|Year : 2020 | Volume
| Issue : 2 | Page : 60-66
Analysis of nonneoplastic medical renal diseases in tumor nephrectomy specimens predicting future renal function
Anusmita Tripathy1, Maya Menon2, Balasubramaniam Ramakrishnan3, Arshee Badar4
1 Department of Pathology, SCB Medical College, Cuttack, Odisha, India
2 Department of Histopathology, Apollo Hospitals, Chennai, Tamil Nadu, India
3 Department of Biostatistics, Apollo Hospitals, Chennai, Tamil Nadu, India
4 Department of Pathology, Apollo Hospitals, Chennai, Tamil Nadu, India
|Date of Submission||17-Sep-2019|
|Date of Decision||06-Jul-2020|
|Date of Acceptance||21-Jul-2020|
|Date of Web Publication||17-Aug-2020|
Plot 955, Samantarapur, Old Town, Bhubaneswar - 751 002, Odisha
Source of Support: None, Conflict of Interest: None
Introduction: Nephrectomy for renal tumor leads to decline in global renal function. The pattern of pathological changes in uninvolved renal parenchyma of nephrectomy specimen is useful to predict the future renal function. Aim: The aim of the present study is to analyze the spectrum of medical renal diseases in nonneoplastic renal parenchyma of tumors nephrectomies and preexisting comorbidities to predict future renal function. Materials and Methods: A prospective study was conducted on 100 nephrectomy patients during the period from November 2015 to February 2019. Nonneoplastic renal parenchyma of nephrectomy specimens was analyzed for the presence of any pathological changes. Serum creatinine levels at preoperative and 6 months after nephrectomy were recorded. Results: Medical renal disease in uninvolved renal parenchyma detected in 52% of cases and arterionephrosclerosis (28%) followed by diabetic nephropathy (10%) was most frequently seen. Diabetes mellitus (DM) and/or hypertension (HTN) were significantly associated with increase in arteriolar hyalinosis, glomerulosclerosis, and interstitial fibrosis/tubular atrophy (P < 0.05). The median follow-up for patients attending 6 months after nephrectomy (n = 41) was 20 months with the mean increase in serum creatinine level from the preoperative period of 0.48 mg/dl (P = 0.011). The increase in serum creatinine level from the preoperative period to 6 months after nephrectomy was significant for patients with preexisting DM alone (P = 0.033), DM along with HTN together (P = 0.008), and patients with diabetic nephropathy (P = 0.0001). Three patients developed chronic kidney disease during follow-up (n = 41). Conclusions: Preexisting DM and HTN should be carefully handled in renal tumor patients and routine evaluation of the nonneoplastic renal parenchyma of nephrectomy specimens is necessary to detect the presence of subclinical renal disease for early treatment measures to reduce future morbidity.
Keywords: Comorbidities, nephrectomy specimen, nonneoplastic pathological changes, renal functions
|How to cite this article:|
Tripathy A, Menon M, Ramakrishnan B, Badar A. Analysis of nonneoplastic medical renal diseases in tumor nephrectomy specimens predicting future renal function. Oncol J India 2020;4:60-6
|How to cite this URL:|
Tripathy A, Menon M, Ramakrishnan B, Badar A. Analysis of nonneoplastic medical renal diseases in tumor nephrectomy specimens predicting future renal function. Oncol J India [serial online] 2020 [cited 2020 Oct 31];4:60-6. Available from: https://www.ojionline.org/text.asp?2020/4/2/60/291903
| Introduction|| |
Radical nephrectomy performed for the renal cell carcinoma (RCC) leads to adaptive hyperfiltration in the remaining kidney due to the loss of a functioning kidney. It results in the development of glomerulosclerosis (GS) and may affect global renal functions significantly. It can be further exacerbated due to the presence of diabetes mellitus (DM) and hypertension (HTN). The pathological changes in nonneoplastic renal parenchyma may predict the renal function of the remaining kidney.
The presence of chronic kidney disease (CKD) adversely affect the patient after nephrectomy in >30% of cases. In recent times, the importance of assessing the uninvolved renal parenchyma of kidneys removed for renal tumors has been stressed. The synoptic reports established by the College of American Pathologist require that the nonneoplastic renal parenchyma should be evaluated and reported for every renal malignancy. This was not earlier emphasized as grading and staging of tumors alone were given importance by practicing surgical pathologists. The common renal parenchymal diseases found in nephrectomy specimens with renal tumors are hypertensive nephrosclerosis and diabetic nephropathy.
The finding of proteinuria during the preoperative evaluation should bring the suspicion of a coexisting medical renal disease in a tumor kidney and in such cases nephrologist consultation must be done before and after the surgery. A greater likelihood of decrease in renal function has been noticed after radical nephrectomy when compared with partial nephrectomy. To prevent morbidity of the patient, nephrologists are being frequently consulted by urology and oncology team in the management of patients with renal mass, especially when there is the presence of comorbid conditions such as diabetes, CKD, and HTN.
With this background, the present prospective study was conducted to evaluate the spectrum of pathological changes in nonneoplastic renal parenchyma among nephrectomy specimen, to analyze their association with preexisting comorbidities and to predict future renal function.
| Materials and Methods|| |
The present prospective, observational study was conducted in the department of histopathology in collaboration with the department of Urology at Apollo Hospitals, Chennai, over a period from November 2015 to February 2019. The patients undergoing nephrectomy from November 2015 to November 2017 were included and followed-up up to February 2019. The Institutional Ethics Committee approval was obtained (registration number: ECR/37/Inst/TN/2013). The written informed consent was obtained from all the patients of age >18 years undergoing nephrectomy enrolled in the study.
Since our study's primary objective is to find out proportion of nonneoplastic kidney diseases in nephrectomy specimens with renal tumors, we kept 15% (adapted from Salvatore et al.) as the medical renal disease identified in renal tumor nephrectomy specimens for the workup of sample size calculation. The formula used for sample size calculation was n = z2pq/d2 where z = standard normal deviate at 95% confidence level, i.e., 1.96, P = proportion of patients having nonneoplastic medical renal disease in renal tumor nephrectomy specimen, i.e., 15%, q= 1 − p i.e., 85%, and d = clinical allowable error, i.e., 7%. Using this formula, a sample size of 100 cases was taken for the study.
Hundred nephrectomy specimens with renal tumor, which were received in a fresh state from the urology department were taken as the study population. The known cases of end-stage renal disease were excluded. Specimens with no grossly visible normal renal parenchyma, i.e., <1 cm and < 0.5 cm of surrounding nonneoplastic renal parenchyma for radical and partial nephrectomies, respectively, were excluded from the study population.
In fresh state, a section of nonneoplastic renal cortical parenchyma lying away from tumor was taken from all nephrectomy specimen and sent fresh in a piece of gauze moistened in saline for direct immunofluorescence testing. After submission of the fresh tissue, all the tumor nephrectomy specimens were fixed with 10% neutral-buffered formalin and studied under light microscopy with Harris hematoxylin and eosin, periodic acid Schiff and periodic acid Schiff Methenamine stain. All the slides were reviewed by nephropathologists blinded for patient's clinical and tumor pathological information.
The percentage of global GS was categorized into two groups, i.e., 0%–5% and >5% as adapted from Salvatore et al. The degree of interstitial fibrosis/tubular atrophy (IF/TA) was categorized into four groups, i.e., <10%, 10%–25%, 26%–50%, and >50%. Arteriosclerosis was graded semiquantitatively into the three categories based on the percentage of narrowing of the arterial lumen due to intimal and medial thickening such as mild (<25% narrowing), moderate (25%–50% narrowing), and severe (>50% narrowing)., Arteriolosclerosis was graded similar to the arteriosclerosis on the basis of luminal narrowing of glomerular hilar arterioles, typically medial hypertrophy with thickened layers of smooth muscle such as mild (<25% narrowing), moderate (25%–50% narrowing), and severe (>50% narrowing). Hyalinosis in arteriolar intima was also documented whether present or absent.
The history of medical disease such as DM and HTN, and laboratory findings such as urine routine analysis and serum creatinine levels were obtained from the hospital's medical records and entered in the pro forma. The preoperative serum creatinine levels taken in the present study were done within 1 week of nephrectomy procedure, whereas the postoperative serum creatinine levels were recorded after 6 months follow-up during the study period. The changes in postoperative serum creatinine in comparison to that of preoperative values and their association with medical renal diseases were calculated. The data on urine protein analysis for all cases were recorded within 1 week of the preoperative period to bring suspicion of a coexisting medical renal disease in a tumor kidney.
The diagnosis of medical renal diseases in the nonneoplastic renal parenchyma was made by correlating the clinical details, light microscopic, and immunofluorescent microscopic findings.
The light microscopic features of arterionephrosclerosis included thickened and hyalinized blood vessel wall, GS, IF, and TA. The features of diabetic nephropathy include diffuse/nodular GS, afferent and efferent arteriolar hyalinosis (AH), etc., immunofluorescene microscopic finding of immunoglobulin A (IgA) nephropathy included the presence of more than 2+ mesangial IgA deposits and granular capillary loop deposits of IgG in membranous nephropathy.
All the continuous variables were assessed for the normality using the Shapiro–Wilk's test. If the variables were normally distributed, they were expressed as mean ± standard deviation otherwise as median + interquartile range. Categorical variables were represented as percentage. The comparison of categorical variables was done by either the Chi-square test or Fisher's exact test. The comparison of continuous variables was done by the independent sample t-test. Data entry was done in MS Excel Spreadsheet. Data analysis and validation were done by the IBM SPSS statistics for Windows, Version 25.0, (Armonk, NY: IBM Crop.). All the P < 0.05 was considered as statistically significant. Pre- and postnormally distributed continuous variables were compared by the paired t-test.
| Results|| |
In our study, 89 out of 100 cases underwent radical nephrectomy, and rest 11 cases underwent partial nephrectomy. The baseline clinical and tumor characteristics are presented in [Table 1]. The mean age of presentation was 54.3 ± 11.9 years within the age range of 48–62 years. The majority of patients were male with a male-to-female ratio of 3.17:1. More than half of our study population had comorbid conditions which included 42% of patients with a clinical history of HTN and 34% with diabetes. RCC was the most common histological diagnosis for the renal masses consisting of 92% cases (clear-cell variant: 76% vs. papillary variant: 14% vs. chromophobe variant: 2%) and followed by others.
The histopathological changes of nonneoplastic renal parenchyma are mentioned in [Table 2]. >5% GS, >50% IF/TA, severe arteriosclerosis, severe arteriolosclerosis, and presence of AH were seen in 19%, 1%, 3%, 6%, and 30% cases, respectively.
|Table 2: Histopathological changes of nonneoplastic renal parenchyma with their frequency|
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Fifty-two percent of cases had medical renal disease in nonneoplastic renal parenchyma out of which the most common was arterionephrosclerosis (28%) followed by diabetic nephropathy (10%), IgA nephropathy (5%), pyelonephritis (2%), IgA nephropathy coexisting with diabetic nephropathy (2%), acute tubular injury (3%), membranous nephropathy (1%), and focal segmental GS (1%). The rest 48% had minimal morphological changes defined as <5% global GS, <10% IF, and TA and mild vascular sclerosis.
In arterionephrosclerosis cases, variable histopathological changes were noted [Figure 1] with normal preoperative and follow-up serum creatinine levels. The diabetic nephropathy cases had variable histological appearances ranging from mild mesangial GS to nodular mesangial GS [Figure 2]. Five diabetic nephropathy cases had preoperative proteinuria and all of these had >5% global GS. Two cases had 10%–25% IF/TA, 2 had 26%–50% IF/TA, and 1 had >50% IF/TA. Four out of 5 IgA nephropathy cases had minimal pathological changes in nonneoplastic renal parenchyma on light microscopy resembling normal renal parenchyma, and the rest 1 case had <5% global GS and 10%–25% IF/TA. We found two cases of IgA nephropathy coexisting with diabetic nephropathy. On immunofluorescence microscopy, all cases had >2 + intensity and mesangial deposits of IgA [Figure 3]a. We found 1 case of membranous glomerulopathy which on immunofluorescence microscopy revealed granular capillary loop deposits of IgG [Figure 3]b. We found one case of focal segmental GS [Figure 4].
|Figure 1: Ischemic shrinkage of glomerulus (black arrow) and ischemic glomerular obsolescence (white arrow) in arterionephrosclerosis (×40, Periodic acid schiff stain)|
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|Figure 2: Kimmelstiel-Wilson mesangial nodule in diabetic glomerulopathy (×400, Periodic Acid Schiff stain)|
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|Figure 3: (a) Mesangial IgA deposits in IgA nephropathy (anti-IgA immunofluorescence, ×100), and (b) Granular capillary loop deposits of IgG in membranous nephropathy (anti-IgG immunofluorescence, ×100)|
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|Figure 4: Focal segmental glomerulosclerosis (shown in arrow) (×400, Periodic Acid Schiff stain)|
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DM had a significant association with the presence of AH (P < 0.001), GS (P < 0.001), and IF/TA (P < 0.001). The presence of both DM and HTN also had a high impact on AH (P = 0.002), GS (P < 0.001), and IF/TA (P < 0.001). Similarly, in our study, HTN alone had association with AH (P = 0.005), GS (P = 0.010), and IF/TA (P = 0.001) [Table 3].
|Table 3: Association of diabetes mellitus and hypertension with nonneoplastic pathological renal changes|
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Forty-one patients could be followed up after 6 months of nephrectomy with a median duration of 20 months. The mean increase in serum creatinine level from the preoperative to postoperative follow-up for 41 patients was 0.48 mg/dl which was statistically significant (P = 0.011). We found a rise in serum creatinine level from preoperative to 6 months after nephrectomy among the patients having comorbid conditions which was significant for DM alone (P = 0.033) or DM along with HTN together (P = 0.008) [Table 4]. Also, there was a trend in rise of such creatinine level among patients having HTN alone although statistically insignificant. In patients having diabetic nephropathy, we found a mean increase of 1.63 ± 1.8 mg/dl in serum creatinine level from preoperative to 6 months after nephrectomy which was statistically significant (P = 0.0001). Radical nephrectomy patients (n = 36) had a higher trend toward increased mean serum creatinine levels from the preoperative to the postoperative period when compared to partial nephrectomy cases (n = 5) i.e., 0.54 ± 1.0 mg/dl versus 0.34 ± 0.4 mg/dl with the P = 0.676. After a follow-up of 6 months, three patients developed adverse renal outcomes in terms of CKD and under dialysis. Among these three cases, 2 had diabetic nephropathy and 1 had diabetic nephropathy with IgA nephropathy.
|Table 4: Change in serum creatinine level after 6 months follow-up in relation to preexisting comorbidities|
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| Discussion|| |
Nonneoplastic renal parenchymal pathological changes in tumor nephrectomies are the most important prognostic determinants for renal function of the remaining kidney and can be easily missed by a surgical pathologist. The awareness about its assessment is important among surgical pathologists and urologists. Nephrectomy due to renal mass leads to hyperfiltration, intraglomerular HTN, and glomerulopathy of the remaining kidney which may results in renal insufficiency. The presence of preexisting comorbidities such as HTN and DM further complicates the hyperfiltration of the remaining kidney contributing to progressive impairment of renal function. We had conducted this study to evaluate the spectrum of medical renal diseases in nephrectomy specimen to predict future renal function and their association with comorbid conditions such as DM and HTN.
We used PAS and methenamine stains to enhance the glomerular architecture and renal parenchyma elements and better identification of any abnormalities. The incidence of nonneoplastic renal parenchymal pathological changes in nephrectomy patients varies among different studies from 5.7% to 74.5% and majority related to vascular disease or DM.,,,,, We found 52% of cases with medical renal disease in nonneoplastic renal parenchyma, of which the most common was arterionephrosclerosis (28%) followed by diabetic nephropathy (10%). As in our study, DM and HTN were found in >50% of cases, diabetic nephropathy, and vascular diseases would be expected common findings. Salvatore et al. in a retrospective analysis detected medical renal diseases in 57 out of 381 nephrectomy specimens (15%) of which diabetic nephropathy (28 cases) was the most common followed by hypertensive nephropathy (11 cases). Bijol et al. in their study reported >60% of nephrectomy cases with nonneoplastic renal parenchymal changes mostly related to vascular disease or DM (28% had parenchymal scarring with marked vascular changes and 24% had changes of diabetic nephropathy). Wee et al. in a retrospective analysis found 74.5% of nephrectomy cases with definitive pathological abnormalities, among which common changes were glomerular abnormalities consisting of 29.4%, diabetic nephropathy (27.5%), and vascular nephropathy (21.6%). Renal malignancy specifically RCC may be associated with paraneoplastic glomerular diseases such as IgA nephropathy, focal segmental GS, membranous glomerulonephropathy, minimal change disease, secondary amyloidosis, and crescentic glomerulonephritis.,, Worldwide, IgA nephropathy is the most common glomerular disease. We found 7% diagnostic rate (7/100 cases) for IgA nephropathy and 2 of these 7 cases had coexistence with diabetic nephropathy. Bijol et al. reported only two cases of IgA nephropathy out of 110 nephrectomy specimens analyzed.
The course of IgA nephropathy is highly variable ranging from a totally benign condition to rapidly progressive renal failure. In our study, all IgA nephropathy cases were clinically silent with normal preoperative serum creatinine levels. Postoperatively, only 1 case was found to have raised serum creatinine of 2.5 mg/dl after 2 years of radical nephrectomy. Rest all IgA nephropathy cases could not be followed up after nephrectomy. We had two cases of diabetic nephropathy coexisting with IgA nephropathy. 1 case preoperatively had serum creatinine 1.7 mg/dl without proteinuria, and on follow-up, the serum creatinine was found to be 5.6 mg/dl after 23 months. The other case had normal serum creatinine preoperatively and on follow-up. There was no significant pathological finding in nonneoplastic renal parenchyma under light microscopy. Immunofluorescence study on nonneoplastic renal parenchyma has helped in detecting IgA nephropathy which can be missed when they are clinically silent and have normal appearing renal parenchyma under light microscopy. Wee et al. had 17.6% of cases diagnosed with IgA nephropathy with clinically asymptomatic similar to our findings and preserved renal function during 3–36 months follow-up period. Magyarlaki et al. in a study found 11 out of 60 cases of RCC with IgA nephropathy, and among which six patients had the regression of preoperative proteinuria and hematuria within a 2–3-month follow-up after nephrectomy.
We found only one case of focal segmental GS detected in the radical nephrectomy specimen of a 36-year-old female who had no comorbid conditions such as diabetes and HTN. Preoperatively, the patient had no proteinuria and the serum creatinine level was normal but, 6-months postoperative status was not available for this patient. Unlike our study, Salvatore et al. detected seven patients with focal segmental GS among which 5 had proteinuria and in 2 data were not available. Magyarlaki et al. detected focal segmental GS in 8.3% of renal tumor cases.
Membranous nephropathy may be rarely seen in nephrectomy specimen of RCC due to damage of glomerular cells by the deposition of tumor immune complex and may cause nephrotic syndrome.,,, We found only one case of membranous nephropathy from partial nephrectomy specimen of a 32-year-old female which had nephrotic range proteinuria and normal serum creatinine levels in both the preoperative and postoperative period. Salvatore et al. also reported only one case of membranous glomerulonephritis with nephrotic range proteinuria from 381 nephrectomy specimens analyzed supporting our data. Wee et al. found 1 case of membranous nephropathy which had no proteinuria initially but later developed de novo CKD after nephrectomy. Few case reports of RCC associated with membranous nephropathy are reported in the literature in which nephrotic syndrome resolved after resection of tumor.,,,
We found 48% of cases with minimal pathological changes. Furthermore, Salvatore et al. had 30.7% of cases with minimal pathologic change and Bazzi et al. found 46% of kidney tumors with no abnormalities in the nontumorous parenchyma.,
Diabetes and HTN are more commonly seen in elderly patients. Several studies reported an increase incidence of RCC in patients with these comorbidities suggesting a higher chance of detecting medical renal diseases in patients with renal neoplasm., About 20% of RCC patients have diabetes. We found >50% of the study population with comorbid conditions such as 42% of patients had a clinical history of HTN and 34% of patients with DM. Wee et al. in a retrospective analysis also found 51% and 39.2% of patients with HTN and DM, respectively, supporting our data. Diabetic nephropathy may have superimposed other glomerular diseases such as membranous nephropathy and IgA nephropathy. Orfila et al. found that 15.15% of diabetic cases had IgA nephropathy associated with diabetic nephropathy. We found two cases of diabetic nephropathy coexisting with IgA nephropathy, 1 case had azotemia with >5% global GS and 26%–50% IF/TA while the other case had only trace proteinuria with normal creatinine levels having ≤5% global GS and 10%–25% IF/TA. In our study, the presence of DM or HTN had a significant association with the presence of AH, GS, and IF/TA (P ≤ 0.05). We found that both DM and HTN together also had a high impact on AH, GS, and IF/TA (P ≤ 0.05). Birendra et al. in their prospective study also found significant adverse renal parenchymal changes such as AH, global GS, and IF/TA in the presence of DM alone when compared to nondiabetic population and also in the presence of both DM and HTN. Whereas, they found no significant parenchymal changes for the presence of HTN alone.
We found an increase in serum creatinine level from preoperative to 6 months after nephrectomy in patients with diabetic nephropathy (P = 0.0001). After a minimum follow-up of 12 months after nephrectomy, Salvatore et al. reported significant increase in postoperative serum creatinine levels for patients with severe arteriosclerosis or arteriolosclerosis, >5% global GS, or >10% IF/TA. A study showed significant change in serum creatinine level from the preoperative period to 6 months postoperative among the patients with severe nonneoplastic parenchymal pathological findings such as parenchymal scarring >20%, global GS, and advanced diffuse diabetic GS.
Furthermore, multiple studies reported substantial decline in renal function among patients after radical nephrectomy when compared to patients after partial nephrectomy. Klarenbach et al. in a study found that radical nephrectomy approximately doubled the risk of adverse renal outcomes in terms of end-stage renal disease, urgent dialysis, CKD, or rapidly progressive CKD when compared to partial nephrectomy. After a follow-up of 6 months, we found an increasing trend in postoperative serum creatinine levels among radical nephrectomy patients when compared to partial nephrectomy patients, although statistically insignificant. Such insignificant result possibly could be due to a smaller number of sample size for partial nephrectomy patients when compared to radical nephrectomy patients. Furthermore, after a follow-up of 6 months, we found only three out of 41 patients with adverse renal outcome, i.e., with CKD and radical nephrectomy were performed in these three cases. Our study had some limitations such as a small sample size and short follow-up period. Hence, further large sample-sized prospective studies with long-term follow-up are necessary to provide a clear image on early recognition of the patients at risk for CKD.
| Conclusions|| |
Medical renal diseases are frequently seen in tumor nephrectomy patients. Patients with preexisting comorbidities such as DM and HTN are at increased risk for postoperative nonneoplastic renal parenchymal pathological changes along with decline in renal function. There is a need to aim for the preservation of renal function among patients undergoing nephrectomy due to renal tumors. Therefore, a thorough preoperative clinical assessment for comorbidities and examination of nonneoplastic renal parenchyma along with long-term follow-up is necessary to predict the patients at risk of progressive renal impairment after nephrectomy and treatment measures with better care can be taken.
Special thanks to S. Anitha, the senior secretary of department of Histopathology, Apollo Hospitals, Chennai, for her contribution in data collection.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]