From kidney injury to kidney cancer
Authors: Anna Julie Peired, Elena Lazzeri, Francesco Guzzi, Hans-Joachim Anders, Paola Romagnani
Journal: Kidney International (2021)

Epidemiologic studies document strong associations between acute or chronic kidney injury and kidney tumors. However, whether these associations are linked by causation, and in which direction, is unclear. Accumulating data from basic and clinical research now shed light on this issue and prompt us to propose a new pathophysiological concept with immanent implications in the management of patients with kidney disease and patients with kidney tumors. As a central paradigm, this review proposes the mechanisms of kidney damage and repair that are active during acute kidney injury but also during persistent injuries in chronic kidney disease as triggers of DNA damage, promoting the expansion of (pre-)malignant cell clones. As renal progenitors have been identified by different studies as the cell of origin for several benign and malignant kidney tumors, we discuss how the different types of kidney tumors relate to renal progenitors at specific sites of injury and to germline or somatic mutations in distinct signaling pathways. We explain how known risk factors for kidney cancer rather represent risk factors for kidney injury as an upstream cause of cancer. Finally, we propose a new role for nephrologists in kidney cancer (i.e., the primary and secondary prevention and treatment of kidney injury to reduce incidence, prevalence, and recurrence of kidney cancer). Epidemiologic studies document strong associations between acute or chronic kidney injury and kidney tumors. However, whether these associations are linked by causation, and in which direction, is unclear. Accumulating data from basic and clinical research now shed light on this issue and prompt us to propose a new pathophysiological concept with immanent implications in the management of patients with kidney disease and patients with kidney tumors. As a central paradigm, this review proposes the mechanisms of kidney damage and repair that are active during acute kidney injury but also during persistent injuries in chronic kidney disease as triggers of DNA damage, promoting the expansion of (pre-)malignant cell clones. As renal progenitors have been identified by different studies as the cell of origin for several benign and malignant kidney tumors, we discuss how the different types of kidney tumors relate to renal progenitors at specific sites of injury and to germline or somatic mutations in distinct signaling pathways. We explain how known risk factors for kidney cancer rather represent risk factors for kidney injury as an upstream cause of cancer. Finally, we propose a new role for nephrologists in kidney cancer (i.e., the primary and secondary prevention and treatment of kidney injury to reduce incidence, prevalence, and recurrence of kidney cancer). Cancerogenesis is a complex process involving germline and/or somatic mutations leading to an uncontrolled expansion of mutated cells. Frequently, this occurs in a series of steps in which numerous combinations of mutations only gradually pass the threshold for unrestricted cell growth.1Kiwerska K. Szyfter K. DNA repair in cancer initiation, progression, and therapy-a double-edged sword.J Appl Genet. 2019; 60: 329-334Crossref PubMed Scopus (0) Google Scholar Tissue injury is a known trigger of cancerogenesis for 2 reasons: (i) its potential to induce DNA damage and somatic mutations, especially in tissue-resident long-lived stem cells2Tomasetti C. Vogelstein B. Cancer etiology: variation in cancer risk among tissues can be explained by the number of stem cell divisions.Science. 2015; 347: 78-81Crossref PubMed Scopus (1076) Google Scholar; and (ii) its potential to promote the expansion of such mutated cells during the process of tissue repair.3Basu A.K. DNA damage, mutagenesis and cancer.Int J Mol Sci. 2018; 19: 970Crossref PubMed Scopus (134) Google Scholar For example, these 2 mechanisms contribute to inflammatory bowel disease–related colorectal cancer4Greuter T. Vavricka S. König A.O. et al.Malignancies in inflammatory bowel disease.Digestion. 2020; 101: 136-145Crossref PubMed Scopus (1) Google Scholar and to lung cancer related to exposures to toxic smokes and dust particulates,5Lipfert F.W. Wyzga R.E. Longitudinal relationships between lung cancer mortality rates, smoking, and ambient air quality: a comprehensive review and analysis.Crit Rev Toxicol. 2019; 49: 790-818Crossref PubMed Scopus (0) Google Scholar atrophic gastritis–related gastric cancer,6Vannella L. Lahner E. Osborn J. et al.Systematic review: gastric cancer incidence in pernicious anaemia.Aliment Pharmacol Ther. 2013; 37: 375-382Crossref PubMed Scopus (97) Google Scholar and cirrhosis-related hepatocellular carcinoma.7Sangiovanni A. Prati G.M. Fasani P. et al.The natural history of compensated cirrhosis due to hepatitis C virus: a 17-year cohort study of 214 patients.Hepatology. 2006; 43: 1303-1310Crossref PubMed Scopus (457) Google Scholar Numerous epidemiologic studies report the association between chronic kidney disease (CKD) and kidney cancer (Table 18Na S.Y. Sung J.Y. Chang J.H. et al.Chronic kidney disease in cancer patients: an independent predictor of cancer-specific mortality.Am J Nephrol. 2011; 33: 121-130Crossref PubMed Scopus (58) Google Scholar, 9Christiansen C.F. Johansen M.B. Langeberg W.J. et al.Incidence of acute kidney injury in cancer patients: a Danish population-based cohort study.Eur J Intern Med. 2011; 22: 399-406Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 10Kitchlu A. McArthur E. Amir E. et al.Acute kidney injury in patients receiving systemic treatment for cancer: a population-based cohort study.J Natl Cancer Inst. 2019; 111: 727-736Crossref PubMed Scopus (30) Google Scholar, 11Kim W.H. Shin K.W. Ji S.H. et al.Robust association between acute kidney injury after radical nephrectomy and long-term renal function.J Clin Med. 2020; 9: 619Crossref Google Scholar, 12Klarenbach S. Moore R.B. Chapman D.W. et al.Adverse renal outcomes in subjects undergoing nephrectomy for renal tumors: a population-based analysis.Eur Urol. 2011; 59: 333-339Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 13Hung P.H. Tsai H.B. Hung K.Y. et al.Increased risk of end-stage renal disease in patients with renal cell carcinoma: a 12-year nationwide follow-up study.Medicine (Baltimore). 2014; 93: e52Crossref PubMed Google Scholar, 14Cho A. Lee J.E. Kwon G.Y. et al.Post-operative acute kidney injury in patients with renal cell carcinoma is a potent risk factor for new-onset chronic kidney disease after radical nephrectomy.Nephrol Dial Transplant. 2011; 26: 3496-3501Crossref PubMed Scopus (65) Google Scholar, 15Sun M. Bianchi M. Hansen J. et al.Chronic kidney disease after nephrectomy in patients with small renal masses: a retrospective observational analysis.Eur Urol. 2012; 62: 696-703Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). Although both occur preferably in the second half of life, it remains unclear whether and how these associations are linked by causation. For example, causation may be one way because tumor therapy, including surgery, and antiangiogenic agents or mechanistic target of rapamycin (mTOR) and immune checkpoint inhibitors involve an increased risk of acute kidney injury (AKI) and CKD.16Erman M. Benekli M. Basaran M. et al.Renal cell cancer: overview of the current therapeutic landscape.Expert Rev Anticancer Ther. 2016; 16: 955-968Crossref PubMed Scopus (11) Google Scholar,17Porta C. Cosmai L. Leibovich B.C. et al.The adjuvant treatment of kidney cancer: a multidisciplinary outlook.Nat Rev Nephrol. 2019; 15: 423-433Crossref PubMed Scopus (25) Google Scholar Similarly, whether kidney injury causes kidney cancer is not clear at all, although some studies suggest that kidney cancer develops following an AKI episode or after years of CKD at the stage of kidney failure (Table 218Weng P.H. Hung K.Y. Huang H.L. et al.Cancer-specific mortality in chronic kidney disease: longitudinal follow-up of a large cohort.Clin J Am Soc Nephrol. 2011; 6: 1121-1128Crossref PubMed Scopus (100) Google Scholar, 19Christensson A. Savage C. Sjoberg D.D. et al.Association of cancer with moderately impaired renal function at baseline in a large, representative, population-based cohort followed for up to 30 years.Int J Cancer. 2013; 133: 1452-1458Crossref PubMed Scopus (50) Google Scholar, 20Lowrance W.T. Ordonez J. Udaltsova N. et al.CKD and the risk of incident cancer.J Am Soc Nephrol. 2014; 25: 2327-2334Crossref PubMed Scopus (113) Google Scholar, 21Stewart J.H. Buccianti G. Agodoa L. et al.Cancers of the kidney and urinary tract in patients on dialysis for end-stage renal disease: analysis of data from the United States, Europe, and Australia and New Zealand.J Am Soc Nephrol. 2003; 14: 197-207Crossref PubMed Scopus (226) Google Scholar, 22Denton M.D. Magee C.C. Ovuworie C. et al.Prevalence of renal cell carcinoma in patients with ESRD pre-transplantation: a pathologic analysis.Kidney Int. 2002; 61: 2201-2209Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar, 23Yanik E.L. Clarke C.A. Snyder J.J. et al.Variation in cancer incidence among patients with ESRD during kidney function and nonfunction intervals.J Am Soc Nephrol. 2016; 27: 1495-1504Crossref PubMed Google Scholar, 24Karami S. Yanik E.L. Moore L.E. et al.Risk of renal cell carcinoma among kidney transplant recipients in the United States.Am J Transplant. 2016; 16: 3479-3489Crossref PubMed Scopus (34) Google Scholar, 25Peired A.J. Antonelli G. Angelotti M.L. et al.Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells.Sci Transl Med. 2020; 12eaaw6003Crossref PubMed Scopus (15) Google Scholar). In this review, we discuss the role of kidney injury as a driver of kidney cancer. Starting out with epidemiologic and genetic evidence, we discuss the evolving experimental support for kidney injury as a trigger of DNA damage and clonal proliferation of mutated kidney cells in different kidney compartments, determining the tumor histotype. We discuss the recent insights on the putative cells of origin for benign and malignant kidney tumors and explain how injury-mediated alterations in the activation of distinct signaling pathways contribute to the different histotypes of kidney tumors. We further explore how the intrinsic mechanisms of kidney repair that transiently operate on AKI episodes and that persistently operate in CKD promote tumor growth and tumor recurrence. Finally, we suggest that prevention of AKI and CKD is the best way to stop renal cell carcinoma (RCC) development and avoid its consequences. This concept of bidirectional causal relationship between kidney disease and kidney tumors calls for a central role of the nephrologist in prevention and treatment of patients with kidney cancer.Table 1Epidemiological evidence that kidney cancer associates with kidney injury: increased risk for kidney disease in patients with kidney cancerExposure (risk factor or disease)OutcomeRisk [95% CI]Strength of evidenceReferenceKidney cancerCKD (stage ≥3)21.4%Crude prevalence at diagnosis8Na S.Y. Sung J.Y. Chang J.H. et al.Chronic kidney disease in cancer patients: an independent predictor of cancer-specific mortality.Am J Nephrol. 2011; 33: 121-130Crossref PubMed Scopus (58) Google ScholarAKI (+50% sCr)IRR, 2.31 [2.05–2.60]Multivariate analysis9Christiansen C.F. Johansen M.B. Langeberg W.J. et al.Incidence of acute kidney injury in cancer patients: a Danish population-based cohort study.Eur J Intern Med. 2011; 22: 399-406Abstract Full Text Full Text PDF PubMed Scopus (106) Google ScholarAKI (+50% sCr)62.8% [57.6–67.5]5-yr Cumulative incidence9Christiansen C.F. Johansen M.B. Langeberg W.J. et al.Incidence of acute kidney injury in cancer patients: a Danish population-based cohort study.Eur J Intern Med. 2011; 22: 399-406Abstract Full Text Full Text PDF PubMed Scopus (106) Google ScholarAKI-HA (severe)13.9% [12.1–15.9]5-yr Cumulative incidence10Kitchlu A. McArthur E. Amir E. et al.Acute kidney injury in patients receiving systemic treatment for cancer: a population-based cohort study.J Natl Cancer Inst. 2019; 111: 727-736Crossref PubMed Scopus (30) Google ScholarAKI-D1.7% [1.1–2.7]5-yr Cumulative incidence10Kitchlu A. McArthur E. Amir E. et al.Acute kidney injury in patients receiving systemic treatment for cancer: a population-based cohort study.J Natl Cancer Inst. 2019; 111: 727-736Crossref PubMed Scopus (30) Google ScholarRCCCKD (stage ≥3)40.5%3-yr Crude prevalence11Kim W.H. Shin K.W. Ji S.H. et al.Robust association between acute kidney injury after radical nephrectomy and long-term renal function.J Clin Med. 2020; 9: 619Crossref Google ScholarCKD (stage ≥4)7.3%32-mo Crude prevalence12Klarenbach S. Moore R.B. Chapman D.W. et al.Adverse renal outcomes in subjects undergoing nephrectomy for renal tumors: a population-based analysis.Eur Urol. 2011; 59: 333-339Abstract Full Text Full Text PDF PubMed Scopus (65) Google ScholarRapid progressive CKD2.1%32-mo Crude prevalence12Klarenbach S. Moore R.B. Chapman D.W. et al.Adverse renal outcomes in subjects undergoing nephrectomy for renal tumors: a population-based analysis.Eur Urol. 2011; 59: 333-339Abstract Full Text Full Text PDF PubMed Scopus (65) Google ScholarESKDHR, 5.36 [4.37–7.24]Multivariable analysis13Hung P.H. Tsai H.B. Hung K.Y. et al.Increased risk of end-stage renal disease in patients with renal cell carcinoma: a 12-year nationwide follow-up study.Medicine (Baltimore). 2014; 93: e52Crossref PubMed Google ScholarESKD (men)HR, 4.79 [3.37–6.82]Multivariate analysis13Hung P.H. Tsai H.B. Hung K.Y. et al.Increased risk of end-stage renal disease in patients with renal cell carcinoma: a 12-year nationwide follow-up study.Medicine (Baltimore). 2014; 93: e52Crossref PubMed Google ScholarESKD (women)HR, 6.95 [4.82–10.1]Multivariate analysis13Hung P.H. Tsai H.B. Hung K.Y. et al.Increased risk of end-stage renal disease in patients with renal cell carcinoma: a 12-year nationwide follow-up study.Medicine (Baltimore). 2014; 93: e52Crossref PubMed Google ScholarAKI-D or ESKDCP, 2.0%32-mo Crude prevalence12Klarenbach S. Moore R.B. Chapman D.W. et al.Adverse renal outcomes in subjects undergoing nephrectomy for renal tumors: a population-based analysis.Eur Urol. 2011; 59: 333-339Abstract Full Text Full Text PDF PubMed Scopus (65) Google ScholarPostoperative AKICP, 33.7%Crude prevalence14Cho A. Lee J.E. Kwon G.Y. et al.Post-operative acute kidney injury in patients with renal cell carcinoma is a potent risk factor for new-onset chronic kidney disease after radical nephrectomy.Nephrol Dial Transplant. 2011; 26: 3496-3501Crossref PubMed Scopus (65) Google ScholarRCC, RN vs. PNCKD (stage ≥3)HR, 1.9 [1.48–2.45]Multivariate analysis15Sun M. Bianchi M. Hansen J. et al.Chronic kidney disease after nephrectomy in patients with small renal masses: a retrospective observational analysis.Eur Urol. 2012; 62: 696-703Abstract Full Text Full Text PDF PubMed Scopus (117) Google ScholarARFHR, 1.41 [1.12–1.79]Multivariate analysis15Sun M. Bianchi M. Hansen J. et al.Chronic kidney disease after nephrectomy in patients with small renal masses: a retrospective observational analysis.Eur Urol. 2012; 62: 696-703Abstract Full Text Full Text PDF PubMed Scopus (117) Google ScholarAKI, acute kidney injury; ARF, acute renal failure; CKD, chronic kidney disease; CI, cumulative incidence; CP, crude prevalence; ESKD, end-stage kidney disease; D, dialysis; HA, hospital acquired; HR, hazard ratio; IRR, incidence rate ratio; PN, partial nephrectomy; RCC, renal cell carcinoma; RN, radical nephrectomy.Analysis of the literature highlights the link between increased risk for kidney disease in patients with kidney cancer and vice versa, as well as known risk factors for CKD and kidney cancer. Open table in a new tab Table 2Epidemiological evidence that kidney cancer associates with kidney injury: increased risk for kidney cancer in patients with kidney diseaseExposure (risk factor or disease)OutcomeRisk [95% CI]Strength of evidenceReferenceCKD (stage ≥3)Death for kidney cancerHR, 3.30 [1.24–8.81]Multivariate analysis18Weng P.H. Hung K.Y. Huang H.L. et al.Cancer-specific mortality in chronic kidney disease: longitudinal follow-up of a large cohort.Clin J Am Soc Nephrol. 2011; 6: 1121-1128Crossref PubMed Scopus (100) Google ScholarDeath for urinary tract cancerHR, 7.30 [2.48–21.46]Multivariate analysis18Weng P.H. Hung K.Y. Huang H.L. et al.Cancer-specific mortality in chronic kidney disease: longitudinal follow-up of a large cohort.Clin J Am Soc Nephrol. 2011; 6: 1121-1128Crossref PubMed Scopus (100) Google ScholarKidney cancerHR, 3.38 [1.48–7.71]Multivariate analysis19Christensson A. Savage C. Sjoberg D.D. et al.Association of cancer with moderately impaired renal function at baseline in a large, representative, population-based cohort followed for up to 30 years.Int J Cancer. 2013; 133: 1452-1458Crossref PubMed Scopus (50) Google ScholarCKD (stage 3A)RCCHR, 1.39 [1.22–1.58]Multivariate analysis20Lowrance W.T. Ordonez J. Udaltsova N. et al.CKD and the risk of incident cancer.J Am Soc Nephrol. 2014; 25: 2327-2334Crossref PubMed Scopus (113) Google ScholarCKD (stage 3B)RCCHR, 1.81 [1.51–2.17]Multivariate analysis20Lowrance W.T. Ordonez J. Udaltsova N. et al.CKD and the risk of incident cancer.J Am Soc Nephrol. 2014; 25: 2327-2334Crossref PubMed Scopus (113) Google ScholarCKD (stage 4)RCCHR, 2.28 [1.78–2.92]Multivariate analysis20Lowrance W.T. Ordonez J. Udaltsova N. et al.CKD and the risk of incident cancer.J Am Soc Nephrol. 2014; 25: 2327-2334Crossref PubMed Scopus (113) Google ScholarESKD: dialysisKidney cancer3.6 [3.5–3.8]Standardized incidence ratio21Stewart J.H. Buccianti G. Agodoa L. et al.Cancers of the kidney and urinary tract in patients on dialysis for end-stage renal disease: analysis of data from the United States, Europe, and Australia and New Zealand.J Am Soc Nephrol. 2003; 14: 197-207Crossref PubMed Scopus (226) Google ScholarKidney cancer6.8 [5.1–8.9]10-yr Standardized incidence ratio21Stewart J.H. Buccianti G. Agodoa L. et al.Cancers of the kidney and urinary tract in patients on dialysis for end-stage renal disease: analysis of data from the United States, Europe, and Australia and New Zealand.J Am Soc Nephrol. 2003; 14: 197-207Crossref PubMed Scopus (226) Google ScholarRCC4.2%1-yr Crude prevalence22Denton M.D. Magee C.C. Ovuworie C. et al.Prevalence of renal cell carcinoma in patients with ESRD pre-transplantation: a pathologic analysis.Kidney Int. 2002; 61: 2201-2209Abstract Full Text Full Text PDF PubMed Scopus (188) Google ScholarOncocytomas0.6%1-yr Crude prevalence22Denton M.D. Magee C.C. Ovuworie C. et al.Prevalence of renal cell carcinoma in patients with ESRD pre-transplantation: a pathologic analysis.Kidney Int. 2002; 61: 2201-2209Abstract Full Text Full Text PDF PubMed Scopus (188) Google ScholarTransplant vs. ESKDKidney cancerHR, 0.77 [0.70–0.84]Multivariate analysis23Yanik E.L. Clarke C.A. Snyder J.J. et al.Variation in cancer incidence among patients with ESRD during kidney function and nonfunction intervals.J Am Soc Nephrol. 2016; 27: 1495-1504Crossref PubMed Google ScholarTransplantRCC5.68 [5.27–6.13]Standardized incidence ratio24Karami S. Yanik E.L. Moore L.E. et al.Risk of renal cell carcinoma among kidney transplant recipients in the United States.Am J Transplant. 2016; 16: 3479-3489Crossref PubMed Scopus (34) Google ScholarpRCC13.3 [11.5–15.3]Standardized incidence ratio24Karami S. Yanik E.L. Moore L.E. et al.Risk of renal cell carcinoma among kidney transplant recipients in the United States.Am J Transplant. 2016; 16: 3479-3489Crossref PubMed Scopus (34) Google ScholarccRCC3.98 [3.47–4.55]Standardized incidence ratio24Karami S. Yanik E.L. Moore L.E. et al.Risk of renal cell carcinoma among kidney transplant recipients in the United States.Am J Transplant. 2016; 16: 3479-3489Crossref PubMed Scopus (34) Google ScholarAKIpRCCOR, 3.48 [1.14–10.67]Multivariate analysis25Peired A.J. Antonelli G. Angelotti M.L. et al.Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells.Sci Transl Med. 2020; 12eaaw6003Crossref PubMed Scopus (15) Google ScholarccRCCOR, 1.55 [0.51–4.67]Multivariate analysis25Peired A.J. Antonelli G. Angelotti M.L. et al.Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells.Sci Transl Med. 2020; 12eaaw6003Crossref PubMed Scopus (15) Google ScholarPostoperative AKIpRCC recurrenceOR, 7.24 [1.65–31.86]Multivariate analysis25Peired A.J. Antonelli G. Angelotti M.L. et al.Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells.Sci Transl Med. 2020; 12eaaw6003Crossref PubMed Scopus (15) Google ScholarAKI, acute kidney injury; ccRCC, clear cell renal cell carcinoma; CKD, chronic kidney disease; CI, cumulative incidence; ESKD, end-stage kidney disease; HR, hazard ratio; OR, odds ratio; RCC, renal cell carcinoma; pRCC, papillary renal cell carcinoma.Analysis of the literature highlights the link between increased risk for kidney disease in patients with kidney cancer and vice versa, as well as known risk factors for CKD and kidney cancer. Open table in a new tab AKI, acute kidney injury; ARF, acute renal failure; CKD, chronic kidney disease; CI, cumulative incidence; CP, crude prevalence; ESKD, end-stage kidney disease; D, dialysis; HA, hospital acquired; HR, hazard ratio; IRR, incidence rate ratio; PN, partial nephrectomy; RCC, renal cell carcinoma; RN, radical nephrectomy. Analysis of the literature highlights the link between increased risk for kidney disease in patients with kidney cancer and vice versa, as well as known risk factors for CKD and kidney cancer. AKI, acute kidney injury; ccRCC, clear cell renal cell carcinoma; CKD, chronic kidney disease; CI, cumulative incidence; ESKD, end-stage kidney disease; HR, hazard ratio; OR, odds ratio; RCC, renal cell carcinoma; pRCC, papillary renal cell carcinoma. Analysis of the literature highlights the link between increased risk for kidney disease in patients with kidney cancer and vice versa, as well as known risk factors for CKD and kidney cancer. Epidemiologic studies identify associations, but without confirming causation, such associations frequently trigger misleading interpretations. For example, in search for the unknown causes of kidney cancer, epidemiologic studies identified several "risk factors" for which a direct causative link to cancerogenesis is not always obvious (Table 326Renehan A.G. Tyson M. Egger M. et al.Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies.Lancet. 2008; 371: 569-578Abstract Full Text Full Text PDF PubMed Scopus (3345) Google Scholar, 27Johansson M. Carreras-Torres R. Scelo G. et al.The influence of obesity-related factors in the etiology of renal cell carcinoma-a mendelian randomization study.PLoS Med. 2019; 16e1002724Crossref PubMed Scopus (21) Google Scholar, 28Liu X. Sun Q. Hou H. et al.The association between BMI and kidney cancer risk: an updated dose-response meta-analysis in accordance with PRISMA guideline.Medicine (Baltimore). 2018; 97e12860Crossref PubMed Scopus (0) Google Scholar, 29Macleod L.C. Hotaling J.M. Wright J.L. et al.Risk factors for renal cell carcinoma in the VITAL study.J Urol. 2013; 190: 1657-1661Crossref PubMed Scopus (85) Google Scholar, 30Adams K.F. Leitzmann M.F. Albanes D. et al.Body size and renal cell cancer incidence in a large US cohort study.Am J Epidemiol. 2008; 168: 268-277Crossref PubMed Scopus (118) Google Scholar, 31Larsson S.C. Wolk A. Diabetes mellitus and incidence of kidney cancer: a meta-analysis of cohort studies.Diabetologia. 2011; 54: 1013-1018Crossref PubMed Scopus (126) Google Scholar, 32Hidayat K. Du X. Zou S.Y. et al.Blood pressure and kidney cancer risk: meta-analysis of prospective studies.J Hypertens. 2017; 35: 1333-1344Crossref PubMed Scopus (38) Google Scholar, 33Kim C.S. Han K.D. Choi H.S. et al.Association of hypertension and blood pressure with kidney cancer risk: a nationwide population-based cohort study.Hypertension. 2020; 75: 1439-1446Crossref PubMed Scopus (2) Google Scholar, 34Weikert S. Boeing H. Pischon T. et al.Blood pressure and risk of renal cell carcinoma in the European prospective investigation into cancer and nutrition.Am J Epidemiol. 2008; 167: 438-446Crossref PubMed Scopus (132) Google Scholar, 35Gago-Dominguez M. Yuan J.M. Castelao J.E. et al.Regular use of analgesics is a risk factor for renal cell carcinoma.Br J Cancer. 1999; 81: 542-548Crossref PubMed Scopus (0) Google Scholar, 36Yoon C. Yang H.S. Jeon I. et al.Use of angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers and cancer risk: a meta-analysis of observational studies.CMAJ. 2011; 183: E1073-E1084Crossref PubMed Scopus (55) Google Scholar, 37Grossman E. Messerli F.H. Goldbourt U. Does diuretic therapy increase the risk of renal cell carcinoma?.Am J Cardiol. 1999; 83: 1090-1093Abstract Full Text PDF PubMed Scopus (89) Google Scholar, 38Colt J.S. Hofmann J.N. Schwartz K. et al.Antihypertensive medication use and risk of renal cell carcinoma.Cancer Causes Control. 2017; 28: 289-297Crossref PubMed Scopus (10) Google Scholar, 39Zaidan M. Stucker F. Stengel B. et al.Increased risk of solid renal tumors in lithium-treated patients.Kidney Int. 2014; 86: 184-190Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 40Cumberbatch M.G. Rota M. Catto J.W. et al.The role of tobacco smoke in bladder and kidney carcinogenesis: a comparison of exposures and meta-analysis of incidence and mortality risks.Eur Urol. 2016; 70: 458-466Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar, 41Boffetta P. Fontana L. Stewart P. et al.Occupational exposure to arsenic, cadmium, chromium, lead and nickel, and renal cell carcinoma: a case-control study from Central and Eastern Europe.Occup Environ Med. 2011; 68: 723-728Crossref PubMed Scopus (45) Google Scholar, 42Song J. Luo H. Yin X. et al.Association between cadmium exposure and renal cancer risk: a meta-analysis of observational studies.Sci Rep. 2015; 5: 17976Crossref PubMed Scopus (43) Google Scholar, 43Mostafa M.G. Cherry N. Arsenic in drinking water and renal cancers in rural Bangladesh.Occup Environ Med. 2013; 70: 768-773Crossref PubMed Scopus (27) Google Scholar). Obesity, diabetes, hypertension, smoking, nephrotoxic drugs, and heavy metals all promote kidney injury, either AKI or CKD, and may link indirectly to injury-related kidney cancer rates.44Carriazo S. Vanessa Perez-Gomez M. Ortiz A. Hypertensive nephropathy: a major roadblock hindering the advance of precision nephrology.Clin Kidney J. 2020; 13: 504-509Crossref PubMed Google Scholar, 45Mulay S.R. Linkermann A. Anders H.J. Necroinflammation in kidney disease.J Am Soc Nephrol. 2016; 27: 27-39Crossref PubMed Google Scholar, 46Romagnani P. Remuzzi G. Glassock R. et al.Chronic kidney disease.Nat Rev Dis Primers. 2017; 3: 17088Crossref PubMed Scopus (208) Google Scholar Indeed, nephrotoxic drugs and heavy metals induce episodes of toxic AKI associated with necroinflammation and oxidative stress.45Mulay S.R. Linkermann A. Anders H.J. Necroinflammation in kidney disease.J Am Soc Nephrol. 2016; 27: 27-39Crossref PubMed Google Scholar Obesity, diabetes, and smoking are well-established risk factors for glomerular hyperfiltration and glomerulosclerosis-related CKD, imposing nephron loss and considerable adaptive cellular changes in the remnant nephrons to accommodate the metabolic needs.46Romagnani P. Remuzzi G. Glassock R. et al.Chronic kidney disease.Nat Rev Dis Primers. 2017; 3: 17088Crossref PubMed Scopus (208) Google Scholar Finally, hypertension, rather than a cause, is frequently a consequence of kidney disease and a sensitive indicator of early CKD.44Carriazo S. Vanessa Perez-Gomez M. Ortiz A. Hypertensive nephropathy: a major roadblock hindering the advance of precision nephrology.Clin Kidney J. 2020; 13: 504-509Crossref PubMed Google ScholarTable 3Epidemiological evidence that kidney cancer associates with kidney injury: risk factors for kidney cancerExposure (risk factor or disease)OutcomeRisk (95% CI)Strength of evidenceReferenceObesity Per 5-kg/m2 BMI increaseKidney cancer (men)RR, 1.24 [1.15–1.34]Meta-analysis26Renehan A.G. Tyson M. Egger M. et al.Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies.Lancet. 2008; 371: 569-578Abstract Full Text Full Text PDF PubMed Scopus (3345) Google ScholarKidney cancer (women)RR, 1.34 [1.25–1.42]Meta-analysis26Renehan A.G. Tyson M. Egger M. et al.Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies.Lancet. 2008; 371: 569-578Abstract Full Text Full Text PDF PubMed Scopus (3345) Google Scholar BMI + 1 SDRCCOR, 1.56 [1.44–1.70]Multivariate analysis27Johansson M. Carreras-Torres R. Scelo G. et al.The influence of obesity-related factors in the etiology of renal cell carcinoma-a mendelian randomization study.PLoS Med. 2019; 16e1002724Crossref PubMed Scopus (21) Google Scholar 25 kg/m2 ≤ BMI < 30 kg/m2Kidney cancerRR, 1.35 [1.27–1.43]Meta-analysis28Liu X. Sun Q. Hou H. et al.The association between BMI and kidney cancer risk: an updated dose-response meta-analysis in accordance with PRISMA guideline.Medicine (Baltimore). 2018; 97e12860Crossref PubMed Scopus (0) Google Scholar BMI ≥ 30 kg/m2Kidney cancerRR, 1.76 [1.61–1.91]Meta-analysis28Liu X. Sun Q. Hou H. et al.The association between BMI and kidney cancer risk: an updated dose-response meta-analysis in accordance with PRISMA guideline.Medicine (Baltimore). 2018; 97e12860Crossref PubMed Scopus