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European UrologyVolume 62, issue 1, pages e1-e30, July 2012
The Effects of Temporary Ischemia in Partial Nephrectomy on Renal Functional Outcomes: How Can Effects Best Be Estimated, and Can They Be Mitigated?
Published online 8 March 2012, pages 136 - 138
Refers to article:
Long-Term Functional Evaluation of the Treated Kidney in a Prospective Series of Patients Who Underwent Laparoscopic Partial Nephrectomy for Small Renal Tumors
Accepted 5 February 2012
July 2012 (Vol. 62, Issue 1, pages 130 - 135)
Partial nephrectomy is currently regarded as the standard of care for good surgical candidates with organ-confined, anatomically amenable renal masses. Over the last decade, the benefits of partial nephrectomy compared to radical nephrectomy  and the correlation between chronic kidney disease and risk of cardiovascular events and death  have been well established. More recently, the topic of renal ischemia and other factors potentially affecting renal function have been the focus of debate  and intense clinical and laboratory research.
In this issue of European Urology, Porpiglia and colleagues  evaluated renal function in a cohort of 54 patients who underwent partial nephrectomy using temporary warm ischemia. The authors conducted a prospective observational study that started with 75 patients treated with laparoscopic partial nephrectomy and later excluded 21 patients when performing the final analysis (due to the presence of horseshoe kidney in 1 patient, postoperative complications in 2 patients, and lack of a minimum of 4-yr follow-up in 18 patients). The study included only patients with tumors <4 cm, estimated glomerular filtration rate (eGFR) >60 ml/min per 1.73 m2, with split renal function (SRF) of the affected kidney in the 45–55% range. Measures of renal function were evaluated at 3 mo and 1 yr and then yearly after surgery. These measures included serum creatinine, eGFR, and SRF and effective renal plasma flow (ERPF), as measured by a MAG-3 renal scan performed at the authors’ institution and evaluated by a dedicated nuclear radiologist. The authors found that serum creatinine and eGFR did not significantly change after surgery, whereas MAG-3 renal scan–derived measures (SRF and ERPF) were significantly worse as early as 3 mo after surgery and remained stable during the subsequent 4 yr after surgery. The authors found that duration of warm ischemia, but not age, comorbidities as measured by the Charlson Comorbidity Index (CCI), body mass index (BMI), tumor size, RENAL score, or peritumoral healthy tissue thickness, were correlated with decline in renal function as measured by MAG-3 renal scan.
Several issues deserve further scrutiny in this study . First, the measure of comorbidity (CCI) used in this study does not include hypertension, a well-known contributor to renal dysfunction. As such, the contribution of comorbidities in this study could be underestimated. Second, the technical details of MAG-3 renal scanning measurements (SRF and ERPF) were not provided. Was the tumor area, for example, included in the region-of-interest measurements? Third, the percentage of renal parenchyma preserved was not specified in this group. Fourth, the study included a favorable patient population that is relatively young (mean age: 57 yr), barely overweight (mean BMI: 26.6 kg/m2), and healthy (mean CCI: 0.90) and that has good renal function (mean eGFR: 85.7 ml/min per 1.73 m2). It is possible that the effect of warm ischemia on renal function in this favorable group might not be as detrimental as expected. Finally, although the change in SRF was statistically significant (p < 0.0001), the true clinical significance of a 6% relative decline in SRF (from approximately 48% to about 45%) is unclear.
Keeping these issues in mind, this prospective study brings to light several questions regarding warm ischemia and partial nephrectomy . How should we define renal function after partial nephrectomy? The urologic community now agrees that creatinine is not an accurate measure, and eGFR has been used consistently in clinical practice and in more recent publications. The authors’ findings challenge this measure, as they found that eGFR was not statistically different after partial nephrectomy with warm ischemia (keeping in mind the small sample size of 54 patients) but MAG-3 measures were. Does this mean that we should now abandon using eGFR (like we abandoned creatinine) and start routinely obtaining MAG-3 renal scans on all patients postoperatively? How can we generalize these results to an unselected patient population (eg, older, obese, poor renal function, multiple comorbidities) undergoing partial nephrectomy? Gill et al.  recently reported on an expanded group of patients that underwent partial nephrectomy using their novel zero-ischemia technique and reported on a subgroup of 11 patients who had preoperative and 6-mo postoperative MAG-3 renal scans. They reported that with even with zero ischemia, split renal function decreased from 49% to 44%. It is interesting to note that even with zero ischemia, Gill et al. still had a 10% relative decrease in renal function on MAG-3 scan compared to 6% in the current study, although the two studies cannot necessarily be compared head to head, as this difference could be simply a function of the amount of preserved parenchyma (Gill et al. reported that these 11 patients had a mean of 18% kidney excised with a range of 5–50%, whereas Porpiglia et al.  did not report the percent of kidney excised or preserved in their cohort).
The decline in renal function after partial nephrectomy is a rather complex process, and we are still trying to understand its intricacies. Studies initially identified warm ischemia as a detrimental factor, so cold ischemia was later used consistently. Duration of warm ischemia has been subsequently minimized to preserve maximal renal function because warm ischemia time was thought to be the most important and relevant factor in determining loss of renal function, with work suggesting incremental effects with longer durations . More recent work from the same authors identified the effect of nonmodifiable risk factors (referred to as kidney quality and quantity) as the primary drivers of renal dysfunction after partial nephrectomy (with ischemia time losing statistical significance when analyzed in a multivariate fashion) . More recently, a group of these authors  confirmed that the percent of renal parenchyma preserved was the most important factor in determining renal function after partial nephrectomy in patients who have “ischemia time within acceptable limits.”
It is now clear that retrospective reviews that incorporate new variables with different times using different patient cohorts will arrive at different conclusions (eg, percent parenchyma preserved and loss of statistical significance of warm ischemia time). At present, three major ischemia categories are being used in clinical practice: standard partial nephrectomy with renal artery clamping (with or without renal vein clamping, with or without ice), partial nephrectomy without any renal artery clamping whatsoever (with potential for major blood loss and intraoperative hypotension in some patients) , , and , and partial nephrectomy with superselective clamping (otherwise referred to as zero-ischemia partial nephrectomy; with prolonged surgical times with pneumoperitoneum, multiple renal artery branches being temporarily clamped or unclamped, renal parenchyma being opened, and third-, fourth-, or fifth-order arteries being controlled) , , and . Such retrospective studies provide very useful clues as to what factors are possibly important determinants of renal damage after partial nephrectomy (and provide important stratification tools for randomized trials) but are of limited value when comparing renal functional outcomes of different surgical techniques for partial nephrectomy.
So where do we go from here? Current prospective patient-based laboratory research is being performed to elucidate the ultrastructural and molecular mechanisms underlying ischemia in the human kidney , which will hopefully lead to better ways to counteract the effects of ischemia when its use is necessary. In addition, research in animal models of ischemia-reperfusion injury is being conducted  using a mitochondria-targeted peptide (SS-31, MTP-131, Bendavia™) that scavenges mitochondrial reactive oxygen species, with early preliminary data showing promising results in reducing ischemic kidney injury. A randomized trial with a renoprotective agent such as SS-31 can be helpful in assessing the effect of such class of drugs on renal functional outcomes after partial nephrectomy. In parallel, a randomized trial with a primary end point of renal functional measures (clearly not serum creatinine but more likely eGFR or MAG-3 measures) could provide the answer as to what surgical technique is better at nephron preservation, as such a trial will actively (by stratifying for baseline renal function, tumor size, comorbidities, percent parenchyma involved by tumor on preoperative imaging, to name a few possibilities) and inactively (through randomization) account for factors that are truly important for maximal nephron preservation.
Conflicts of interest
The authors have nothing to disclose.
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Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
© 2012 European Association of Urology, Published by Elsevier B.V.
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