Stesura Seveso Archivio Italiano di Urologia e Andrologia 2023; 95(3):11625 1 SYSTEMATIC REVIEW INTRODUCTION Renal artery infarction (RI) describes the presence of blood clot in the main renal artery or its branches causing com- plete or partial obstruction of the blood supply. Its etiol- ogy is either related with intrinsic disorders of the renal vasculature or with cardiovascular disorders outside the kidney (1-2). The blood perfusion impairment results in renal injury and failure, partial or total, permanent or not, though the final outcome is primarily related with the prompt diagnosis and treatment (3-5). The correct diagnosis of RI is a challenge for the physi- cian. The disease may mimic the renal colic or other con- ditions such as urinary tract infection, acute abdomen, cardiac and pulmonary diseases, necessitating a multidis- ciplinary diagnostic work up (1-2, 6-8). Several case series are referred to RI management, mainly reflecting the experience and preferences of each group, but high- quality comparative series investigating the prognostic factors, the optimal diagnostic algorithm, the best treat- ment strategy and the role of prompt management in dis- ease outcome are lacking. A number of different pharma- Aim: Renal artery infarction (RI) is the pres- ence of blood clot in the main renal artery or its branches causing complete or partial obstruction of the blood supply. Its etiology is either related with disorders of the renal vasculature or with cardiovascular diseases. Recently, the SARS- CoV-2 virus is an emerging cause of thromboembolic events and the incidence of RI is anticipated to increase after the pandemic. Methods: A systematic review based on COVID-19 associated RI was conducted. Protocol: A systematic review of the Medline/Pubmed and Scopus databases was conducted in accor- dance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (the PRISMA statement). Search strategy and information sources: A hand-search was performed using the terms “SARS-Cov-2” OR “COVID-19” AND “renal throm- bosis” OR “renal infarction” OR “renal “thromboembolism”. Eligibility criteria: all types of publications (case reports, case series, letters to the editor, short communications) were evaluat- ed for relevance. Inclusion criteria were: confirmed SARS-Cov-2 infection irrespectively of the age, diagnosis of RI during or after the onset of viral infection, and exclusion of other potential causes of thromboembolic event except of SARS-Cov-2. Patients with renal transplantation were also considered. Study criteria selection: after checking for relevance based on the title and the abstract, the full texts of the selected papers were retrieved and were further evaluated. Duplicated and irrelevant cases were excluded. Any disagreement was resolved by consensus with the involvement of a third reviewer. Quality of studies: The assess- ment of the quality case reports was based on four different domains: selection, ascertainment, casualty and reporting. Each paper was classified as “Good”, “Moderate” and “Poor” for any of the four domains. Data extractions: Crucial data for the con- duct of the study were extracted including: age, sex, time from SARS-Cov-2 infection till RI development, medical history, pre- vious or current antithrombotic protection or treatment, laterali- ty and degree of obstruction, other sites of thromboembolism, treatment for thromboembolism and SARS-Cov-2 and final out- come. Data analysis: methods of descriptive statistics were implicated for analysis and presentation of the data. Results: The systematic review retrieved 35 cases in 33 reports. In most cases, RI was diagnosed within a month from the SARS- Cov-2 infection albeit 17 out of 35 patients were receiving or had recently received thromboprophylaxis. Right, left, bilateral and allograft obstruction was diagnosed in 7, 15, 8 and 5 patients respectively. 17 cases experienced additional extrarenal thromboembolism primarily in aorta, spleen, brain and lower limbs. Low molecular weight heparins (LMWH) (usually 60-80 mg enoxaparine bid) was the primary treatment, followed by combinations of unfractionated heparin and salicylic acid, apix- Renal artery infarction in the SARS-Cov-2 era: A systematic review of case reports Diomidis Kozyrakis, Georgios Kallinikas, Anastasios Zarkadas, Dimitrios Bozios, Vasileios Konstantinopoulos, Georgios Charonis, Konstantinos Safioleas, Athanasios Filios, Evangelos Rodinos, Despoina Mytiliniou, Gerasimos Vlassopoulos, Ioannis Gkerzelis, Panagiotis Filios Konstantopouleio General Hospital of Nea Ionia, Department of Urology, Nea Ionia, Attiki, Greece. DOI: 10.4081/aiua.2023.11625 Summary aban and rivaraxaban, warfarin, acenocoumarol or clopidogrel. Kidney replacement therapy was offered to five patients while invasive therapies with thrombus aspiration or catheter directed thrombolysis were performed in two. Regarding the outcomes, five of the patients died. The total renal function was preserved in 17 cases and renal impairment with or without hemodialysis was recorded in 5 patients, two of them having lost their kidney allografts. Limitations: The majority of included studies are of moderate quality. The results and the conclusions are based on case-reports only and crucial data are dissimilarly presented or missing through the relevant publications. Conclusions: Thromboprophylaxis may not offer adequate pro- tection against SARS-Cov-2 induced thrombosis. Most patients could be effectively treated with conservative measures, while in more severe cases aggressive treatment could be recommended. Implications of key findings: Therapeutic doses of LMWH could be considered for protection against RI in SARS-Cov-2 cases. Interventional treatment could be offered in a minority of more severe cases after carful balancing the risks and benefits. KEY WORDS: Keywords: Renal; Artery infarction; Thromboembolism; SARS-Cov-2; COVID-19. Submitted 30 July 2023; Accepted 3 September 2023 Archivio Italiano di Urologia e Andrologia 2023; 95(3):11625 D. Kozyrakis, G. Kallinikas, A. Zarkadas, et al. 2 ceutical regimens and interventional therapies have been tested in RI patients but with inconclusive results in terms of preservation of renal function (1-3, 6-10). The new SARS-Cov-2 infection, the etiology of the COVID-19 pandemic outbreak may cause significant infection of the respiratory system and at the same time may affect multiple other organs through a prothrombot- ic and inflammatory effect involving the immune and vas- cular system albeit the mechanism of activation of the cascade of events leading to clot formation is still under investigation (11-13). The incidence of RI is anticipated to increase after the SARS-CoV-2 pandemic. At present, the management of post COVID-19 RI is based on the experience accumulat- ed before the pandemic onset and therefore contempo- rary clinical research might be beneficial. Attempting to add on the existing body of evidence we conducted a review of the literature exclusively with patients who developed RI during or after the infection with SARS- Cov-2. Emphasis is given in the history, the diagnostic workup, the laboratory findings and the treatment options. A discussion regarding the role of the new virus in the development of the thrombosis is also attempted. The optimal treatment of respiratory infection due to SARS-Cov-2 is beyond the scope of this review. MATERIALS AND METHODS Protocol A systematic review of the Medline/ Pubmed and Scopus databases was conducted in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (the PRISMA statement) (14). Search strategy and information sources The aforementioned databases were hand-searched until mid December 2022 using the terms “SARS-Cov-2” OR “COVID-19” AND “renal thrombosis” OR “renal infarc- tion” OR “renal “thromboem- bolism”. Eligibility criteria Based on the title and the abstract’s content all types of publications (case reports, case series, letters to the editor, short communications) were independently evaluated for relevance by two of the authors of this manuscript (DK and GK). Inclusion criteria were: 1. confirmed SARS-Cov-2 infec- tion irrespectively of the age, 2. diagnosis of RI during or after the onset of viral infection, and 3. exclusion of other poten- tial causes of thromboembolic event except of SARS-Cov- 2. Patients with renal transplantation or/and the co-exis- tence of thromboembolic events outside the renal vascular system were also considered. Exclusion criteria were the absence of SARS-Cov-2 infection or of RI, the inade- quate/poor presentation of the case, included the abstract- only cases and the non-English articles. Study selection After checking for relevance based on the title and the abstract, the full texts of the selected papers were retrieved and were further evaluated. Duplicated and irrelevant cases were excluded. Any disagreements were resolved by consensus with the involvement of a third reviewer (PF). Data extraction Three of the authors (DK, VK, PF) determined and extract- ed the crucial data for the conduct of the study: Age, sex, time from SARS-Cov-2 infection till RI development, med- ical history, previous or current antithrombotic protection or treatment, laterality and degree of obstruction, other sites of thromboembolism, treatment for thromboem- bolism and SARS-Cov-2 and final outcome. Figure 1. Prisma Flow diagram of selected cases. Archivio Italiano di Urologia e Andrologia 2023; 95(3):11625 3 Renal artery infarction as a sequela of SARS-Cov-2 infection Quality of studies Two of the authors independently assessed the quality of each paper included in the study. Murad et al. (15) published a guide of assessment tools of a case report quality based on four different domains: Selection, Ascertainment, Causalty and Reporting. Considering that all the included papers were case report the studies were rated accordingly. Each paper was classified as “Good”, “Moderate” and “Poor” for any of the four domains. Any disagreement in quality assessment was resolved with third part involvement (GV or IG). Data analysis Methods of descriptive statistics were applied for analysis and presentation of the demographics and clinical char- acteristics of the included population. RESULTS A checklist of the included items in PRISMA systematic review is presented in supplementary Table 1. 33 papers with 35 RI cases were retrieved after the search of the databases (Figure 1). An overview of the quality of the papers is provided in Table 1 (12, 13, 16-46). Most of the case reports were assessed with moderate risk of bias. The overview of the retrieved papers is provided in Table 2. The demographics and clinical characteristics with the relevant rates are provided in Table 3. All the patients except one were adults, the majority of whom were males in their sixth or seventh decade of their lives usually with a history of obesity, diabetes mellitus (DM) and/or smok- ing. Noteworthy, 17.6% of the patients had unremark- able medical history. In most of the cases the RI event was diagnosed within a month from the SARS-Cov-2 infection (mean 15.3 days). It is of interest that almost half of the cases (17/35) were receiving or had recently received thromboprophylaxis. The most frequently used thromboprophylaxis was low Table 1. Assessment of risk of bias for each one of the included case reports for the domains of Selection, Ascertainment, Causality and Report. For each one of the four domains a classification in low (L), moderate (M) and high (H) risk is provided. Author Selection Ascertainment Causality Report Xu (16) H M M L Acharya (17) H M H M Mocerino (18) H L M L Mukherjee (19) H L L L Deshmukh (20) H H H M Ramanathan (21) H M L M Post (12) M M M L M M L L Añazco (22) H M L M Lushina (23) H M H M Kundal (13) H M H M Besutti (24) M L M H M M H H Imoto (25) H M M M Ammous (26) H L M L Kenizou (27) H L M M Webb (28) H H M L Plouffe (29) M H H M Singh (30) H H H M Tantisattamo (31) M M H L Belfort (32) M L M L Topel (33) H M H M Sethi (34) H M L M Jentzsch (35) H M L L Farias (36) H M L M Al-Mashdali (37) H M M L Mavraganis (38) H L L L Jain (39) H L M M Rigual (40) H M M L Huang (41) H L M L Mancini (42) H L L L Gjonbalaj (43) H M M L Brem (44) H L L M Kourien (45) H M H M Veterano (46) H M H L Table 2. Overview of retrieved papers. Author Age Sex Days after Antithrombotic/ Laterality, Other sites of Tx for Tx for Outcome (y) COVID-19 anti-PLT Tx & degree thromboembolism SARS-Cov-2 thromboembolism diagnosis/history before RI of obstruction Xu 2020 (16) Acharya 2020 (17) Mocerino 2020 (18) Mukherjee 2020 (19) Deshmukh 2020 (20) 46 77 69 71 55 M F F M F 27/DM, kidney–pancreas transplant ND/hypothyreoidism, CAD, COPD, smoking, lung cancer, aortic aneurysm and bilateral renal stenting, recent embolization for leak ND/DM, AH, CAD 9/unremarkable 3/recent appendicitis Intermittent enoxaparin 40 mg bid ASA ASA, Clopidogrel Enoxaparin No Segmental artery, incomplete Bilateral incomplete Left main incomplete Left superior Bilateral left incomplete, right complete No No No Ascending aorta Abdominal aorta Suppl O2, azithromycin, prednisone, lopinavir/ritonavir, HCLQ cefuroxime ND ND Suppl O2, methylprednisolone, lopinavir/ritonavir, HCLQ ND Alive, RF ND Alive, RF ND Preservation RF Preservation RF Multiorgan dysfunction, sepsis Enoxaparin 80 mg bid, at discharge apixaban 5 mg bid ASA IV heparine then apixaban Stop enoxaparin, Heparine IV, Clopidogrel then apixaban + clopidogrel ND Archivio Italiano di Urologia e Andrologia 2023; 95(3):11625 D. Kozyrakis, G. Kallinikas, A. Zarkadas, et al. 4 Ramanathan 2020 (21) Post 2020 (12) Añazco 2020 (22) Lushina 2020 (23) Kundal 2020 (13) Besutti 2020 (24) Imoto 2020 (25) Ammous 2021 (26) Kenizou 2021 (27) Webb 2021 (28) Plouffe 2021 (29) Singh 2021 (30) Tantisattamo 2021 (31) Belfort 2021 (32) Topel 2021 (33) Sethi 2021 (34) Jentzsch 2021 (35) Farias 2021 (36) Al-Mashdali 2021 (37) Mavraganis 2022 (38) Jain 2022 (39) 54 62 58 41 84 39 54 53 64 62 78 49 6 32 33 28 55 62 28 37 43 64 62 M M M F M F M M M M M M M M M M M F M M M M 11/obesity 9/AH, Henoch–Schonlein glomerulonephritis, kidney transplantation 2/sleep apnea 3/obesity, DM 0/AH, AF ND/obesity, AH, contraceptives, patent foramen ovale 9/former smoker, asthma, ulcerative colitis 6/AH, mitral valve replacement 15/gastric & duodenal ulcer 16/AH, asthma 9/obesity, pulmonary embolism, phlebitis 27/CKI, kidney transplan- tation, rejection** 63 (suspected covid)/ unremarkable 30/unremarkable 9/obesity, DM, ESKD, kidney transplantation, post-transplant AKI 3/DM, heart transplantation, dyslipidemia 28/smoking, AH 5/unremarkable 0/smoking, asthma, migraines 10/NA -4/type B aortic dissection, deafness, smoking 19/overweight 8/unremarkable No Dalteparine 2500 U Nadroparin 5700 No No No No ASA No LMWH prphylaxis (Stopped 2 days before RATE) Rivaroxaban 10 mg Enoxaparin 80 mg then 40 mg No No Clopidogrel, stop due to GI bleeding, heparin IV No Enoxaparin stopped 14 d before RATE LMWH prophylaxis No No No No No Bilateral Segmental Allograft segmental Bilateral segmental Bilateral segmental massive left Left upper segmental Right segmental Right main incomplete Left segmental Bilateral Left segmental Right main complete Kidney Allograft, complete Right segmental incomplete Right main complete Allograft segment, incomplete, microangiopathy Right Proximal segment incomplete Left segmental Left segmental Left segmental Left main Right main Left anterior segmental Left main complete Spleen No Bowel, lower limb No Lung, brain, aortic arc Aorta Spleen Spleen Brain, spleen No Left upper extremity, lung, brain, abdominal aorta No No No No Descending thoracic aorta Abdominal aorta, lower limb No No No Spleen Spleen, aorta Descending thoracic aorta DXM, albuterol Prednisone, high flow O2 Non rebreathing mask O2, mechanical ventilation O2, DXM, ceftriaxone, ivermectin Intubation ND Lopinavir/ritonavir, HCLQ Lopinavir/ritonavir, HCLQ, tocilizumab Favipiravir, ciclesonide, intubation, ECMO, meropenem, steroid, teicoplanin Suppl O2 Cefotaxime, azithromycin Prednisone, high flow O2, carbapenem Ceftriaxone Suppl O2 Norepinephrine, levofloxacin, ceftriaxone, intubation, remdesivir, DXM Prednisone, ceftriaxone, azthriomycin, hydrocortisole Supp O2, azithromycin, prednisole, favipravir Supp O2, methylprednisolone, lopinavir/ritonavir ND ND Suppl O2 DXM, remdesivir, tocilizumab, ceftaroline, high flow nasal O2 High flow nasal O2, IV steroids, IV antibiotics Preservation RF Slow improvement ICU, rehab center Ventilation, AKI, death Died Discharged home Discharged home Discharged home Died Preservation RF Ischemic stroke, GI bleeding, death Graft loss Full recovery Mucormycois, death Cardiac arrest (survived), renal dialysis, new onset AF Improved Improving, palpable limb pulses GI bleeding, normal RF Improved NA Chronic renal impairment, no dialysis Improving Improving Heparine 18U/Kgr/h then Apixaban 10 mg x2, shift to 5 mg x1 Dalteparin 15000U then Acenocoumarol Heparin and Nadroparin + kidney replacement therapy bowel resection Enoxaparin 60 mg bid, hemodialysis Thrombectomy for brain thrombus Apixaban (therapeutic dose) LMWH 6,000 UI bid LMWH 6,000 UI bid Enoxaparin Heparin, then novel oral anticoagulant IV heparin, rivaroxaban stop, fogarty embolecto- my for humeral thrombus Enoxaparin 40 mg Aspirine 81 mg for 6 m Nephrectomy IV Heparine, allograft nephrectomy Enoxaparin, then warfarine Thrombectomy for limb infarct, enoxaparine 0.8 mg, ASA 300 mg, pentoxyfylline 600 mg Renal dialysis, LMWH therapeutic dose Enoxaparin 1 mg/kg bid, then ASA81 mg + rivaroxaban 20 mg Enoxaparin 60 mg bid, then warfarin 5 mg/d IV heparin, then warfarine 3.5 mg (target INR 2-3) Enoxaparine 8000 bid + ASA 80 mg, then enoxaparine replaced by fondaparinux 7.5 mg LMW heparin 80 mg bid followed by dabigatran 150 mg bid Archivio Italiano di Urologia e Andrologia 2023; 95(3):11625 5 Renal artery infarction as a sequela of SARS-Cov-2 infection dose low molecular weight heparins (LMWH), usually enoxaparin, followed by amino-salicylic acid (ASA), either as monotherapy or combined with heparin. Of the 35 patients, five experienced allograft thrombosis. In the rest 30 patients, right, left and bilateral obstruction was diagnosed in 7, 15 and 8 patients respectively. In 17 cases, one or more organs outside the urinary tract were affected by the thromboembolic event with the aorta being most frequently involved (10 cases), followed by the spleen (8 cases), brain (3 cases), lower limb (3 cases), lung (3 cases) and elsewhere (2 cases). All the patients were reported to complain about pain of sudden onset in the upper lateral abdominal quadrant and/or in the costovertebral angle ipsilateral to the affect- ed kidney. The abdomen was tender in the affected side but the guarding reflex was rarely elicited. The WBC level is frequently elevated with the reported values being mostly above 15000 WBC/μL. Serum LDH and D-Dimers are almost uniformly above the normal range. Kidney injury is described in 12 cases while for 7 others reliable information were lacking. The mainstay of the diagnosis was the contrast-enhanced CT (CECT) scan or preferably CT angiography (CTA) and in only one case digital subtractive angiography (DSA) as an adjuvant diagnostic modality to the CT scans. In two other cases the diagnosis of ischemia was established with renal biopsy. Massive or complete thromboembolism was revealed in eight patients. The rest of the patients had incomplete infarction of either the main artery or the seg- mental branches. As it is shown in Table 3, the treatment for SARS-Cov-2 is reported for 29 patients and different combinations of drugs have been used. Steroids were most frequently deliv- ered (51.4% of patients), followed by antibiotics (37.1%) and by antiviral treatment (31.4%). Hydroxychloroquine was delivered in 5 patients and monoclonal antibodies in 3. LMWH, mainly high dose enoxaparin (60-80 mg bid), was the primary treatment against thromboembolism in 19 cases, followed by therapeutic combinations contain- ing unfractionated heparin (9 patients) and salicylic acid in dosages ranging from 81 to 300 mg/day. Upfront apix- aban or other antithrombotic and anti-platelet agents (rivaraxaban, warfarin, acenocoumarol or clopidogrel) have also been delivered in RI patients. Kidney replacement therapy was urgently offered to only five of the cases. Invasive therapies were performed in two patients. In one of them, with mid-distal segmental occlu- sion, aspiration and stent placement was performed and tirofiban was delivered to the thrombus site while the patient was under treatment with unfractionated heparin plus ASA. The patient experienced full recovery (43). In another 56-year female with massive allograft thrombo- sis, history of chronic kidney disease, obesity, heart failure, diabetes type 2, arterial hypertention and lower limb Rigual 2022 (40) Huang 2022 (41) Mancini 2022 (42) Gjonbalaj 2022 (43) Brem 2022 (44) Kourien 2022 (45) Veterano 2022 (46) NV: normal values, DM: diabetes mellitus, CAD: coronary artery disease, COPD: chronic obstructive pulmonary disease, RF: renal function, ND: not defined, AF: atrial fibrillation, AH: arterial hypertension, ICU: intensive care unit, GI: gastrointestinal, AKI: acute kidney injury CKI: chronic kidney injury, SC: subcutaneous, ASA: acetylsalicylic acid, ESKD: end stage kidney disease, LMWH: low molecular weight heparin, CKD: chronic kidney disease, HCLQ: Hydroxychloroquine, Suppl O2: Supplementary oxygen, DXM: dexamethasone, ECMO: extracorporeal membrane oxygenation, IV intravenous. 53 62 43 5th decade 59 32 56 M M M M M M F 10/cerebral infarction Tx with IV thrombolysis + thrombectomy 19/DM 3/mild stenosis of aortic valve, adrenal adenoma (non functioning) 60/unremarkable 14/DM 30/unremarkable 30/Idiopathic CKD, kidney transplant, allograft dysfunction, obesity, heart failure, DM, AH, popliteal vein thrombosis Enoxaparin 1 mg/kg, ASA 100 mg No No No LMWH prophylaxis Enoxaparin prophylaxis ASA, enoxaparin 20 mg, prophylaxis Bilateral segmental Left main & posterior complete Left upper, middle segmental Left mid/distal segmental Left Bilateral segmental Allograft main, quasi-complete Spleen No No No Spleen, lung, femoral artery thoracic aorta No No Suppl O2, methylprednisolone Suppl O2, methylpred- nisolone, ceftriaxone, antiviral Piperacillin/ tazobactam ND Azithromycin, ceftriax- one, HCLQ Remdesivir, methylpred- nisolone, tocilizumab, positive pressure O2 DXM, O2 with nasal cannula Rehab center Preservation RF DMSA 28% relative renal function Full recovery Limb amputation, RF preservation Permanent hemodialysis Allograft preservation, RF improved 1 mg enoxaparin/kg, ASA 100 mg, then ASA 300 mg Clopidogrel 75 mg, nadroparin 3800U/q12h then rivaroxaban Enoxaparin 7000 UI bid, recur of thrombosis, then enoxaparin 8000 UI bid + ASA 100 mg ASA 100 mg/d + heparin 25,000 UI/d thrombus aspiration + tirofiban 5 ml, stent, then ASA 100 mg+ Clopidogrel 75 mg LMWH 60 mg bid, limb embolectomy Bilateral nephrectomy, combined antfungal agents Catheter directed thrombolysis (alteplase, 5cc bolus, then 0.8 mg/h + IV heparine 500U/h) for 2 days + endoprosthesis, ASA 100 mg + enoxaparin 60 mg bid, then apixaban 5 mg bid Archivio Italiano di Urologia e Andrologia 2023; 95(3):11625 D. Kozyrakis, G. Kallinikas, A. Zarkadas, et al. 6 thrombosis, the treatment consisted of catheter directed thrombolysis with alteplase combined with IV heparin, endoprothesis placement, ASA and enoxaparin resulting in preservation of the transplant and improvement of renal function (46). Nephrectomy was necessitated in three other cases, one bilateral one unilateral and one for allograft removal. Regarding the outcomes, five of the patients died. The total renal function was preserved or improving in 16 cases, while in another one the relative function was diminished to 28% in DMSA scans without affecting though the overall renal function. Renal impairment with or without hemodialysis was recorded in 5 patients, two of them having lost their kidney allografts. For 7 cases data regarding renal function outcome are inconclusive. DISCUSSION The most frequent etiologic factor for RI of any cause is Table 3. Patients’ demographics and clinical characteristics. Epidemiology Age (range) years 52.1 (6-84) Male/female ratio 3.4/1 Male %, Female % 77%, 23% Days for RI after COVID-19 diagnosis 15.3 d (0-63)* History (for 34 pts) Unremarkable (%) 6 (17.6) Transplantation (%) 6 (17.6) Heart diseases CAD (%) 2 (6) Chronic heart diseases (%) 4 (11.7) AF (%) 1 (3) AH (%) 8 (23.5) DM (%) 7 (20.5) Obesity/overweight (%) 7 (20.5) Smoking (%) 4 (11.7) Pulmonary diseases Asthma (%) 3 (8.8) COPD (%) 1 (3) Sleep apnea (%) 1 (3) Lung cancer (%) 1 (3) Vascular diseases Vasculitis/thromboembolism (%) 6 (17.7) Aorta aneurysm/dissection (%) 2 (6) Renal dysfunction (%) ** 4 (11.7) Gastrointestinal diseases (%) 2 (6) Others Appendicitis (%) 1 (3) Migraines (%) 1 (3) Dyslipidemia (%) 1 (3) Deafness (%) 1 (3) Adrenal adenoma (%) 1 (3) Hypothyroidism (%) 1 (3) Contraceptive drug consumption (%) 1 (3) Antithrombotic/anti-PLT Tx before RI (17 cases) LMWH (%) 11 (31.4) IV Heparin (%) 1 (2.8) ASA (%) 5 (14.3) Clopidogrel (%) 2 (5.7) Laterality Right side (%) 7 (20) Left side (%) 15 (42.9) Bilateral (%) 8 (22.8) Allograft (%) 5 (14.3) Degree of obstruction Segmental artery (%) 25 (58) Main artery (%) 9 (21) The arterial site is not defined (%) 9 (21) Incomplete *** 9 Complete *** 6 Massive/quasi-complete *** 2 Other sites of thromboembolism Aorta (%) 10 (28.6) Spleen (%) 8 (22.8) Lower limb (%) 3 (8.6) Lung (%) 3 (8.6) Brain (%) 3 (8.6) Upper limb (%) 1 (2.9) Bowel (%) 1 (2.9) No (%) 18 (51.4) Tx for SARS-Cov-2 Antibiotics (some pts received Azithromycin 6 combinations) 13 pts (37.1%) Cefuroxime 1 Ceftriaxone/Cefotaxime 7 Ceftaroline 1 Levofloxacin 1 Piperacillin/tazobactam 1 Meropenem/carbapenem 2 Teicoplanin 1 ND antibiotics 1 Steroid agents (51.4%) Prednisone/methylprednisolone/DXM 18 Antiviral 11 pts (31.4%) Remdesivir 3 Opinavir/ritonavir 5 Favipiravir 2 ND antiviral 1 HCLQ (14.3%) HCLQ 5 Inhaler (5.7%) Albuterol 1 Ciclesonide 1 Mechanical ventilation/ Mechanical ventilation/intubation 4 intubation (11.4%) Ivermectin 1 Others Tocilizumab 3 ECMO 1 Norepinephrine 1 O2 treatment (45.7%) Positive pressure 1 ND (Supplementary) 10 High flow 4 Non-rebreathing 1 ND (20%) ND 7 Overview of primary Tx Therapeutic agent in primary Tx Long term Tx or Tx after for RI (%) for RI (no of pts) Discharge (no of pts) Single medical Tx 22 pts (62.9) LMWH (19) Apixaban (5) Combined medical Tx 7 pts (20) ASA (7) ASA (5) Surgical Tx 2 pts (5.7) Heparin IV (9) Clopidogrel (2) ND 4 pts (11.4) Clopidogrel (2) Acenocoumarol (1) Apixaban (2) Oral anticoagulant (1) ND Heparin (1) Warfarine (2) Nephrectomy (2) Rivaroxaban (2) Interventional/endovascular treatment (2) Fondaparinux (1) ND (4) Dabigatran (1) Outcomes: no of pts Dead: 5, Alive: 30 RF preservation: 8 Full recovery: 2 Improved /improving: 6 Multiorgan dysfunction/sepsis: 1 ICU: 2 Discharged home (no further info): 3 Discharged to rehabilitation center: 2 Renal dysfunction: 5 Loss of renal unit: 1 Cardiac arrest, AF: 1 GI bleeding: 2 * In one case RI was diagnosed 4 days before the definite SARS-Cov-2 diagnosis. ** Irrelevant to history of transplantation. *** Rates are not displayed due to missing data. Archivio Italiano di Urologia e Andrologia 2023; 95(3):11625 7 Renal artery infarction as a sequela of SARS-Cov-2 infection atrial fibrillation (AF) encountered 25% to 75% of the patients (2, 8, 47). However, amongst patients with COVID-19-induced RI, AF is a rare occasion. The cytokine storm has been described in these patients predisposing to pro-inflammatory, prothrombotic and profibrotic effects induced by activated neutrophils and monocytes, as well as in causing damage to the endothelium (endothelitis) through the activation of angiotensin-converting enzyme-2 receptor. This cascade of events leads to activation and aggregation of factor VII, von Willebrand factor and fib- rinogen and consequently to thrombin activation and fib- rin clot formation and also in aggregation of platelets resulting in multiple thrombotic events (28, 32). Several other factors predispose to the onset of the RI such as diabetes mellitus, arterial hypertension, hyper- lipidemia, congestive heart failure, coronary artery dis- ease, myocardial infarction, mitral valve disease and cere- brovascular disease (10, 47, 48). A relevant history has also been recorded in many patients of this review. Occasionally, in situ thrombosis may be iatrogenic in ori- gin or traumatic (4, 49). History of a previous embolic event or thrombophilia with potential resistance of acti- vated protein C and deficiency of protein S should also be examined (4, 5, 9). Almost half of the COVID-19 related RI cases were receiv- ing or had recently received thromboprophylaxis. It seems that low dose of LMWH or ASA do not offer adequate pro- tection against RI so as to overcome the cytokine storm effect. The use of intermediate-dose enoxaparin in COVID- 19-induced-hypoxia and before the onset of RI could be proposed as a measure to overcome the failure of throbo- prophylaxis attributed to high levels of factor VII, von Willebrand factor and fibrinogen (28). Therefore based on the results of a randomized clinical trial Spyropoulos et al. recommended the administration of 1mg/kg bid of LMWH and 0.5 mg/kg bid for patients with clearance creatinine ≥ 30 and < 30 mL/min/1.73 m2 respectively for hospital- ized patients. The beneficial effect of the proposed dosages was evident in non ICU patients though (50). The prompt diagnosis and treatment is the cornerstone of a favorable outcome for RI of any case. 90 minutes of nor- mothermic ischemia can lead to irreversible damage of the renal parenchyma (3, 4), albeit this threshold is not always confirmed in clinical practice. Several groups have report- ed the preservation of renal function after many hours or even days after the onset of infarction (6, 51). In COVID- 19-associated RI the delay in seeking for medical help can- not be evaluated because this piece of information is not reported in many of the included case reports but it seems that the degree of obstruction is more crucial than the delay in diagnosis. Three out of the five deaths of the review were recorded in the 8 patients with complete or massive infarction, indicating that the high degree of obstruction might be life threatening compared with the lower degree of RI. The most frequently affected renal unit by COVID-19 was the left-sided, representing a finding that is poorly under- stood. In most case series with RI of any etiology both sides were almost equally infracted (2, 6, 9, 51). Three case series of the pre-COVID-19 era demonstrated a pre- dominance of left RI which is a finding similar to that of the present review (47, 48, 52). Another paper from Korea though reported a higher incidence of right-sided RI (1). Domanovits et al. favor the hypothesis that the right renal artery has an acute angle of divergence with the aorta (48). In a more recent report it was revealed that the degrees of angulation were similar for both sides but the left orifice is larger than the right one and this fact may have influenced the laterality of RI (52). Apart from the dimensions of the orifice, it could be speculated that the length of renal arteries as well as the distance of the branching from the orifice may also play a role in the pre- dominance of the left side. Noteworthy pulmonary embolism (PE) among SARS-Cov-2 patients is a usual finding with an overall incidence of 16.5% (53). In the present review however PE was a rare finding among RI patients with the aorta and spleen being most frequently affected. If pulmonary infection was the triggering event of thromboembolism through the dissem- ination of infection and inflammation to the adjacent lung vessels it is anticipated that the incidence of PE would be much higher. However, the figure of three PE events of this review is too low to support this assumption. It has been shown that the virus may directly attack the respira- tory system causing pneumonia, while the cardio-vascular system is affected either directly from the virus or indi- rectly through the blood stream with activation of cytokine storm and pro-inflammatory pathways. It seems that some vessels are more vulnerable than others perhaps due to endothelitis or to increased permeability of the endothelium enhancing the clot formation and platelet aggregation (54). This might explain the higher incidence of aortic and splenic infarctions compared to pulmonary or brain embolism. Moreover, in some patients the syn- chronous diagnosis of viral pneumonia and visceral infarc- tion is indicative of the direct attack against the vascular system, while in others the long time interval (up to 63 days) between the COVID-19 pneumonia till the onset of infarction could be associated with an indirect assault (54). In most of the cases the WHO definition of long post-COVID-19 syndrome is met should the duration of RI symptoms lasts at least 2 months (55). In the pre-SARS-CoV-2 era some authors advocate the DSA as the diagnostic gold standard. The sensitivity rates are as high as 100% but at a cost of increased invasiveness (3, 4). This modality has now been broadly replaced by contrast enhanced CT (CECT) imaging and CT angiography (CTA) showing single or multiple wedge-shaped filling defects of the renal parenchyma or global hypo-attenua- tion of the affected renal unit (compared with the healthy one). The blood clots may be also revealed in the vascu- lar system. Infarcts involving greater than 50% of the renal parenchyma are considered global. Smaller single or multiples lesions (less than 50% of the renal unit) are classified as focal or multifocal respectively (56). The CECT/CTA sensitivity ranges from 80 to 97.3%, repre- senting a rapid, non invasive, comprehensive and inform- ative method for the diagnosis of RI and it should be per- formed as early as possible should renal infarction is sus- pected (2, 8, 48). Nephrotoxicity due to radiopaque agents is well described and acute kidney injury may occur in the grounds of an already impaired renal function (57). However, the correct diagnosis cannot be established with other means and the Archivio Italiano di Urologia e Andrologia 2023; 95(3):11625 D. Kozyrakis, G. Kallinikas, A. Zarkadas, et al. 8 benefits from the administration of the contrast agent should be balanced against the potential risks. Therefore many authors proceeded to IVC administration in patients with renal impairment even at the risk of subsequent hemodialysis (12, 16, 20, 22, 27, 34, 37, 44, 46). The treatment options against SARS-Cov-2 show a sig- nificant variability among the different medical centers. The combinations of regimens comprise mainly steroids plus broad spectrum antibiotics and usually antiviral treatment. Due to this variability the impact of anti-SARS- Cov-2 treatment on the natural history of thrombosis cannot not be reliably evaluated. Large scale studies with meticulous designed statistical analysis models might address the question whether some medications or com- binations might play a preventive role against infarction. Revascularization of RI is rarely attempted (1, 6, 8). In one of the biggest series comprising 438 RI of any cause the rate of thrombolysis with urokinase and embolectomy was as low as 4.5% and 0% respectively (2). However, it could be assumed that following a prompt diagnosis and perhaps in the settings of a massive or bilateral RI, endovascular surgery or thrombolytic management may be applied despite the risks of complications (3-5, 46, 48). In the present review, revascularization techniques were applied in one case with almost complete allograft obstruction and in another with a lesser degree of occlu- sion both with favorable results (43, 46). Mortality rate after RI of any cause ranges from 0% to 23.4% (1-3, 7-9). The total number of 5 deaths in 35 patients with post COVID-19 RI corresponds to a rate of 14.3% which is reasonable for a severe disease burdened by the unfavorable prognosis of SARS-Cov-2. Perhaps the prompt diagnosis with modern CT-scanners, the close monitoring of the patients and the availability of new generation anti-coagula- tive agents may all have contributed to acceptable survival rates. Nevertheless, the broader use of higher dosages of thromboprophylaxis might further enhance the outcomes in post-COVID-19 renal infarction (28, 50). This review has several limitations. As it is shown in table 2 the majority of included studies are of moderate quality. The results and the conclusions are based only on case- reports and data are missing through the relevant publi- cations. Any treatment of RI is based upon the prefer- ences of the responsible physicians since therapeutic and follow up protocols differ among the medical centers. The outcomes are dissimilarly presented increasing the likeli- hood of bias. Therefore, a direct comparison of the stud- ies or classification of the patients from different reports should be made with caution. Moreover, papers pub- lished in non English language and presentations in sci- entific meetings were not included in this review increas- ing the likelihood of missing data. 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Zarkadas, et al. 10 Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science. Cardiovasc Res. 2020; 116:2177-84. 55. Soriano JB, Murthy S, Marshall JC, et al. WHO Clinical Case Definition Working Group on Post-COVID-19 Condition. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022; 22:e102-7. 56. Suzer O, Shirkhoda A, Jafri SZ, et al. CT features of renal infarc- tion. Eur J Radiol. 2002; 44:59-64. 57. Obed M, Gabriel MM, Dumann E, et al. Risk of acute kidney injury after contrast-enhanced computerized tomography: a system- atic review and meta-analysis of 21 propensity score-matched cohort studies. Eur Radiol. 2022; 32:8432-42. Correspondence Diomidis Kozyrakis, MD (Corresponding Author) dkozirakis@yahoo.gr; urology@konstatnopouleio.gr Konstantopouleio General Hospital of Nea Ionia, Department of Urology Th. Konstantopoulou 3-5 Str., Nea Ionia, 14233, Attiki, Greece Georgios Kallinikas, MD georgioskallinikas@gmail.com Anastasios Zarkadas, MD azark13@hotmail.com Dimitris Bozios, MD dbozios@gmail.com Vasileios Konstantinopoulos, MD vkonstantinopoulos@yahoo.com Georgios Charonis, MD george.xarwnhs@gmail.com Konstantinos Safioleas, MD konstantinossafioleas@yahoo.gr Athanasios Filios, MD athanfilios@gmail.com Evangelos Rodinos, MD vag.international@hotmail.com Despoina Mytiliniou, MD dmitiliniou@yahoo.gr Gerasimos Vlassopoulos, MD vlassger@gmail.com Ioannis Gkerzelis, MD ioannisgkerzelis@gmail.com Panagiotis Filios, MD panosfilios@yahoo.gr Konstantopouleio General Hospital of Nea Ionia, Department of Urology, Nea Ionia, Attiki, Greece Conflict of interest: The authors declare no potential conflict of interest.