From kidney injury to kidney cancer

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