capillaries, their length is usually several times longer, creating higher vascular resistance. To offset that, viscosity needs to be maintained at its lowest demonstrated in Poiseuille’s law:
Several rat models have shown association between plasma viscosity, increased vascular resistance, and contrast-media infusion. As viscosity increases, resistance in the vasa recta can rise to cause significant renal tissue hypoperfusion[2] Some agents have an inherently higher viscosity leading to higher resistance while others can interact with red blood cells causing a decrease in deformability and a secondary increase in resistance.[3]
Increased viscosity also transfers to tubular fluid which is usually low in proteins and less viscous than plasma. Some models have shown that as urine concentration occurs in the tubules, viscosity increases significantly in the renal tubules leading to an increase in renal interstitial pressure.[4][5] The rising pressure further increases vasa recta hypoperfusion and also contributing to hypoxia.
Tubuloglomerular Feedback
The tubuloglomerular feedback (TGF) describes the function of the macula densa, a dense collection of specialized epithelial cells at the junction of the thick ascending loop and the distal convoluted tubule. The macula densa senses sodium delivery to the distal tubules via a Na+/K+/2Cl-transporter. High sodium delivery is perceived as high glomerular filtration which causes adenosine release from the macula densa and vasoconstriction of the afferent arteriole to decrease filtration.[6] The osmotic diuresis theory hypothesizes that contrast media cause increased natriuresis and thus activate TGF leading to vasoconstriction. This theory has been challenged multiple times and studies have shown little or no effect of the TGF on CIN. Tangibly, the use of furosemide, a Na+/K+/2Cl-transporter transporter blocker, was not shown to significantly prevent CIN after cardiac angiography.[7]
Vasoconstriction and Vasoactive substances
Initial animal studies showed that contrast media infusion causes a biphasic vascular response. With early infusion, a short phase of renal vasodilation arises followed by a prolonged phase of vasoconstriction eventually leading to tissue hypoxia.[8] Several studies have tried to explain the mechanism underlying the vasoconstrictive phase with common emphasis on an imbalance of vasoactive substances brought on by the contrast media.
- Adenosine
- Endothelin
- Nitric Oxide
- Prostaglandins
Cytotoxic Effects of Contrast
Contrast Media can directly cause renal tubular injury.[9] Another mechanism had been described by the generation of free oxygen radicals such as superoxide anions, hydrogen peroxide, hydroxyl radicals and hypochlorous acid. The endothelial dysfunction discussed above is also partly due to oxygen free-radical generation during post ischemic reperfusion as they decrease bioavailibility of nitric oxide leading to vasoconstriction. Also the oxidative and nitrosative effects mediated by these reactive species on the sulfhydrylic groups and aromatic rings of proteins, cellular membrane lipids and nucleic acids associated with the vasoconstriction. This occurs through the nitrosation of tyrosine residues of enzymes which are involved in the synthesis of medulla vasodilators, such as prostacycline synthase and nitric oxide synthase.[10] Other causes reported to contribute in this mechanism through studies have been done on animals are the mitochondrial injury, cytochrome-c release, and plasma membrane damage.[11] Creatinine clearence has also been seen reduced with increase in adenosine excreation on administration of low osmolality, non-ionic contrast, and with use of theophylline the fall in creatinine clearance declined.[12]
Effect of Contrast Osmolarity
Although the proposed mechanism for the osmotic theory could not be verified, osmolarity of the contrast medium has been clinically linked to differences in outcome. Initially, small scale studies showed no difference between high-osmolar and low-osmolar contrast media.[13] However, in 1995, a prospective randomized trial by Rudnick et al revealed that patients with renal insufficiency and diabetes mellitus had a significantly lower risk of CIN with low-osmolar media.[14] With the introduction of iso-osmolar media, several comparative studies most importantly the NEPHRIC trial by Aspelin et al showed that iso-osmolar media is highly superior in high risk patients with pre-existing renal disease and diabetes. The NEPHRIC trial demonstrated that the incidence of CIN in the iso-osmolar contrast group was 3.1% compared with 26.2% in the low-osmolar contrast group.[15] Results of the NEPHRIC trial have sometimes been questioned to the lack of reproducibility in other trials. However, it is generally agreed that iso-osmolar contrast media pose the lowest risk of CIN among other contrast agents. Despite those findings, the underlying mechanism linking osmolarity to CIN is still poorly understood.
References
- ↑ Wong PC, Li Z, Guo J, Zhang A (2012). "Pathophysiology of contrast-induced nephropathy". Int J Cardiol. 158 (2): 186–92. doi:10.1016/j.ijcard.2011.06.115. PMID 21784541.
- ↑ 2.0 2.1 Persson PB, Hansell P, Liss P (2005). "Pathophysiology of contrast medium-induced nephropathy". Kidney Int. 68 (1): 14–22. doi:10.1111/j.1523-1755.2005.00377.x. PMID 15954892.
- ↑ Schiantarelli P, Peroni F, Tirone P, Rosati G (1973). "Effects of iodinated contrast media on erythrocytes. I. Effects of canine erythrocytes on morphology". Invest Radiol. 8 (4): 199–204. PMID 4724805.
- ↑ Ueda J, Nygren A, Hansell P, Erikson U (1992). "Influence of contrast media on single nephron glomerular filtration rate in rat kidney. A comparison between diatrizoate, iohexol, ioxaglate, and iotrolan". Acta Radiol. 33 (6): 596–9. PMID 1449888.
- ↑ Ueda J, Nygren A, Hansell P, Ulfendahl HR (1993). "Effect of intravenous contrast media on proximal and distal tubular hydrostatic pressure in the rat kidney". Acta Radiol. 34 (1): 83–7. PMID 8427755.
- ↑ Burke M, Pabbidi MR, Farley J, Roman RJ (2013). "Molecular Mechanisms of Renal Blood Flow Autoregulation". Curr Vasc Pharmacol. PMID 24066938.
- ↑ Solomon R, Werner C, Mann D, D'Elia J, Silva P (1994). "Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents". N Engl J Med. 331 (21): 1416–20. doi:10.1056/NEJM199411243312104. PMID 7969280.
- ↑ Bakris GL, Burnett JC (1985). "A role for calcium in radiocontrast-induced reductions in renal hemodynamics". Kidney Int. 27 (2): 465–8. PMID 2581011.
- ↑ Heinrich MC, Kuhlmann MK, Grgic A, Heckmann M, Kramann B, Uder M (2005). "Cytotoxic effects of ionic high-osmolar, nonionic monomeric, and nonionic iso-osmolar dimeric iodinated contrast media on renal tubular cells in vitro". Radiology. 235 (3): 843–9. doi:10.1148/radiol.2353040726. PMID 15845795. Retrieved 2011-03-08. Unknown parameter
|month=ignored (help) - ↑ Detrenis S, Meschi M, Musini S, Savazzi G (2005). "Lights and shadows on the pathogenesis of contrast-induced nephropathy: state of the art". Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 20 (8): 1542–50. doi:10.1093/ndt/gfh868. PMID 16033768. Retrieved 2011-03-08. Unknown parameter
|month=ignored (help) - ↑ Zager RA, Johnson AC, Hanson SY (2003). "Radiographic contrast media-induced tubular injury: evaluation of oxidant stress and plasma membrane integrity". Kidney International. 64 (1): 128–39. doi:10.1046/j.1523-1755.2003.00059.x. PMID 12787403. Retrieved 2011-03-08. Unknown parameter
|month=ignored (help) - ↑ Katholi RE, Taylor GJ, McCann WP, Woods WT, Womack KA, McCoy CD, Katholi CR, Moses HW, Mishkel GJ, Lucore CL (1995). "Nephrotoxicity from contrast media: attenuation with theophylline". Radiology. 195 (1): 17–22. PMID 7892462. Retrieved 2011-03-08. Unknown parameter
|month=ignored (help) - ↑ Tepel M, Aspelin P, Lameire N (2006). "Contrast-induced nephropathy: a clinical and evidence-based approach". Circulation. 113 (14): 1799–806. doi:10.1161/CIRCULATIONAHA.105.595090. PMID 16606801.
- ↑ Rudnick MR, Goldfarb S, Wexler L, Ludbrook PA, Murphy MJ, Halpern EF; et al. (1995). "Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial. The Iohexol Cooperative Study". Kidney Int. 47 (1): 254–61. PMID 7731155.
- ↑ Aspelin P, Aubry P, Fransson SG, Strasser R, Willenbrock R, Berg KJ; et al. (2003). "Nephrotoxic effects in high-risk patients undergoing angiography". N Engl J Med. 348 (6): 491–9. doi:10.1056/NEJMoa021833. PMID 12571256.