Partial Nephrectomy: Does Ischemia Matter?

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1 Partial Nephrectomy: Does Ischemia Matter? Karim Touijer, MD, MPH Attending Surgeon Memorial Sloan-Kettering Cancer Center Associate Professor of Urology Weill Cornell Medical College, New York No disclosures

2 Ischemia and AKI Vascular: persistent vasoconstriction and endothelial cell damage Obstructive: tubular epithelial cells sloughing Reperfusion Injury: Oxygen free radicals/microvessel congestion Abuelo et al NEJM 2007;357 Secin et al. Adv Urol 2008

3 Tubulo-interstitial Fibrosis Occlusive arteriosclerosis Acute injury tubular epithelium cells apoptosis

4 Geng H, Lan R, Wang G, Siddiqi AR, Naski MC, Brooks AI, Barnes JL, Saikumar P, Weinberg JM, Venkatachalam MA. Inhibition of autoregulated TGFbeta signaling simultaneously enhances proliferation and differentiation of kidney epithelium and promotes repair following renal ischemia. Am J Pathol 174: , 2009

5 Schematic diagram to illustrate how tubules regenerating after acute injury may fail to differentiate and exhibit profibrotic paracrine activity before they become atrophic. Manjeri A. Venkatachalam et al. Am J Physiol Renal Physiol 2010;298:F1078-F1094

6 Proximal Tubule Cellular Degeneration Start at 20 min Moderate after 30 min Complete after > 60 min Lower tolerance to ischemia in predamaged kidneys (DM, vasculopathy ) Novick. Urol Clin North Am 1983;10 Marberger et al. Renal Preservation. Baltimore, MD. Williams an d Wilkins

7 Tubulo-interstitial fibrosis after ischemic AKI in solitary kidney is Indistinguishable from the pathology of CKD Dilated shrunken tubules Thickened tubular basement membrane Interstitial fibrosis Increased capillary density Forbes JM, Hewitson TD, Becker GJ, Jones CL. Ischemic acute renal failure: long-term histology of cell and matrix changes in the rat. Kidney Int 57: , 2000 Pagtalunan ME, Olson JL, Tilney NL, Meyer TW. Late consequences of acute ischemic injury to a solitary kidney. J Am Soc Nephrol 10: , 1999

8 Solitary Kidney Model Warm (> 20min) and cold ischemia (> 35min) are associated with with increased risk of acute, chronic renal failure and temporary dialysis compared to no ischemia. Thompson et al. J Urol 2007; 177 OR for ARF : 1.05 for each 1-min increase in ischemia p<0.001 OR for EGFR <15: 1.06 p<0.001 HR for new onset stage 4 CKD: 1:06; p<0.001 Thompson et al.eur Urol 2010;58

9 Solitary Kidney Model Study N Median Ischemia time Determinants of outcome Thompson et al. Urology 2012; (Range: 4-55) WIT, % parenchymal preservation. Preop egfr Lane et al. J Urol 2008; OPN 21 (IQR:17-27) LPN 29 (IQR: 19-35) WIT Age Preop egfr

10 Bilateral Kidney Model egfr <45 ml/min per 1.73m 2 was less likely after shorter ischemia (<30 min) vs. longer ischemia (11% vs. 19%) Lane et al. J Urol. 2010;184 Diff Function Baseline 5 days 3 months 12 months 48% 37% 41% 43% WIT and renal volume loss were predictors of outcome. WIT >32 mn associated with worse renal functional loss Propiglia et al. Eur Urol 2012;62

11 Early Unclamping Techniques Reducing WIT is associated with better renal function preservations WIT= 14.4 min is associated with a reduction of 90 days egfr of 11% vs 20% for WIT of 31.6 (p<0.001) min Gill et al. J Urol 2010; 183 Baumert et al. Eur Urol 2007; 52 Bollens et al. Eur Urol 2007; 52

12 GFR Recovery period Plateau AKI Time from surgery, in months

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16 Conclusions The degree of ischemia affects postoperative renal function Animal studies may not correlate well with human response to ischemia The large evidence is based on retrospective data The prospective evidence is provocative but limited