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International Journal of Urology (2015) 22, 14–21
doi: 10.1111/iju.12612
Review Article
Renal parenchymal histopathology predicts life-threatening chronic kidney disease as a result of radical nephrectomy Takehiro Sejima, Masashi Honda and Atsushi Takenaka Division of Urology, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Japan
Abbreviations & Acronyms AS = arteriosclerosis CKD = chronic kidney disease CKD-EPI = Chronic Kidney Disease Epidemiology CVD = cardiovascular disease DM = diabetes mellitus ED = erectile dysfunction eGFR = estimated glomerular filtration rate ESRD = end-stage renal disease GS = glomerulosclerosis MDRD = Modification of Diet in Renal Disease NSS = nephron-sparing surgery QOL = quality of life RCC = renal cell carcinoma RN = radical nephrectomy Correspondence: Takehiro Sejima, M.D., Ph.D., Division of Urology, Department of Surgery, Tottori University Faculty of Medicine, 36-1 Nishimachi, Yonago 683-8504, Japan. Email: [email protected] .ac.jp Received 28 June 2014; accepted 3 August 2014. Online publication 4 September 2014
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Abstract: The preoperative prediction of post-radical nephrectomy renal insufficiency plays an important role in the decision-making process regarding renal surgery options. Furthermore, the prediction of both postoperative renal insufficiency and postoperative cardiovascular disease occurrence, which is suggested to be an adverse consequence caused by renal insufficiency, contributes to the preoperative policy decision as well as the precise informed consent for a renal cell carcinoma patient. Preoperative nomograms for the prediction of post-radical nephrectomy renal insufficiency, calculated using patient backgrounds, are advocated. The use of these nomograms together with other types of nomograms predicting oncological outcome is beneficial. Post-radical nephrectomy attending physicians can predict renal insufficiency based on the normal renal parenchymal pathology in addition to preoperative patient characteristics. It is suggested that a high level of global glomerulosclerosis in nephrectomized normal renal parenchyma is closely associated with severe renal insufficiency. Some studies showed that post-radical nephrectomy severe renal insufficiency might have an association with increased mortality as a result of cardiovascular disease. Therefore, such pathophysiology should be recognized as life-threatening, surgically-related chronic kidney disease. On the contrary, the investigation of the prediction of mild post-radical nephrectomy renal insufficiency, which is not related to adverse consequences in the postoperative long-term period, is also promising because the prediction of mild renal insufficiency might be the basis for the substitution of radical nephrectomy for nephron-sparing surgery in technically difficult or compromised cases. The deterioration of quality of life caused by post-radical nephrectomy renal insufficiency should be investigated in conjunction with life-threatening matters. Key words:
cardiovascular disease, chronic kidney disease, radical nephrectomy, renal cell carcinoma, renal parenchymal pathology.
Introduction Over the past three decades, there has been a gradual increase in the incidence of RCC, which has coincided with the widespread use of routine abdominal imaging.1 This trend in Western countries contributes to the early detection of asymptomatic localized RCC and ultimately improves the prognosis of all RCC patients. More than 60 000 people are diagnosed annually with RCC in the USA,2 and 70% of these patients present with localized disease.3,4 There is no doubt that surgical treatment is practically the only effective therapeutic modality for localized RCC. Although RN is still effective treatment from the aspect of oncological control, NSS is indicated for small renal tumors. The concerns after RN for patients with RCC involve not only the oncological outcome, but also CKD progression because of the large amount of nephron tissue loss. The long-term adverse consequences of RN develop as a result of a hyperfiltration injury to the remaining glomeruli, and might include proteinuria, hypertension and decreased renal function.5,6 It is well known that the loss of renal parenchyma is related to functional and structural adaptations of the remaining nephrons, including glomerular hyperfiltration and intraglomerular hypertension, and that these changes eventually result in marked proteinuria and progression to chronic renal failure, with consequent focal and segmental glomerulosclerosis in experimental 5/6 nephrectomy animal models.7,8 Although these findings are not expected in unilateral nephrectomies in patients with RCC and otherwise unremarkable renal anatomy and function, some functional compromise might be expected in patients with pre-existing renal disease, especially in the context of common predisposing medical conditions. The adverse renal outcomes in patients undergoing nephrectomy for RCC were determined by a large populationbased analysis.9 Such obstacles have also been investigated in living recipients of kidney © 2014 The Japanese Urological Association
Post-radical nephrectomy renal insufficiency
transplantation. Post-donor nephrectomy CKD has become a medical problem in recent years, and risk factors associated with the deterioration of renal function after donor nephrectomy have been investigated.10–12 Therefore, the prediction and prevention of adverse outcomes related to CKD progression after RN are crucial in the management of postoperative RCC patients. In the present review article, various aspects of the unfavorable phenomenon of postoperative renal insufficiency that is inevitable in RN treatment are discussed, in particular, the nephrectomized normal renal parenchymal pathology.
Accurate and convenient assessment of renal function in clinical practice There are several types of examination procedures that indicate renal function. Some examinations are cost- and timeconsuming; however, they show great accuracy. On the contrary, some examinations are easy to use; however, the accuracy is inferior. Although serum creatinine level was widely acceptable as a reliable indicator of renal function for many years, the recent consensus is that eGFR has replaced it as an accurate and convenient examination tool. The problem with eGFR is that there are several equations for determination, each of which has limitations as a result of race, muscle volume or renal function. Detailed here are two types of equations that are used worldwide. The MDRD equation was developed from multicenter, controlled trial data in 1628 black and white CKD patients to predict GFR using serum creatinine concentration and demographic factors.13 The CKD-EPI equation was developed recently from the data of a huge number of participants in multiple studies and National Health and Nutrition Examination Survey to predict GFR more accurately than the MDRD equation.14
MDRD = 186 × (creatinine / 88.4)−1.154 × age−0.203 × 0.742 (if female) × 1.210 (if black). 2 CKD-EPI = 141 × min (creatinine / k,1)a × max (creatinine / k,1)−1.209 × 0.993Age × 1.018 (if female) × 1.159 (if black). k: 0.9 (if male), 0.7 (if female); a: – 0.411 (if male), – 0.329 (if female). min: the minimum of creatinine/k or 1 max: the maximum of creatinine/k or 1.
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Earley et al. carried out a cross-sectional investigation with regard to the comparison of several eGFR equations using the MEDLINE database and concluded that neither the MDRD nor CKD-EPI equations were effective if the examination range was set for all ranges of renal function in all patient cohorts. They also argued that one should select an appropriate equation if renal function is quite high or low.15 In Japan, the following equation (applicable for an age over 18 years), which was modified from the MDRD equation, was often used.16 This equation calculates the corrected GFR as the standard physique (height 170 cm; weight 63 kg; body surface area 1.73 m2).
eGFR = 194 × serum creatinine −1.094 × age −0.287 (for females, × 0.739) . This formula is currently recommended by the Japanese Society of Nephrology. © 2014 The Japanese Urological Association
Measurement, assessment and transition of post-RN renal insufficiency Post-RN renal insufficiency is inevitable because of the complete loss of a unilateral kidney. As long as ESRD does not occur, post-RN renal insufficiency has been overlooked in the latter part of the 20th century. Since the beginning of the 21st century, with the increased survival rate of RCC patients treated by RN (mainly as a result of the increased rate of early stage cases), clinical research has focused on the effect of post-RN renal insufficiency on post-RN life expectancy. The most reliable method of renal function evaluation that is easy to use in clinical practice is the calculation of eGFR. The percent eGFR decline is a reliable assessment of post-RN renal insufficiency regardless of various values of preoperative eGFR in each patient. Although the post-RN percent eGFR decline in the major studies varies from 20% to 35%, the natural history of the transition of post-RN renal insufficiency is still unknown.17–19 Non-negligible rates of patients with preoperative renal functional deterioration were included in the RCC patient cohort treated by RN, in which 10.7–29.9% of patients had CKD with a GFR less than 60 mL/min/1.73 m2 preoperatively.20–24 The preoperative baseline of renal function and various types of comorbidities can affect post-RN percent eGFR decline. Post-RN percent eGFR decline is defined as (preoperative eGFR – post-RN eGFR) / preoperative eGFR × 100). The interpretation of post-RN percent eGFR decline can be changed according to the time-point of postoperative eGFR assessment, because one’s postoperative eGFR might be different in a longterm post-RN period. The preoperative baseline of renal function, comorbidities and transitional renal function of the remnant kidney during a long-term post-RN period are deeply intertwined disease processes for post-RN CKD progression.
Preoperative prediction of post-RN renal insufficiency One of the contributions of preoperative prediction of post-RN renal insufficiency is the ability to inform patients of their predicted renal function deterioration together with their predicted recurrence rate and cancer-specific survival rate. Early post-RN consulting with nephrologists based on the preoperative prediction of post-RN renal insufficiency is an ideal post-RN follow-up procedure. Another contribution is for the serious consideration of policy decision-making regarding the types of renal surgery. Many investigations regarding the prediction of post-RN renal insufficiency have been based on research that searched for significant factors associated with post-RN insufficiency. The characteristics of factors analyzed were wide-ranging, from clinical aspects, including patient demographics and comorbidities, remnant kidney size calculated by radiographic findings and tumor size,18,20,25 to basic aspects, including histopathology and molecular biomarker expression in nephrectomized normal renal parenchyma.26,27 However, the first investigation that was specifically focused on constructing the predictive model was first carried out by Sorbellini et al. They constructed the initial type of nomogram predicting a 7-year probability of freedom from renal insufficiency calculated using the factors of age, sex, the American Society of Anesthesiologists classification score, preoperative 15
T SEJIMA ET AL.
Proposal of life-threatening surgical CKD CKD is currently defined as a GFR less than 60 mL/min/ 1.73 m2 for more than 90 days.32 Go et al. studied a cohort of more than 1 million patients, and found an independent graded association between CKD and all-cause mortality, all-cause hospitalization and cardiovascular death, even after adjusting for comorbid conditions, including coronary artery disease, DM and hypertension.33 Of patients undergoing RN or NSS for suspected renal cancers 24–30% have CKD before surgery.19,20 Compared with patients without preoperative CKD, these patients have correspondingly worse renal function after surgery, and are at an increased risk for complications and reduced overall survival.34 In general, the term CKD is widely applied to renal insufficiency as a result of a medical cause. However, recently, as the attention to post-renal surgical renal insufficiency has increased, the term CKD is not necessarily applied to CKD due to only a medical cause. As long as a natural history of CKD as a result of renal surgery is not conclusive, surgically-induced CKD should be discussed as being distinguishable from CKD due to a medical cause. It is entirely proper to discuss this debate? Should we manage medical CKD the same way as surgical CKD? Lane et al. showed that surgical CKD is associated with a relatively low risk of progressive renal function decline, and the impact on survival does not appear to be substantial, although preoperative medical CKD is associated with an increased risk of death during intermediate-term follow up in a 4180 patient cohort.35 We originally carried out post-RN long-term follow up (median 80.2, range 12.5–164.2 months) in 100 patients with unilateral kidney removal for RCC and upper urinary tract urothelial carcinoma to determine the cause of death. If the cause of death was limited to CVD, including coronary disease, heart failure, stroke or peripheral arterial disease, the CVD-specific survival rates in a post-RN severe renal insufficiency group (which was categorized as post-RN eGFR decline over 45% 1-year postoperatively) was significantly worse than in the counterpart group (Fig. 1).27 Although the limitation of that study was that the patient cohort was a mixture of RCC and upper urinary tract urothelial carcinoma patients, we suggest that there is clinical significance to the degree of post-RN eGFR decline as a predictor of life-threatening surgical CKD. When CVD caused by CKD progression was discussed, the statistical end-points of a patient’s outcome were CVD occurrence or CVD death. There is no doubt that the latter outcome of CVD death is the ultimate end-point. However, it is not easy to capture the outcome of CVD death in a post-RN patient cohort, because it takes a relatively long time after surgery to cause CVD death, and the rate of CVD death is not necessarily high. With regard to the CVD death rate in RCC patients treated with RN, there have 16
Non post-RN severe renal insufficiency (n = 87)
1 CVD-specific survival rate
serum creatinine level and percent change in remnant kidney volume.28 More recently, an externally validated nomogram predicting the risk of CKD within 3 years, using the factors of age, presence of DM and preoperative eGFR, was shown in a Japanese patient cohort.29 The application of not only oncological prognostic nomograms, but also post-RN renal functional nomograms to preoperative patients with RCC contributes to a meaningful and accurate informed consent for the patients.30,31
0.8
P = 0.0013
0.6 Post-RN severe renal insufficiency (n = 13)
0.4 0.2 0 0
20
40
60
80
100
120
140
160
Month Fig. 1 Comparison of the CVD-specific (death as a result of CVD) survival rate between two groups according to the occurrence of post-RN severe renal insufficiency, which was categorized as post-RN eGFR decline over 45% 1-year post, Non post-RN severe renal operatively (adapted from Sejima et al.27). , post-RN severe renal insufficiency (n = 13). insufficiency (n = 87);
been a few studies in which the rate varies from 2.4% to 8.2%.36–39 The data for CVD death rate are influenced by factors, such as follow-up duration, age and comorbid evaluation in patient cohorts. To our knowledge, there is no comparative analysis study of the CVD death rate between surgical CKD and medical CKD patient cohorts. Table 1 summarizes previously published data of the CVD death rate in a post-RN patient cohort36–39 compared with that in a 1253 medical CKD patients cohort.40 Future studies in a large post-RN patient cohort for the purpose of investigating CVD mortality might determine whether CVD mortality is different between medical CKD and surgical CKD.
Proposal of two types of post-RN renal insufficiency: Mild and severe renal insufficiency NSS is an ideal surgical procedure that can reduce the chance of postoperative renal insufficiency, and its application for large (>4 cm) tumors has been reported recently.41,42 However, NSS is still technically more difficult than RN for large, endophytic renal tumors, and can result in more postoperative complications, a longer operation time and greater estimated blood loss, especially when minimally-invasive procedures are used. Therefore, physicians might waver in their decision regarding renal surgery types in some compromised cases. Despite all of the aforementioned factors, there is no doubt that RN is still one of the key treatments for RCC, although its limitation is inevitable postoperative renal insufficiency as a result of the loss of large amounts of normal nephron tissue. If physicians can predict the degree of eGFR decline after two types of renal surgery, it will help in deciding what type of renal surgery to use in compromised cases. However, the accumulation of investigations addressing the preoperative prediction of renal insufficiency after NSS in compromised cases is too few to show clinical significance. Therefore, physicians have no choice but to predict postoperative renal insufficiency based on RN data. If the degree of eGFR decline after RN is predicted to be quite low in cases with high complexity in the nephrometry scoring system or complicated conditions, such as bleeding tendency © 2014 The Japanese Urological Association
Post-radical nephrectomy renal insufficiency
Table 1
CVD death rates in post-RN and medical CKD patients cohorts
No. patients (RN or CKD) Age (mean or median) Charlson Comorbidity Index 0–1 ≥2 Follow up (median) No. CVD deaths CVD death rate
Kates et al.36
Huang et al.37
Weight et al.38
Sejima et al.39
Meisinger et al.40
1915 (RN) 58.9 year
2435 (RN) Over 66 year
298 (RN) 63 year
147 (RN) 65.7 year
1253 (CKD; eGFR 15–59) Male: 62.4 year Female: 61.5 year
NA
NA 43 months 146 146/2435 (6.0%)
109 (74%) 38 (26%) 62.3 months 12 12/147 (8.2%)
NA
36 months 59 59/1915 (3.1%)
199 (78%) 56 (22%) 41 months 7 7/298 (2.4%)
caused by postoperative mandatory anticoagulants administration, the decision-making of challenging NSS might be altered to RN. On the contrary, if the degree of eGFR decline is predicted to be quite high after RN or if ESRD can be predicted postoperatively, challenging NSS might be indicated in compromised cases. Such serious considerations contribute to preoperative informed consent, thus physicians and patients can share the predicted outcome not only from an oncological aspect, but also from a functional aspect. It seems that the issue of post-RN renal insufficiency should enter the next stage of investigation, which is the prediction of two distinct types of categories; that is, mild and severe post-RN renal insufficiency. Recently, in our 175 RCC patient cohort treated by RN, we initially categorized mild and severe post-RN renal insufficiency. Mild renal insufficiency was categorized as a percent eGFR decline below 20, whereas severe renal insufficiency was categorized as a percent eGFR decline over 40, because the mean percent eGFR decline has been determined to be approximately 30% in previous major studies.17–19 Multivariate analyses of various factors, including patient demographics, tumor pathology and remnant kidney status, showed that the absence of comorbidities, larger remnant kidney/body surface area ratio and larger tumor diameter were significantly predictive of post-RN mild renal insufficiency, whereas smaller tumor diameter was significantly predictive of post-RN severe renal insufficiency (Table 2; esteemed designation of “Outstanding Poster” at 109th American Urological Association Meeting, Orlando, 18 May 2014). The appropriate cut-off value for our original new predictor, the remnant kidney/body surface area ratio, was 115, with a sensitivity of 47.6% and a specificity of 79.2% when used to predict mild renal insufficiency using a receiver operating characteristic curve. Remnant kidney status has a close relationship with compensatory hypertrophy, which is hypothesized to occur not only after RN, but also before RN, though the natural history of remnant kidney change is still unclear. A detailed evaluation of renal size using various radiographic modalities after unilateral nephrectomy has shown that the compensatory hypertrophy of remnant kidneys occurred even after several postoperative days.43,44 If the compensatory hypertrophy of the normal-side kidney (as a result of reduced normal nephron tissue by RCC progression in the diseased-side kidney) is hypothesized to occur preoperatively, post-RN renal insufficiency might be mild in large tumor cases because of the completed compensatory hypertrophy of the remnant kidney in addition to a small loss of normal nephron tissue. Whatever the © 2014 The Japanese Urological Association
12.5 years 155 155/1253 (12.4%)
Table 2 Multivariate analyses of potent factors (P < 0.1 in univariate analyses) for prediction of post-RN mild and severe renal insufficiency
Prediction of mild renal insufficiency (n = 21)
Prediction of severe renal insufficiency (n = 32)
Variables
Odds ratio (95% CI)
P-value
Remnant kidney volume Remnant kidney volume/body surface area ratio Tumor diameter Absence of comorbidity (yes vs no) Remnant kidney volume Remnant kidney volume/body surface area ratio Tumor diameter DM (yes vs no) Proteinuria (yes vs no) Age
0.987 (0.962–1.012) 1.054 (1.005–1.106)
0.2971 0.032
1.338 (1.122–1.596) 3.659 (1.285–10.422)
0.0012 0.0151
0.994 (0.966–1.024) 0.976 (0.927–1.027)
0.7026 0.3475
0.796 (0.642–0.987) 2.146 (0.809–5.692) 1.732 (0.512–5.858)
0.0378 0.1251 0.3768
1.026 (0.980–1.073)
0.2738
case, our data suggest that remnant kidney status is the key point in the investigation of post-RN renal insufficiency.
Nephrectomized normal renal parenchymal pathology: What can it show? Histopathological evaluation of nephrectomized normal renal parenchyma Traditionally, non-neoplastic parenchyma has received little attention, and important medical renal diseases might be overlooked.45 Hypertension, smoking, obesity, DM and increasing age are risk factors for renal malignancy, and independently, they all have a strong impact on renal function as well.46–49 It seems that the same population of patients who is at an increased risk of undergoing nephrectomy is also at an increased risk of chronic renal failure as a result of already compromised renal function secondary to DM, hypertension or other aforementioned factors. There have been several studies of medical renal disease in nephrectomized specimens.45,50–52 Arterial sclerotic vascular disease and DM lead the list, affecting 20–30% of patients.53 Bijol et al. also showed the presence of pathological arteriosclerosis and DM as the frequent finding in nephrectomized normal renal parenchyma in a 110 consecutive renal tumor patient cohort (Table 3).51 They also showed that although the difference of post-RN renal insufficiency among the four groups 17
T SEJIMA ET AL.
Table 3 Frequent two medical disease findings in 110 cases of nephrectomized normal renal parenchyma Pathological findings Arterial sclerotic vascular disease No AS Mild AS Moderate AS Severe AS Total Diabetic GS Glomerular hypertrophy Early Moderate Advanced (nodular) Total
No. cases (%)
11 (10.0) 5 (4.6) 11 (10.0) 15 (13.6) 42 (38.2) 4 (3.6) 15 (13.6) 4 (3.6) 3 (2.7) 26 (23.6)
Adapted from Bijol et al.51
stratified by arteriole occlusion was not conclusive, 14 of the patient cohort (12.7%) who showed severe pathological arteriosclerosis commonly had systemic CVD, such as ischemic heart disease, stroke, transitory ischemic attacks, coronary artery disease, aorto-iliac occlusion, deep vein thrombosis and pulmonary emboli. In contrast, DM is the most common cause of ESRD, and diabetic GS is the second most common form of GS in nephrectomized specimens.54–58 If moderate to severe arterial sclerotic vascular disease, greater than 20% global GS or nodular diabetic GS is present, a significant decline in renal function can be expected within 6 months.45,51 A comprehensive evaluation of diabetic GS in conjunction with the data in clinical practice of DM is not practical without the contribution of internal medicine physicians. Therefore, we analyzed the relationships of AS severity, stratified by the grade of arteriole occlusion (Fig. 2a–c) as described in the aforementioned study,51 and global GS (Fig. 2d) with clinical significance, including post-RN renal insufficiency, because AS and global GS are relatively easy for urologists to evaluate. Our preliminary data show no association between AS severity in nephrectomized normal renal parenchyma and post-RN renal insufficiency; however, a global GS extent over 14% was significantly associated with severe post-RN renal insufficiency, which showed an eGFR decline of over 40% and a significantly increased mortality as a result of CVD in a 100 RCC patients cohort (109th American Urological Association Meeting, Orlando, 18 May 2014). This result is roughly in accordance with a previous study by Gautam et al., in which a positive correlation between global GS extent and post-RN percent eGFR decline was shown.26 The elucidation of global GS extent in nephrectomized normal renal parenchyma is suggested to have a great impact on the prediction of post-RN renal insufficiency, and seems to be a mandatory procedure for a high-quality post-RN follow up.
Utility of molecular biomarker expression in nephrectomized normal renal parenchyma Despite numerous investigations of the expression of various molecular biomarkers that show tumor aggressiveness in RCC, the expression of these biomarkers in normal kidney tissue has not been the focus of translational research. Biomarker expression in normal kidney tissue has been considered as a compara18
tive indicator of tumors in many studies in which different expression levels between normal and tumor tissues were compared. We explored the new translational research area of the association of molecular biomarker expression in nephrectomized normal renal parenchyma and post-RN renal function, and focused on Fas, which is a major apoptotic regulatory molecule. The role of Fas expression in RCC has been elucidated using immunohistochemistry and competitive reverse transcription polymerase chain reaction in our patient cohort,59 and by using immunohistochemistry and tissue microarray in a multi-institutional German patient cohort.60 Fas plays a pivotal role in the non-neoplastic pathogenesis of renal parenchyma. During renal injury, renal cells express the Fas ligand, and the activation of the Fas receptor promotes the apoptosis of these cells.61,62 Fas agonists can induce glomerular injury with subsequent mesangial cell proliferation. Glomerular expression and elevated levels of Fas and Bcl-2 could contribute to glomerular injury during the evolution of lupus nephritis.63 Our study showed the significance of Fas expression in nephrectomized normal renal parenchyma as a predictor of post-RN severe renal insufficiency, and increased mortality as a result of CVD in 80 RCC and 20 upper urinary tract urothelial carcinoma cases.27 A few glomerular cells positively immunostained for Fas (Fig. 3a) were associated with post-RN severe renal insufficiency, whereas the meaning of a relatively strong and diffuse positive immunostaining of tubular cells for Fas (Fig. 3b) was not conclusive in our study.
Limitation of the prediction of post-RN renal insufficiency based on histopathological and molecular evaluation in nephrectomized normal renal parenchyma The prediction of post-RN renal insufficiency utilizing nephrectomized normal renal tissues has a certain limitation. The methodology involves the elucidation of the contralateral remnant kidney function based on the results from the resected kidney. The hypothesis is that the histopathological and molecular environment of the resected normal kidney tissue is identical to that of the contralateral remnant kidney. Therefore, great care must be taken to exclude the contribution of tumor invasion to the renal insufficiency of the disease-side kidney by carefully selecting cases utilizing preoperative radiographic examinations, such as a dynamic computed tomography scan with contrast material or intravenous pyelography.
Preventing the adverse consequences of post-RN In the prevention of life-threatening consequences after RN, physicians might undertake the management of medical CKD, especially in patients with comorbidities of cardiovascular and metabolic disorders. Because CKD and CVD are interrelated, it is important to note the trends in the prevalence of CKD and the common risk factors it shares with CVD, such as hypertension and DM, which constitute target diseases that should be controlled or prevented during CKD management. Three prospective, randomized controlled trials in non-diabetic CKD patients suggested that a lower blood pressure treatment goal (4 cm: intermediate-term oncologic and functional outcomes. Urology 2009; 73: 1077–82. 42 Nouralizadeh A, Simforoosh N, Tabibi A et al. Laparoscopic partial nephrectomy for tumours >4 cm compared with smaller tumours: perioperative results. Int. Urol. Nephrol. 2011; 43: 371–6. 43 Funahashi Y, Hattori R, Yamamoto T, Kamihira O, Moriya Y, Gotoh M. Change in contralateral renal parenchymal volume 1 week after unilateral nephrectomy. Urology 2009; 74: 708–12. 44 Funahashi Y, Hattori R, Yamamoto T, Aoki S, Majima T, Gotoh M. Renal parenchymal volume increases after contralateral nephrectomy: assessment using three-dimensional ultrasonography. Int. J. Urol. 2011; 18: 857–60. 45 Henriksen KJ, Meehan SM, Chang A. Non-neoplastic renal diseases are often unrecognized in adult tumor nephrectomy specimens: a review of 246 cases. Am. J. Surg. Pathol. 2007; 31: 1703–8. 46 Lindblad P, Chow WH, Chan J et al. The role of diabetes mellitus in the aetiology of renal cell cancer. Diabetologia 1999; 42: 107–12. 47 Shapiro JA, Williams MA, Weiss NS, Stergachis A, LaCroix AZ, Barlow WE. Hypertension, antihypertensive medication use, and risk of renal cell carcinoma. Am. J. Epidemiol. 1999; 149: 521–30. 48 Shapiro JA, Williams MA, Weiss NS. Body mass index and risk of renal cell carcinoma. Epidemiology 1999; 10: 188–91. 49 Yuan JM, Castelao JE, Gago-Dominguez M, Yu MC, Ross RK. Tobacco use in relation to renal cell carcinoma. Cancer Epidemiol. Biomarkers Prev. 1998; 7: 429–33. 50 Peces R, Martínez-Ara J, Miguel JL et al. Renal cell carcinoma co-existent with other renal disease: clinico-pathological features in pre-dialysis patients and those receiving dialysis or renal transplantation. Nephrol. Dial. Transplant. 2004; 19: 2789–96. 51 Bijol V, Mendez GP, Hurwitz S, Rennke HG, Nosé V. Evaluation of the nonneoplastic pathology in tumor nephrectomy specimens: predicting the risk of progressive renal failure. Am. J. Surg. Pathol. 2006; 30: 575–84. 52 Truong LD, Shen SS, Park MH, Krishnan B. Diagnosing nonneoplastic lesions in nephrectomy specimens. Arch. Pathol. Lab. Med. 2009; 133: 189–200. 53 Bonsib SM, Pei Y. The non-neoplastic kidney in tumor nephrectomy specimens: what can it show and what is important? Adv. Anat. Pathol. 2010; 17: 235–50. 54 Ruggenenti P, Remuzzi G. Nephropathy of type-2 diabetes mellitus. J. Am. Soc. Nephrol. 1998; 9: 2157–69. 55 Osterby R. Glomerular structural changes in type 1 (insulin-dependent) diabetes mellitus: causes, consequences, and prevention. Diabetologia 1992; 35: 803–12. 56 Drummond K, Mauer M, International Diabetic Nephropathy Study Group. The early natural history of nephropathy in type 1 diabetes: II. Early renal structural changes in type 1 diabetes. Diabetes 2002; 51: 1580–7. 57 Stout LC, Kumar S, Whorton EB. Insudative lesions – their pathogenesis and association with glomerular obsolescence in diabetes: a dynamic hypothesis based on single views of advancing human diabetic nephropathy. Hum. Pathol. 1994; 25: 1213–27.
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58 Stout LC, Kumar S, Whorton EB. Focal mesangiolysis and the pathogenesis of the Kimmelstiel-Wilson nodule. Hum. Pathol. 1993; 24: 77–89. 59 Sejima T, Morizane S, Hinata N et al. Fas expression in renal cell carcinoma accurately predicts patient survival after radical nephrectomy. Urol. Int. 2012; 88: 263–70. 60 Macher-Goeppinger S, Bermejo JL, Wagener N et al. Expression and prognostic relevance of the death receptor CD95 (Fas/APO1) in renal cell carcinomas. Cancer Lett. 2011; 301: 203–11. 61 Takemura T, Murakami K, Miyazato H, Yagi K, Yoshioka K. Expression of Fas antigen and Bcl-2 in human glomerulonephritis. Kidney Int. 1995; 48: 1886–92. 62 Ug˘uz A, Gönlüs¸en G, Ergin M, Tuncer I. Expression of Fas, Bcl-2 and p53 molecules in glomerulonephritis and their correlations with clinical and laboratory findings. Nephrology (Carlton) 2005; 10: 311–16. 63 Fathi NA, Hussein MR, Hassan HI, Mosad E, Galal H, Afifi NA. Glomerular expression and elevated serum Bcl-2 and Fas proteins in lupus nephritis: preliminary findings. Clin. Exp. Immunol. 2006; 146: 339–43. 64 Schneider MP, Hilgers KF. What should be the goal blood pressure in nondiabetic chronic kidney disease? Curr. Opin. Nephrol. Hypertens. 2014; 23: 180–5. 65 Ito S. Usefulness of RAS inhibition depends on baseline albuminuria. Nat. Rev. Nephrol. 2010; 6: 10–11. 66 Ruggenenti P, Remuzzi G. Proteinuria: is the ONTARGET renal substudy actually off target? Nat. Rev. Nephrol. 2009; 5: 436–7. 67 Casas JP, Chua W, Loukogeorgakis S et al. Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis. Lancet 2005; 366: 2026–33. 68 Rahman M, Ford CE, Cutler JA et al. Long-term renal and cardiovascular outcomes in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants by baseline estimated GFR. Clin. J. Am. Soc. Nephrol. 2012; 7: 989–1002. 69 Gaede P, Vedel P, Parving HH, Pedersen O. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet 1999; 353: 617–22. 70 Pedersen TR, Kjekshus J, Berg K et al. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). 1994. Atheroscler. Suppl. 2004; 5: 81–7. 71 Costa C, Virag R. The endothelial-erectile dysfunction connection: an essential update. J. Sex. Med. 2009; 6: 2390–404. 72 Guay AT. ED2: erectile dysfunction = endothelial dysfunction. Endocrinol. Metab. Clin. North Am. 2007; 36: 453–63. 73 Bellinghieri G, Savica V, Santoro D. Vascular erectile dysfunction in chronic renal failure. Semin. Nephrol. 2006; 26: 42–5. 74 Navaneethan SD, Vecchio M, Johnson DW et al. Prevalence and correlates of self-reported sexual dysfunction in CKD: a meta-analysis of observational studies. Am. J. Kidney Dis. 2010; 56: 670–85. 75 Mehrsai A, Mousavi S, Nikoobakht M, Khanlarpoor T, Shekarpour L, Pourmand G. Improvement of erectile dysfunction after kidney transplantation: the role of the associated factors. Urol. J. 2006; 3: 240–4. 76 Wang Y, Bao X. Effects of uric acid on endothelial dysfunction in early chronic kidney disease and its mechanisms. Eur. J. Med. Res. 2013; 18: 26. 77 Choi JH, Kim KL, Huh W et al. Decreased number and impaired angiogenic function of endothelial progenitor cells in patients with chronic renal failure. Arterioscler. Thromb. Vasc. Biol. 2004; 24: 1246–52. 78 Leavey SF, Weitzel WF. Endocrine abnormalities in chronic renal failure. Endocrinol. Metab. Clin. North Am. 2002; 31: 107–19. 79 Abdel-Gawad M, Huynh H, Brock GB. Experimental chronic renal Failure-Associated erectile dysfunction: molecular alterations in nitric oxide synthase pathway and IGF-I system. Mol. Urol. 1999; 3: 117–25. 80 Kopp RP, Dicks BM, Goldstein I et al. Does radical nephrectomy increase the risk of erectile dysfunction compared with partial nephrectomy? A cohort analysis. BJU Int. 2013; 111: E98–102. 81 Guo P, Xie Z, Wang Y, Wang J. Prevalence of erectile dysfunction in living donors before and after nephrectomy in China. Urology 2010; 76: 370–2. 82 Montorsi F, Briganti A, Salonia A et al. Erectile dysfunction prevalence, time of onset and association with risk factors in 300 consecutive patients with acute chest pain and angiographically documented coronary artery disease. Eur. Urol. 2003; 44: 360–4. 83 Thompson IM, Tangen CM, Goodman PJ, Probstfield JL, Moinpour CM, Coltman CA. Erectile dysfunction and subsequent cardiovascular disease. JAMA 2005; 294: 2996–3002.
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International Journal of Urology (2015) 22, 14–21
doi: 10.1111/iju.12612
Review Article
Renal parenchymal histopathology predicts life-threatening chronic kidney disease as a result of radical nephrectomy Takehiro Sejima, Masashi Honda and Atsushi Takenaka Division of Urology, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Japan
Abbreviations & Acronyms AS = arteriosclerosis CKD = chronic kidney disease CKD-EPI = Chronic Kidney Disease Epidemiology CVD = cardiovascular disease DM = diabetes mellitus ED = erectile dysfunction eGFR = estimated glomerular filtration rate ESRD = end-stage renal disease GS = glomerulosclerosis MDRD = Modification of Diet in Renal Disease NSS = nephron-sparing surgery QOL = quality of life RCC = renal cell carcinoma RN = radical nephrectomy Correspondence: Takehiro Sejima, M.D., Ph.D., Division of Urology, Department of Surgery, Tottori University Faculty of Medicine, 36-1 Nishimachi, Yonago 683-8504, Japan. Email: [email protected] .ac.jp Received 28 June 2014; accepted 3 August 2014. Online publication 4 September 2014
14
Abstract: The preoperative prediction of post-radical nephrectomy renal insufficiency plays an important role in the decision-making process regarding renal surgery options. Furthermore, the prediction of both postoperative renal insufficiency and postoperative cardiovascular disease occurrence, which is suggested to be an adverse consequence caused by renal insufficiency, contributes to the preoperative policy decision as well as the precise informed consent for a renal cell carcinoma patient. Preoperative nomograms for the prediction of post-radical nephrectomy renal insufficiency, calculated using patient backgrounds, are advocated. The use of these nomograms together with other types of nomograms predicting oncological outcome is beneficial. Post-radical nephrectomy attending physicians can predict renal insufficiency based on the normal renal parenchymal pathology in addition to preoperative patient characteristics. It is suggested that a high level of global glomerulosclerosis in nephrectomized normal renal parenchyma is closely associated with severe renal insufficiency. Some studies showed that post-radical nephrectomy severe renal insufficiency might have an association with increased mortality as a result of cardiovascular disease. Therefore, such pathophysiology should be recognized as life-threatening, surgically-related chronic kidney disease. On the contrary, the investigation of the prediction of mild post-radical nephrectomy renal insufficiency, which is not related to adverse consequences in the postoperative long-term period, is also promising because the prediction of mild renal insufficiency might be the basis for the substitution of radical nephrectomy for nephron-sparing surgery in technically difficult or compromised cases. The deterioration of quality of life caused by post-radical nephrectomy renal insufficiency should be investigated in conjunction with life-threatening matters. Key words:
cardiovascular disease, chronic kidney disease, radical nephrectomy, renal cell carcinoma, renal parenchymal pathology.
Introduction Over the past three decades, there has been a gradual increase in the incidence of RCC, which has coincided with the widespread use of routine abdominal imaging.1 This trend in Western countries contributes to the early detection of asymptomatic localized RCC and ultimately improves the prognosis of all RCC patients. More than 60 000 people are diagnosed annually with RCC in the USA,2 and 70% of these patients present with localized disease.3,4 There is no doubt that surgical treatment is practically the only effective therapeutic modality for localized RCC. Although RN is still effective treatment from the aspect of oncological control, NSS is indicated for small renal tumors. The concerns after RN for patients with RCC involve not only the oncological outcome, but also CKD progression because of the large amount of nephron tissue loss. The long-term adverse consequences of RN develop as a result of a hyperfiltration injury to the remaining glomeruli, and might include proteinuria, hypertension and decreased renal function.5,6 It is well known that the loss of renal parenchyma is related to functional and structural adaptations of the remaining nephrons, including glomerular hyperfiltration and intraglomerular hypertension, and that these changes eventually result in marked proteinuria and progression to chronic renal failure, with consequent focal and segmental glomerulosclerosis in experimental 5/6 nephrectomy animal models.7,8 Although these findings are not expected in unilateral nephrectomies in patients with RCC and otherwise unremarkable renal anatomy and function, some functional compromise might be expected in patients with pre-existing renal disease, especially in the context of common predisposing medical conditions. The adverse renal outcomes in patients undergoing nephrectomy for RCC were determined by a large populationbased analysis.9 Such obstacles have also been investigated in living recipients of kidney © 2014 The Japanese Urological Association
Post-radical nephrectomy renal insufficiency
transplantation. Post-donor nephrectomy CKD has become a medical problem in recent years, and risk factors associated with the deterioration of renal function after donor nephrectomy have been investigated.10–12 Therefore, the prediction and prevention of adverse outcomes related to CKD progression after RN are crucial in the management of postoperative RCC patients. In the present review article, various aspects of the unfavorable phenomenon of postoperative renal insufficiency that is inevitable in RN treatment are discussed, in particular, the nephrectomized normal renal parenchymal pathology.
Accurate and convenient assessment of renal function in clinical practice There are several types of examination procedures that indicate renal function. Some examinations are cost- and timeconsuming; however, they show great accuracy. On the contrary, some examinations are easy to use; however, the accuracy is inferior. Although serum creatinine level was widely acceptable as a reliable indicator of renal function for many years, the recent consensus is that eGFR has replaced it as an accurate and convenient examination tool. The problem with eGFR is that there are several equations for determination, each of which has limitations as a result of race, muscle volume or renal function. Detailed here are two types of equations that are used worldwide. The MDRD equation was developed from multicenter, controlled trial data in 1628 black and white CKD patients to predict GFR using serum creatinine concentration and demographic factors.13 The CKD-EPI equation was developed recently from the data of a huge number of participants in multiple studies and National Health and Nutrition Examination Survey to predict GFR more accurately than the MDRD equation.14
MDRD = 186 × (creatinine / 88.4)−1.154 × age−0.203 × 0.742 (if female) × 1.210 (if black). 2 CKD-EPI = 141 × min (creatinine / k,1)a × max (creatinine / k,1)−1.209 × 0.993Age × 1.018 (if female) × 1.159 (if black). k: 0.9 (if male), 0.7 (if female); a: – 0.411 (if male), – 0.329 (if female). min: the minimum of creatinine/k or 1 max: the maximum of creatinine/k or 1.
1
Earley et al. carried out a cross-sectional investigation with regard to the comparison of several eGFR equations using the MEDLINE database and concluded that neither the MDRD nor CKD-EPI equations were effective if the examination range was set for all ranges of renal function in all patient cohorts. They also argued that one should select an appropriate equation if renal function is quite high or low.15 In Japan, the following equation (applicable for an age over 18 years), which was modified from the MDRD equation, was often used.16 This equation calculates the corrected GFR as the standard physique (height 170 cm; weight 63 kg; body surface area 1.73 m2).
eGFR = 194 × serum creatinine −1.094 × age −0.287 (for females, × 0.739) . This formula is currently recommended by the Japanese Society of Nephrology. © 2014 The Japanese Urological Association
Measurement, assessment and transition of post-RN renal insufficiency Post-RN renal insufficiency is inevitable because of the complete loss of a unilateral kidney. As long as ESRD does not occur, post-RN renal insufficiency has been overlooked in the latter part of the 20th century. Since the beginning of the 21st century, with the increased survival rate of RCC patients treated by RN (mainly as a result of the increased rate of early stage cases), clinical research has focused on the effect of post-RN renal insufficiency on post-RN life expectancy. The most reliable method of renal function evaluation that is easy to use in clinical practice is the calculation of eGFR. The percent eGFR decline is a reliable assessment of post-RN renal insufficiency regardless of various values of preoperative eGFR in each patient. Although the post-RN percent eGFR decline in the major studies varies from 20% to 35%, the natural history of the transition of post-RN renal insufficiency is still unknown.17–19 Non-negligible rates of patients with preoperative renal functional deterioration were included in the RCC patient cohort treated by RN, in which 10.7–29.9% of patients had CKD with a GFR less than 60 mL/min/1.73 m2 preoperatively.20–24 The preoperative baseline of renal function and various types of comorbidities can affect post-RN percent eGFR decline. Post-RN percent eGFR decline is defined as (preoperative eGFR – post-RN eGFR) / preoperative eGFR × 100). The interpretation of post-RN percent eGFR decline can be changed according to the time-point of postoperative eGFR assessment, because one’s postoperative eGFR might be different in a longterm post-RN period. The preoperative baseline of renal function, comorbidities and transitional renal function of the remnant kidney during a long-term post-RN period are deeply intertwined disease processes for post-RN CKD progression.
Preoperative prediction of post-RN renal insufficiency One of the contributions of preoperative prediction of post-RN renal insufficiency is the ability to inform patients of their predicted renal function deterioration together with their predicted recurrence rate and cancer-specific survival rate. Early post-RN consulting with nephrologists based on the preoperative prediction of post-RN renal insufficiency is an ideal post-RN follow-up procedure. Another contribution is for the serious consideration of policy decision-making regarding the types of renal surgery. Many investigations regarding the prediction of post-RN renal insufficiency have been based on research that searched for significant factors associated with post-RN insufficiency. The characteristics of factors analyzed were wide-ranging, from clinical aspects, including patient demographics and comorbidities, remnant kidney size calculated by radiographic findings and tumor size,18,20,25 to basic aspects, including histopathology and molecular biomarker expression in nephrectomized normal renal parenchyma.26,27 However, the first investigation that was specifically focused on constructing the predictive model was first carried out by Sorbellini et al. They constructed the initial type of nomogram predicting a 7-year probability of freedom from renal insufficiency calculated using the factors of age, sex, the American Society of Anesthesiologists classification score, preoperative 15
T SEJIMA ET AL.
Proposal of life-threatening surgical CKD CKD is currently defined as a GFR less than 60 mL/min/ 1.73 m2 for more than 90 days.32 Go et al. studied a cohort of more than 1 million patients, and found an independent graded association between CKD and all-cause mortality, all-cause hospitalization and cardiovascular death, even after adjusting for comorbid conditions, including coronary artery disease, DM and hypertension.33 Of patients undergoing RN or NSS for suspected renal cancers 24–30% have CKD before surgery.19,20 Compared with patients without preoperative CKD, these patients have correspondingly worse renal function after surgery, and are at an increased risk for complications and reduced overall survival.34 In general, the term CKD is widely applied to renal insufficiency as a result of a medical cause. However, recently, as the attention to post-renal surgical renal insufficiency has increased, the term CKD is not necessarily applied to CKD due to only a medical cause. As long as a natural history of CKD as a result of renal surgery is not conclusive, surgically-induced CKD should be discussed as being distinguishable from CKD due to a medical cause. It is entirely proper to discuss this debate? Should we manage medical CKD the same way as surgical CKD? Lane et al. showed that surgical CKD is associated with a relatively low risk of progressive renal function decline, and the impact on survival does not appear to be substantial, although preoperative medical CKD is associated with an increased risk of death during intermediate-term follow up in a 4180 patient cohort.35 We originally carried out post-RN long-term follow up (median 80.2, range 12.5–164.2 months) in 100 patients with unilateral kidney removal for RCC and upper urinary tract urothelial carcinoma to determine the cause of death. If the cause of death was limited to CVD, including coronary disease, heart failure, stroke or peripheral arterial disease, the CVD-specific survival rates in a post-RN severe renal insufficiency group (which was categorized as post-RN eGFR decline over 45% 1-year postoperatively) was significantly worse than in the counterpart group (Fig. 1).27 Although the limitation of that study was that the patient cohort was a mixture of RCC and upper urinary tract urothelial carcinoma patients, we suggest that there is clinical significance to the degree of post-RN eGFR decline as a predictor of life-threatening surgical CKD. When CVD caused by CKD progression was discussed, the statistical end-points of a patient’s outcome were CVD occurrence or CVD death. There is no doubt that the latter outcome of CVD death is the ultimate end-point. However, it is not easy to capture the outcome of CVD death in a post-RN patient cohort, because it takes a relatively long time after surgery to cause CVD death, and the rate of CVD death is not necessarily high. With regard to the CVD death rate in RCC patients treated with RN, there have 16
Non post-RN severe renal insufficiency (n = 87)
1 CVD-specific survival rate
serum creatinine level and percent change in remnant kidney volume.28 More recently, an externally validated nomogram predicting the risk of CKD within 3 years, using the factors of age, presence of DM and preoperative eGFR, was shown in a Japanese patient cohort.29 The application of not only oncological prognostic nomograms, but also post-RN renal functional nomograms to preoperative patients with RCC contributes to a meaningful and accurate informed consent for the patients.30,31
0.8
P = 0.0013
0.6 Post-RN severe renal insufficiency (n = 13)
0.4 0.2 0 0
20
40
60
80
100
120
140
160
Month Fig. 1 Comparison of the CVD-specific (death as a result of CVD) survival rate between two groups according to the occurrence of post-RN severe renal insufficiency, which was categorized as post-RN eGFR decline over 45% 1-year post, Non post-RN severe renal operatively (adapted from Sejima et al.27). , post-RN severe renal insufficiency (n = 13). insufficiency (n = 87);
been a few studies in which the rate varies from 2.4% to 8.2%.36–39 The data for CVD death rate are influenced by factors, such as follow-up duration, age and comorbid evaluation in patient cohorts. To our knowledge, there is no comparative analysis study of the CVD death rate between surgical CKD and medical CKD patient cohorts. Table 1 summarizes previously published data of the CVD death rate in a post-RN patient cohort36–39 compared with that in a 1253 medical CKD patients cohort.40 Future studies in a large post-RN patient cohort for the purpose of investigating CVD mortality might determine whether CVD mortality is different between medical CKD and surgical CKD.
Proposal of two types of post-RN renal insufficiency: Mild and severe renal insufficiency NSS is an ideal surgical procedure that can reduce the chance of postoperative renal insufficiency, and its application for large (>4 cm) tumors has been reported recently.41,42 However, NSS is still technically more difficult than RN for large, endophytic renal tumors, and can result in more postoperative complications, a longer operation time and greater estimated blood loss, especially when minimally-invasive procedures are used. Therefore, physicians might waver in their decision regarding renal surgery types in some compromised cases. Despite all of the aforementioned factors, there is no doubt that RN is still one of the key treatments for RCC, although its limitation is inevitable postoperative renal insufficiency as a result of the loss of large amounts of normal nephron tissue. If physicians can predict the degree of eGFR decline after two types of renal surgery, it will help in deciding what type of renal surgery to use in compromised cases. However, the accumulation of investigations addressing the preoperative prediction of renal insufficiency after NSS in compromised cases is too few to show clinical significance. Therefore, physicians have no choice but to predict postoperative renal insufficiency based on RN data. If the degree of eGFR decline after RN is predicted to be quite low in cases with high complexity in the nephrometry scoring system or complicated conditions, such as bleeding tendency © 2014 The Japanese Urological Association
Post-radical nephrectomy renal insufficiency
Table 1
CVD death rates in post-RN and medical CKD patients cohorts
No. patients (RN or CKD) Age (mean or median) Charlson Comorbidity Index 0–1 ≥2 Follow up (median) No. CVD deaths CVD death rate
Kates et al.36
Huang et al.37
Weight et al.38
Sejima et al.39
Meisinger et al.40
1915 (RN) 58.9 year
2435 (RN) Over 66 year
298 (RN) 63 year
147 (RN) 65.7 year
1253 (CKD; eGFR 15–59) Male: 62.4 year Female: 61.5 year
NA
NA 43 months 146 146/2435 (6.0%)
109 (74%) 38 (26%) 62.3 months 12 12/147 (8.2%)
NA
36 months 59 59/1915 (3.1%)
199 (78%) 56 (22%) 41 months 7 7/298 (2.4%)
caused by postoperative mandatory anticoagulants administration, the decision-making of challenging NSS might be altered to RN. On the contrary, if the degree of eGFR decline is predicted to be quite high after RN or if ESRD can be predicted postoperatively, challenging NSS might be indicated in compromised cases. Such serious considerations contribute to preoperative informed consent, thus physicians and patients can share the predicted outcome not only from an oncological aspect, but also from a functional aspect. It seems that the issue of post-RN renal insufficiency should enter the next stage of investigation, which is the prediction of two distinct types of categories; that is, mild and severe post-RN renal insufficiency. Recently, in our 175 RCC patient cohort treated by RN, we initially categorized mild and severe post-RN renal insufficiency. Mild renal insufficiency was categorized as a percent eGFR decline below 20, whereas severe renal insufficiency was categorized as a percent eGFR decline over 40, because the mean percent eGFR decline has been determined to be approximately 30% in previous major studies.17–19 Multivariate analyses of various factors, including patient demographics, tumor pathology and remnant kidney status, showed that the absence of comorbidities, larger remnant kidney/body surface area ratio and larger tumor diameter were significantly predictive of post-RN mild renal insufficiency, whereas smaller tumor diameter was significantly predictive of post-RN severe renal insufficiency (Table 2; esteemed designation of “Outstanding Poster” at 109th American Urological Association Meeting, Orlando, 18 May 2014). The appropriate cut-off value for our original new predictor, the remnant kidney/body surface area ratio, was 115, with a sensitivity of 47.6% and a specificity of 79.2% when used to predict mild renal insufficiency using a receiver operating characteristic curve. Remnant kidney status has a close relationship with compensatory hypertrophy, which is hypothesized to occur not only after RN, but also before RN, though the natural history of remnant kidney change is still unclear. A detailed evaluation of renal size using various radiographic modalities after unilateral nephrectomy has shown that the compensatory hypertrophy of remnant kidneys occurred even after several postoperative days.43,44 If the compensatory hypertrophy of the normal-side kidney (as a result of reduced normal nephron tissue by RCC progression in the diseased-side kidney) is hypothesized to occur preoperatively, post-RN renal insufficiency might be mild in large tumor cases because of the completed compensatory hypertrophy of the remnant kidney in addition to a small loss of normal nephron tissue. Whatever the © 2014 The Japanese Urological Association
12.5 years 155 155/1253 (12.4%)
Table 2 Multivariate analyses of potent factors (P < 0.1 in univariate analyses) for prediction of post-RN mild and severe renal insufficiency
Prediction of mild renal insufficiency (n = 21)
Prediction of severe renal insufficiency (n = 32)
Variables
Odds ratio (95% CI)
P-value
Remnant kidney volume Remnant kidney volume/body surface area ratio Tumor diameter Absence of comorbidity (yes vs no) Remnant kidney volume Remnant kidney volume/body surface area ratio Tumor diameter DM (yes vs no) Proteinuria (yes vs no) Age
0.987 (0.962–1.012) 1.054 (1.005–1.106)
0.2971 0.032
1.338 (1.122–1.596) 3.659 (1.285–10.422)
0.0012 0.0151
0.994 (0.966–1.024) 0.976 (0.927–1.027)
0.7026 0.3475
0.796 (0.642–0.987) 2.146 (0.809–5.692) 1.732 (0.512–5.858)
0.0378 0.1251 0.3768
1.026 (0.980–1.073)
0.2738
case, our data suggest that remnant kidney status is the key point in the investigation of post-RN renal insufficiency.
Nephrectomized normal renal parenchymal pathology: What can it show? Histopathological evaluation of nephrectomized normal renal parenchyma Traditionally, non-neoplastic parenchyma has received little attention, and important medical renal diseases might be overlooked.45 Hypertension, smoking, obesity, DM and increasing age are risk factors for renal malignancy, and independently, they all have a strong impact on renal function as well.46–49 It seems that the same population of patients who is at an increased risk of undergoing nephrectomy is also at an increased risk of chronic renal failure as a result of already compromised renal function secondary to DM, hypertension or other aforementioned factors. There have been several studies of medical renal disease in nephrectomized specimens.45,50–52 Arterial sclerotic vascular disease and DM lead the list, affecting 20–30% of patients.53 Bijol et al. also showed the presence of pathological arteriosclerosis and DM as the frequent finding in nephrectomized normal renal parenchyma in a 110 consecutive renal tumor patient cohort (Table 3).51 They also showed that although the difference of post-RN renal insufficiency among the four groups 17
T SEJIMA ET AL.
Table 3 Frequent two medical disease findings in 110 cases of nephrectomized normal renal parenchyma Pathological findings Arterial sclerotic vascular disease No AS Mild AS Moderate AS Severe AS Total Diabetic GS Glomerular hypertrophy Early Moderate Advanced (nodular) Total
No. cases (%)
11 (10.0) 5 (4.6) 11 (10.0) 15 (13.6) 42 (38.2) 4 (3.6) 15 (13.6) 4 (3.6) 3 (2.7) 26 (23.6)
Adapted from Bijol et al.51
stratified by arteriole occlusion was not conclusive, 14 of the patient cohort (12.7%) who showed severe pathological arteriosclerosis commonly had systemic CVD, such as ischemic heart disease, stroke, transitory ischemic attacks, coronary artery disease, aorto-iliac occlusion, deep vein thrombosis and pulmonary emboli. In contrast, DM is the most common cause of ESRD, and diabetic GS is the second most common form of GS in nephrectomized specimens.54–58 If moderate to severe arterial sclerotic vascular disease, greater than 20% global GS or nodular diabetic GS is present, a significant decline in renal function can be expected within 6 months.45,51 A comprehensive evaluation of diabetic GS in conjunction with the data in clinical practice of DM is not practical without the contribution of internal medicine physicians. Therefore, we analyzed the relationships of AS severity, stratified by the grade of arteriole occlusion (Fig. 2a–c) as described in the aforementioned study,51 and global GS (Fig. 2d) with clinical significance, including post-RN renal insufficiency, because AS and global GS are relatively easy for urologists to evaluate. Our preliminary data show no association between AS severity in nephrectomized normal renal parenchyma and post-RN renal insufficiency; however, a global GS extent over 14% was significantly associated with severe post-RN renal insufficiency, which showed an eGFR decline of over 40% and a significantly increased mortality as a result of CVD in a 100 RCC patients cohort (109th American Urological Association Meeting, Orlando, 18 May 2014). This result is roughly in accordance with a previous study by Gautam et al., in which a positive correlation between global GS extent and post-RN percent eGFR decline was shown.26 The elucidation of global GS extent in nephrectomized normal renal parenchyma is suggested to have a great impact on the prediction of post-RN renal insufficiency, and seems to be a mandatory procedure for a high-quality post-RN follow up.
Utility of molecular biomarker expression in nephrectomized normal renal parenchyma Despite numerous investigations of the expression of various molecular biomarkers that show tumor aggressiveness in RCC, the expression of these biomarkers in normal kidney tissue has not been the focus of translational research. Biomarker expression in normal kidney tissue has been considered as a compara18
tive indicator of tumors in many studies in which different expression levels between normal and tumor tissues were compared. We explored the new translational research area of the association of molecular biomarker expression in nephrectomized normal renal parenchyma and post-RN renal function, and focused on Fas, which is a major apoptotic regulatory molecule. The role of Fas expression in RCC has been elucidated using immunohistochemistry and competitive reverse transcription polymerase chain reaction in our patient cohort,59 and by using immunohistochemistry and tissue microarray in a multi-institutional German patient cohort.60 Fas plays a pivotal role in the non-neoplastic pathogenesis of renal parenchyma. During renal injury, renal cells express the Fas ligand, and the activation of the Fas receptor promotes the apoptosis of these cells.61,62 Fas agonists can induce glomerular injury with subsequent mesangial cell proliferation. Glomerular expression and elevated levels of Fas and Bcl-2 could contribute to glomerular injury during the evolution of lupus nephritis.63 Our study showed the significance of Fas expression in nephrectomized normal renal parenchyma as a predictor of post-RN severe renal insufficiency, and increased mortality as a result of CVD in 80 RCC and 20 upper urinary tract urothelial carcinoma cases.27 A few glomerular cells positively immunostained for Fas (Fig. 3a) were associated with post-RN severe renal insufficiency, whereas the meaning of a relatively strong and diffuse positive immunostaining of tubular cells for Fas (Fig. 3b) was not conclusive in our study.
Limitation of the prediction of post-RN renal insufficiency based on histopathological and molecular evaluation in nephrectomized normal renal parenchyma The prediction of post-RN renal insufficiency utilizing nephrectomized normal renal tissues has a certain limitation. The methodology involves the elucidation of the contralateral remnant kidney function based on the results from the resected kidney. The hypothesis is that the histopathological and molecular environment of the resected normal kidney tissue is identical to that of the contralateral remnant kidney. Therefore, great care must be taken to exclude the contribution of tumor invasion to the renal insufficiency of the disease-side kidney by carefully selecting cases utilizing preoperative radiographic examinations, such as a dynamic computed tomography scan with contrast material or intravenous pyelography.
Preventing the adverse consequences of post-RN In the prevention of life-threatening consequences after RN, physicians might undertake the management of medical CKD, especially in patients with comorbidities of cardiovascular and metabolic disorders. Because CKD and CVD are interrelated, it is important to note the trends in the prevalence of CKD and the common risk factors it shares with CVD, such as hypertension and DM, which constitute target diseases that should be controlled or prevented during CKD management. Three prospective, randomized controlled trials in non-diabetic CKD patients suggested that a lower blood pressure treatment goal (4 cm: intermediate-term oncologic and functional outcomes. Urology 2009; 73: 1077–82. 42 Nouralizadeh A, Simforoosh N, Tabibi A et al. Laparoscopic partial nephrectomy for tumours >4 cm compared with smaller tumours: perioperative results. Int. Urol. Nephrol. 2011; 43: 371–6. 43 Funahashi Y, Hattori R, Yamamoto T, Kamihira O, Moriya Y, Gotoh M. Change in contralateral renal parenchymal volume 1 week after unilateral nephrectomy. Urology 2009; 74: 708–12. 44 Funahashi Y, Hattori R, Yamamoto T, Aoki S, Majima T, Gotoh M. Renal parenchymal volume increases after contralateral nephrectomy: assessment using three-dimensional ultrasonography. Int. J. Urol. 2011; 18: 857–60. 45 Henriksen KJ, Meehan SM, Chang A. Non-neoplastic renal diseases are often unrecognized in adult tumor nephrectomy specimens: a review of 246 cases. Am. J. Surg. Pathol. 2007; 31: 1703–8. 46 Lindblad P, Chow WH, Chan J et al. The role of diabetes mellitus in the aetiology of renal cell cancer. Diabetologia 1999; 42: 107–12. 47 Shapiro JA, Williams MA, Weiss NS, Stergachis A, LaCroix AZ, Barlow WE. Hypertension, antihypertensive medication use, and risk of renal cell carcinoma. Am. J. Epidemiol. 1999; 149: 521–30. 48 Shapiro JA, Williams MA, Weiss NS. Body mass index and risk of renal cell carcinoma. Epidemiology 1999; 10: 188–91. 49 Yuan JM, Castelao JE, Gago-Dominguez M, Yu MC, Ross RK. Tobacco use in relation to renal cell carcinoma. Cancer Epidemiol. Biomarkers Prev. 1998; 7: 429–33. 50 Peces R, Martínez-Ara J, Miguel JL et al. Renal cell carcinoma co-existent with other renal disease: clinico-pathological features in pre-dialysis patients and those receiving dialysis or renal transplantation. Nephrol. Dial. Transplant. 2004; 19: 2789–96. 51 Bijol V, Mendez GP, Hurwitz S, Rennke HG, Nosé V. Evaluation of the nonneoplastic pathology in tumor nephrectomy specimens: predicting the risk of progressive renal failure. Am. J. Surg. Pathol. 2006; 30: 575–84. 52 Truong LD, Shen SS, Park MH, Krishnan B. Diagnosing nonneoplastic lesions in nephrectomy specimens. Arch. Pathol. Lab. Med. 2009; 133: 189–200. 53 Bonsib SM, Pei Y. The non-neoplastic kidney in tumor nephrectomy specimens: what can it show and what is important? Adv. Anat. Pathol. 2010; 17: 235–50. 54 Ruggenenti P, Remuzzi G. Nephropathy of type-2 diabetes mellitus. J. Am. Soc. Nephrol. 1998; 9: 2157–69. 55 Osterby R. Glomerular structural changes in type 1 (insulin-dependent) diabetes mellitus: causes, consequences, and prevention. Diabetologia 1992; 35: 803–12. 56 Drummond K, Mauer M, International Diabetic Nephropathy Study Group. The early natural history of nephropathy in type 1 diabetes: II. Early renal structural changes in type 1 diabetes. Diabetes 2002; 51: 1580–7. 57 Stout LC, Kumar S, Whorton EB. Insudative lesions – their pathogenesis and association with glomerular obsolescence in diabetes: a dynamic hypothesis based on single views of advancing human diabetic nephropathy. Hum. Pathol. 1994; 25: 1213–27.
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