Objectives: This study was devised to investigate papal deaths due to acute kidney injury, a topic for which scarce data exist.
Materials and Methods: We studied all popes between John XXI, who died in 1277 of crush syndrome, and John Paul II, who died of anuria and urinary sepsis in 2005.
Results: Between pontification years from 1277 to 2005, 21 of 78 popes (26.9%) died of acute kidney injury. Sepsis was identified as the leading cause of acute kidney injury and death in 20 of 21 popes (95.2%). Mean ± SE age at death of the 21 popes was 69.4 ± 2.26 years. Six popes (28.6%) died of stroke.
Conclusions: Sepsis-associated acute kidney injury, a syndrome with a complex pathogenesis and poor prognosis, which is far from being fully understood, contributed to a high number of papal deaths.

Key words : Renal failure, Ureterolithiasis, Urosepsis

Introduction

There are few studies that describe the deaths, particularly renal deaths, of Roman pontiffs, a category of long-lived religious and political rulers whose mean lifespan between 1492 and 2005 was 73.6 years.^1-6 Only 1 study on acute kidney injury (AKI) exists, which discusses Pope John XXI.⁷

Acute kidney injury has been defined “as an abrupt (within hours) decrease in kidney function, which encompasses both injury (structural damage) and impairment (loss of function). It is a syndrome that rarely has a sole and distinct pathophysiology. Many patients with AKI have a mixed etiology where the presence of sepsis, ischemia, and nephrotoxicity often coexist and complicate recognition and treatment.”⁸ Acute kidney injury is common in older adults (8.3%); the age-AKI curve is U shaped and increases for adults aged 75 years and above.⁹

We devised this study to identify all Roman pontiffs who died of AKI, from John XXI (who died of crush syndrome in 1277) to John Paul II (who died from anuria and urinary sepsis resistant to antibiotics in 2005).

Materials and Methods

We studied all popes who died of AKI through the works of Retief and Cilliers,¹ Gualino,¹⁰ Ceccarelli,¹¹ Cosmacini,¹² Paravicini-Bagliani,¹³ Maxwell-Stuart,¹⁴ and Reardon.¹⁵ We also scrutinized the histories of archiaters by Bartolomeo Sacchi, known as Platina (1421-1481) and Luigi Gaetano Marini (1782-1815), and the many volumes with the histories of the papacy by Giuseppe de Novaes (1736-1821), Leopold von Ranke (1795-1896), Mathieu-Richard Auguste Henrion (1805-1862), and Ludwig von Pastor (1854-1928), as well as the online encyclopedias Treccani, Britannica, and Catholic.

Results

Twenty-one of 78 popes (29.5%) died of AKI between 1277 and 2005. As shown in Table 1, Pope John XXI died of crush syndrome, whereas Marcellus II, Pius IV, and Innocent XI died of AKI superimposed on chronic kidney disease. Callixtus III, Pius II, Sixtus IV, Pius III, Marcellus II, Pius IV, Gregory XV, Clement X, Innocent XI, Clement XII, and Benedict XIV formed uric acid renal stones. Boniface IX, Hadrian VI, Pius V, Gregory XIV, Leo XI, Alexander VII, Clement IX, and Innocent XII formed calcium renal stones.

Sepsis-associated AKI (sa-AKI) was the cause of death in 20 of 21 popes (95.2%). John Paul II was the only pope for whom urinary sepsis was resistant to antibiotics, and anuria was reported in the death certificate (Table 1). Six popes died of urosepsis and stroke. Four of these popes (Sixtus IV, Marcellus II, Clement XII, and Benedict XIV) had gout, whereas Pius V and Clement IX formed calcium renal stones (Table 1).

Age at death of the whole group was 69.4 ± 2.26 years. Popes with uric acid stones died at a mean age of 73.3 ± 3.02 years, whereas popes with calcium stones died at a mean age of 63.1 ± 2.66 years (P < .056) (Table 2).

Discussion

Among popes that reigned from 1277 to 2005, 29.5% died of AKI. Historical data indicated that the leading, but unrecognized, cause of papal deaths was sa-AKI, with sepsis caused by complicated urogenital infections.¹⁶ The findings aligned with current knowledge on mortality and acute renal failure in sepsis, a topic very much debated recently.^17-19

We now know that urosepsis accounts for nearly 25% of all adult cases of sepsis and is due to obstruction of the upper urinary tract, mainly due to ureterolithiasis. It has a complex pathogenic process characterized by dysregulation of the inflammatory response, dysregulation of the plasmatic cascade (complementopathy and coagulopathy), dysregulation of fibrinolysis, and dysregulation of the autonomic nervous system (parasympathetic branch, sympathetic branch) and enteral nervous system.²⁰

The pathogenic process is switched when pathogen-associated or damage-associated molecular patterns are recognized by the host’s immune system, causing a cytokine storm.

Sepsis has an intriguing unfinished history that attracted Hippocrates (460-377 BC), Avicenna (980-1037 AD), Louis Pasteur (1822-1875), Ignace Semmelweiss(1818-1865), Hugo Schottmüller (1867-1936), Lewis Thomas (1913-1993), and Roger C. Bone (1941-1997). The latter understood the value of the host response as the cause of the disease. This theory resulted in a large number of experimental and clinical studies, which eventually shifted the focus of sepsis research from the infectious agent to the host immune response. Finally, the concept entered into daily clinical practice when Roger Bone and colleagues defined sepsis as a systemic inflammatory response syndrome that can occur during infection.^16,19-21

Mean ± SE age at death of studied popes was 69.4 ± 2.26 years (Table 1). One might speculate that, because of the severity of the disease, they lived 4.2 years less than popes ruling between the years from 1492 to 2005 who died at a mean age of 73.6 years.¹ However, the 2 mean values should not be compared since lifespans of the popes listed in Table 1 do not overlap with the list of popes of Retief and Cilliers.¹ However, the age at death of 8 popes with kidney stone disease and urosepsis (Boniface IX, Hadrian VI, Alexander VII, Pius IV, Gregory XIV, Leon XI, Clement IX, and Innocent XIII) was 63 ± 2.7 years. Thus, their lifespan was shorter but not significantly shorter (P < .056). The finding suggests that urosepsis originating in patients with gout was less severe than urosepsis originating in popes with kidney stone disease of nongout origin; the lack of statistical significance is also probably driven by the small size of the data.

Stroke was an expected complication on the basis of what we know about it with regard to kidney stone disease. In fact, many studies have shown an increased risk of ischemic and hemorrhagic stroke in patients with urinary stones, especially in people older than 40 years,^22-28 although the mechanism underlying the increased risk is presently not known¹⁴ and warrants further studies.²⁹

The pathophysiology for sa-AKI, although poorly understood, attributes a primary role to hypoper-fusion and shock leading to decreased renal blood flow that, in turn, causes tubular epithelial cell necrosis. However, sa-AKI may also occur in patients with a stable circulatory condition and even in patients with increased renal blood flow.³⁰

Marcellus II, Pius IV, and Innocent XI died of AKI superimposed on chronic kidney disease. This indicates that the risk of acute renal failure in patients with chronic kidney disease emerged well before the advent of the present technological developments in assessing kidney function.³¹

Conclusions

From 1277 to 2005, a high, hitherto unnoticed, number of papal deaths were caused by AKI associated with urosepsis, complicating the course of kidney stone disease of gout and nongout origin.

References:

1. Retief FP, Cilliers L. Diseases and causes of death among the Popes. Acta Theologica. 2006;26(2 Suppl 7):S233-S246. doi:10.4314/actat.v26i2.52576
   CrossRef - PubMed
   
2. De Santo NG, Bisaccia C, De Santo LS. Papal deaths caused by cardiorenal disease. First approach. Arch Hellenic Med. 2020;37(S2):S177-S181.
   CrossRef - PubMed
   
3. De Santo NG, Bisaccia C, De Santo LS. Causes of death due to disease of the genito-urinary system and of the heart among 264 popes in the years 65-2005 AD: first approach. Nephrol Dial Transplant. 2019;34(Suppl 1):gfz103.SP804. doi:10.1093/ndt/gfz103.SP804
   CrossRef - PubMed
   
4. Bisacccia C, De Santo LS, De Santo NG. Gout a papal disease: a study in 20 pontiffs (540-1830). Nephrol Dial Transplant. 2020;35(Suppl 3):gfaa144.P1836. doi:10.1093/ndt/gfaa144.P1836
   CrossRef - PubMed
   
5. Bisaccia C, De Santo LS, De Santo NG. MO1029. Renal stone disease in 193 pontiffs from Vigilius to Pius VIII (537-1830). Nephrol Dial Transplant. 2021;36(Suppl 1). doi:10.1093/ndt/gfab105.001
   CrossRef - PubMed
   
6. De Santo NG, Bisaccia C, De Santo LS. Gout: a papal disease—a historical review of 25 gouty popes (34-2005 AD). J Nephrol. 2021;34(5):1565-1567. doi:10.1007/s40620-021-01117-8
   CrossRef - PubMed
   
7. De Santo NG, Bisaccia C, DeSanto LS, Cucu AI, Costea CF. John XXI, the pope philosopher and physician–scientist of Portuguese origins died of crush syndrome in 1277. J Relig Health. 2021;60(2):1305-1317. doi:10.1007/s10943-020-01096-3
   CrossRef - PubMed
   
8. Thomas ME, Blaine C, Dawnay A, et al. The definition of acute kidney injury and its use in practice. Kidney Int. 2015;87(1):62-73. doi.org/10.1038/ki.2014.328.
   CrossRef - PubMed
   
9. Ge S, Nie S, Liu Z, et al. Epidemiology and outcomes of acute kidney injury in elderly Chinese patients: a subgroup analysis from the EACH study. BMC Nephrol. 2016;17(1):136. doi:10.1186/s12882-016-0351-2.
   CrossRef - PubMed
   
10. Gualino L. Storia medica dei romani pontefici. Turin: Minerva Medica; 1934.
    CrossRef - PubMed
    
11. Ceccarelli G. La salute dei pontefici. Ancora; 2001.
    CrossRef - PubMed
    
12. Cosmacini G. La medicina dei papi. Laterza; 2018.
    CrossRef - PubMed
    
13. Paravicini-Bagliani A. The Pope’s Body. Chicago: University of Chicago Press; 2000.
    CrossRef - PubMed
    
14. Maxwell-Stuart PG. Chronicle of the Popes: The Reign-by-Reign Record of the Papacy From St. Peter to the Present. London: Thames & Hudson; 2000.
    CrossRef - PubMed
    
15. Reardon WJ. The Deaths of the Popes: Comprehensive Accounts, Including Funerals, Burial Places and Epitaphs. Jefferson, NC: McFarland & Company; 2004.
    CrossRef - PubMed
    
16. Wagenlehner FME, Lichtenstern C, Rolfes C, et al. Diagnosis and management of urosepsis. Int J Urol. 2013;20(10):963-9701. doi:10.1111/iju.12200
    CrossRef - PubMed
    
17. Schrier RW, Wang W. Acute renal failure and sepsis. N Engl J Med. 2004;351(2):159-69. doi:10.1056/NEJMra032401
    CrossRef - PubMed
    
18. Oppert M, Engel C, Bunkhorst FM, et al. Acute renal failure in patients with severe sepsis and septic shock—a significant independent risk factor for mortality: results from the German Prevalence Study. Nephrol Dial Transplant. 2008;23(3):904-909. doi:10.1093/ndt/gfm610
    CrossRef - PubMed
    
19. Morrell ED, Kellum JA, Hallows KR, Pastor-Soler NM. Epithelial transport during septic acute kidney injury. Nephrol Dial Transplant. 2014;29(7):1312-1319. doi:10.1093/ndt/gft503
    CrossRef - PubMed
    
20. Rittirsch D, Flierl MA, Ward PA. Harmful molecular mechanisms in sepsis. Nat Rev Immunol. 2008;8(10):776-787. doi:10.1038/nri2402
    CrossRef - PubMed
    
21. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101(6):1644-1655. doi:10.1378/chest.101.6.1644
    CrossRef - PubMed
    
22. Kim SY, Guevara JP, Kim KM, Choi HK, Heitjan DF, Albert DA. Hyperuricemia and risk of stroke: a systematic review and meta-analysis. Arthritis Rheum. 2009;61(7):885-892. doi:10.1002/art.24612
    CrossRef - PubMed
    
23. Lin SY, Lin CL, Chang YJ, et al. Association between kidney stones and risk of stroke. a nationwide population-based cohort study. Medicine (Baltimore). 2016;95(8):e2847. doi:10.1097/MD.0000000000002847
    CrossRef - PubMed
    
24. Chou PS, Chang WP, Chou YH. Urolithiasis is associated with an increased risk of stroke: a population-based 5-year follow-up study. Intern Med J. 2018;48(4):445-450. doi:10.1111/imj.13622
    CrossRef - PubMed
    
25. Hsu CY, Chen YT, Huang PH, et al. The association between urinary calculi and increased risk of future cardiovascular events: a nationwide population-based study. J Cardiol. 2016;67(5):463-470. doi:10.1016/j.jjcc.2015.07.016
    CrossRef - PubMed
    
26. Chung SD, Liu SP, Keller JJ, Lin HC. Urinary calculi and an increased risk of stroke: a population-based follow-up study. BJU Int. 2012;110(11 Pt C):E1053-E1059. doi:10.1111/j.1464-410X.2012.11210.x
    CrossRef - PubMed
    
27. Li C, Engstrom G, Hedblad B, Berglund G, Janzon L. Risk factors for stroke in subjects with normal blood pressure: a prospective cohort study. Stroke. 2005;36(2):234-238. doi:10.1161/01.STR.0000152328.66493.0a
    CrossRef - PubMed
    
28. Kim SY, Song CM, Bang W, Lim J, Park B, Choi HG. Nephrolithiasis predicts ischemic stroke: a longitudinal follow-up study using a national sample cohort. Int J Med Sci. 2019;16(8):1050-1056. doi:10.7150/ijms.34417
    CrossRef - PubMed
    
29. Yuan, M, Zhou HY, Hu F, et al. Association between kidney stones and risk of developing stroke: a meta-analysis. Neurol Sci. 2021;42(11):4521-4529. doi:10.1007/s10072-021-05113-5
    CrossRef - PubMed
    
30. Jarczak D, Kluge S, Nierhaus A. Sepsis-pathophysiology and therapeutic concepts. Front Med (Lausanne). 2021;8:628302. doi:10.3389/fmed.2021.628302
    CrossRef - PubMed
    
31. Hsu CY, Ordoñez JD, Chertow GM, Fan D, McCulloch CE, Go AS. The risk of acute renal failure in patients with chronic kidney disease. Kidney Int. 2008;74(1):101-107. doi:10.1038/ki.2008.107
    CrossRef - PubMed