Does treatment with dutasteride or finasteride has impact on renal morphology? Experimental study

Marcello Henrique Araújo da Silva João Henrique Duque Estrada Bianca Martins Gregório Francisco José Barcellos Sampaio Diogo Benchimol de Souza About the authors

ABSTRACT

Purpose:

To investigate whether renal modifications occur following treatment with dutasteride or finasteride.

Methods:

Twenty-four male rats were divided into three groups: control (that received distilled water), dutasteride (0.5 mg/kg/day), and finasteride (5 mg/kg/day) groups. All administrations were given by gavage for 40 consecutive days. After inducing euthanasia, blood was collected for urea and creatinine analyses, and both the kidneys were collected for stereological analyses of kidney morphology.

Results:

Serum urea and creatinine levels were increased in both the finasteride and the dutasteride groups compared with those in the control group. In addition, kidney weight, kidney volume, cortical volume, glomerular volumetric density, and mean glomerular volume were reduced in both treatment groups. Finally, the number of glomeruli per kidney was reduced by 26.8% in the finasteride group and by 51.6% in the dutasteride group compared with that in the control group.

Conclusions:

The 5-ARIs finasteride and dutasteride promoted morphological and functional damages in rat kidneys. In addition, rats in the dutasteride group showed more severe renal modifications than those in the finasteride group.

Key words
Prostatic Hyperplasia; Dutasteride; Finasteride; Kidney; Models; Animal

Introduction

Benign prostatic hyperplasia (BPH) is a disease characterized by the enlargement of prostatic epithelial and stromal tissues and reduced urinary flow, resulting in manifestations commonly known as lower urinary tract symptoms (LUTS)11 Egan KB. The epidemiology of benign prostatic hyperplasia associated with lower urinary tract symptoms: prevalence and incident rates. Urol Clin North Am. 2016;43:289-97. https://doi.org/10.1016/j.ucl.2016.04.001
https://doi.org/10.1016/j.ucl.2016.04.00...
. It is well known that ageing is correlated with BPH, which affects 50% of men older than 50 years old and 90% of men in their 80s11 Egan KB. The epidemiology of benign prostatic hyperplasia associated with lower urinary tract symptoms: prevalence and incident rates. Urol Clin North Am. 2016;43:289-97. https://doi.org/10.1016/j.ucl.2016.04.001
https://doi.org/10.1016/j.ucl.2016.04.00...
,22 Da Silva MHA, De Souza DB. Current evidence for the involvement of sex steroid receptors and sex hormones in benign prostatic hyperplasia. Res Rep Urol. 2019;11:1-8. https://doi.org/10.2147/RRU.S155609
https://doi.org/10.2147/RRU.S155609...
.

The first-line pharmacological treatment for BPH indicated by the European Association of Urology and the American Urological Association comprises 5-alpha reductase inhibitors (5-ARIs)33 Gratzke C, Bachmann A, Descazeaud A, Drake MJ, Madersbacher S, Mamoulakis C, Oelke M, Tikkinen KAO, Gravas S. EAU Guidelines on the assessment of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol. 2015;67:1099-109. https://doi.org/10.1016/j.eururo.2014.12.038
https://doi.org/10.1016/j.eururo.2014.12...
,44 Foster HE, Barry MJ, Dahm P, Gandhi MC, Kaplan SA, Kohler TS, Lerner LB, Lightner DJ, Parsons JK, Roehrborn CG, Welliver C, Wilt TJ, McVary KT. Surgical management of lower urinary tract symptoms attributed to benign prostatic hyperplasia: AUA guideline. J Urol. 2018;200:612-9. https://doi.org/10.1016/j.juro.2018.05.048
https://doi.org/10.1016/j.juro.2018.05.0...
. This class of drugs prevents the conversion of testosterone to dihydrotestosterone (DHT), which is the most active androgen22 Da Silva MHA, De Souza DB. Current evidence for the involvement of sex steroid receptors and sex hormones in benign prostatic hyperplasia. Res Rep Urol. 2019;11:1-8. https://doi.org/10.2147/RRU.S155609
https://doi.org/10.2147/RRU.S155609...
,55 Da Silva MHA, Costa WS, FJ BS, De Souza DB. The corpus cavernosum after treatment with dutasteride or finasteride: a histomorphometric study in a benign prostatic hyperplasia rodent model. Asian J Androl. 2018;20:505-10. https://doi.org/10.4103/aja.aja_28_18
https://doi.org/10.4103/aja.aja_28_18...
. As the prostate is an androgen-dependent organ, the reduction of DHT levels is often enough to reduce prostate volume and treat clinical symptoms associated with BPH.

However, treatment with 5-ARIs may result in adverse effects. For example, histomorphometrical alterations of the corpus cavernosum associated with erectile function have been previously described55 Da Silva MHA, Costa WS, FJ BS, De Souza DB. The corpus cavernosum after treatment with dutasteride or finasteride: a histomorphometric study in a benign prostatic hyperplasia rodent model. Asian J Androl. 2018;20:505-10. https://doi.org/10.4103/aja.aja_28_18
https://doi.org/10.4103/aja.aja_28_18...

6 Da Silva MHA, Medeiros JL, Jr., Costa WS, Sampaio FJB, De Souza DB. Effects of the dutasteride and sildenafil association in the penis of a benign prostatic hyperplasia animal model. Aging Male. 2019;20:1-7. https://doi.org/10.1080/13685538.2019.1653839
https://doi.org/10.1080/13685538.2019.16...
-77 Pinsky MR, Gur S, Tracey AJ, Harbin A, Hellstrom WJ. The effects of chronic 5-alpha-reductase inhibitor (dutasteride) treatment on rat erectile function. J Sex Med. 2011;8:3066-74. https://doi.org/10.1111/j.1743-6109.2011.02425.x
https://doi.org/10.1111/j.1743-6109.2011...
. Furthermore, 5-ARIs decrease the expression of endothelial growth factor (VEGF) and inhibit angiogenesis in the prostate, which explains decreased bleeding observed following prostatectomies88 Canda AE, Mungan MU, Yilmaz O, Yorukoglu K, Tuzel E, Kirkali Z. Effects of finasteride on the vascular surface density, number of microvessels and vascular endothelial growth factor expression of the rat prostate. Int Urol Nephrol. 2006;38:275-80. https://doi.org/10.1007/s11255-006-0017-2
https://doi.org/10.1007/s11255-006-0017-...
,99 Haggstrom S, Torring N, Moller K, Jensen E, Lund L, Nielsen JE, Bergh A, Damber J-E. Effects of finasteride on vascular endothelial growth factor. Scand J Urol Nephrol. 2002;36:182-7. https://doi.org/10.1080/003655902320131848
https://doi.org/10.1080/0036559023201318...
.

Nevertheless, information regarding renal damage associated with 5-ARIs in the literature is limited. Recently, it has been shown that finasteride may cause renal damage, inducing apoptosis and tubular changes1010 Baig MS, Kolasa-Wolosiuk A, Pilutin A, Safranow K, Baranowska-Bosiacka I, Kabat-Koperska J, Wiszniewska B. Finasteride-induced inhibition of 5alpha-reductase type 2 could lead to kidney damage-animal, experimental study. Int J Environ Res Public Health. 2019;16:16. https://doi.org/10.3390/ijerph16101726
https://doi.org/10.3390/ijerph16101726...
. It was further observed that this drug reduces VEGF and vascularization of renal tissue of diabetic rats1111 Tian HL, Zhao CX, Wu HY, Xu ZX, Wei LS, Zhao RT, Jin D. Finasteride reduces microvessel density and expression of vascular endothelial growth factor in renal tissue of diabetic rats. Am J Med Sci. 2015;349:516-20. https://doi.org/10.1097/MAJ.0000000000000451
https://doi.org/10.1097/MAJ.000000000000...
. However, it is not known whether treatment with 5-ARIs can modify glomerular morphology.

Thus, the objective of this study was to investigate whether treatment with the 5-ARIs dutasteride or finasteride can promote renal (specifically, glomerular) morphological modifications.

Methods

This project was approved by the local ethics committee under the protocol number CEUA-041/2017.

Twenty-four male Wistar Kyoto rats were used in this study. All animals were bred in the Urogenital Research Unit facility and were housed in a room with controlled temperature (23°C ± 1°C), artificial 12-hour dark-light cycle (lights on from 7 a.m. to 7 p.m.), and free access to the standard rat chow and water.

Rats (4 months of age) were randomly assigned to one of three groups:

  • Ctrl (n = 8): the control one, received distilled water;

  • Dut (n = 8): received 0.5 mg/kg/day of dutasteride (Dastene, Aché, Indaiatuba, SP, Brazil)55 Da Silva MHA, Costa WS, FJ BS, De Souza DB. The corpus cavernosum after treatment with dutasteride or finasteride: a histomorphometric study in a benign prostatic hyperplasia rodent model. Asian J Androl. 2018;20:505-10. https://doi.org/10.4103/aja.aja_28_18
    https://doi.org/10.4103/aja.aja_28_18...
    ,66 Da Silva MHA, Medeiros JL, Jr., Costa WS, Sampaio FJB, De Souza DB. Effects of the dutasteride and sildenafil association in the penis of a benign prostatic hyperplasia animal model. Aging Male. 2019;20:1-7. https://doi.org/10.1080/13685538.2019.1653839
    https://doi.org/10.1080/13685538.2019.16...
    ;

  • Fin (n = 8): received 5 mg/kg/day of finasteride (Finasterida, Eurofarma, São Paulo, SP, Brazil)55 Da Silva MHA, Costa WS, FJ BS, De Souza DB. The corpus cavernosum after treatment with dutasteride or finasteride: a histomorphometric study in a benign prostatic hyperplasia rodent model. Asian J Androl. 2018;20:505-10. https://doi.org/10.4103/aja.aja_28_18
    https://doi.org/10.4103/aja.aja_28_18...
    ,1010 Baig MS, Kolasa-Wolosiuk A, Pilutin A, Safranow K, Baranowska-Bosiacka I, Kabat-Koperska J, Wiszniewska B. Finasteride-induced inhibition of 5alpha-reductase type 2 could lead to kidney damage-animal, experimental study. Int J Environ Res Public Health. 2019;16:16. https://doi.org/10.3390/ijerph16101726
    https://doi.org/10.3390/ijerph16101726...
    ,1212 Garcia PV, Barbieri MF, Perobelli JE, Consonni SR, Mesquita Sde F, Kempinas WG, Pereira LAV. Morphometric-stereological and functional epididymal alterations and a decrease in fertility in rats treated with finasteride and after a 30-day post-treatment recovery period. Fertil Steril. 2012;97:1444-51. https://doi.org/10.1016/j.fertnstert.2012.03.025
    https://doi.org/10.1016/j.fertnstert.201...
    .

The drugs and the distilled water were administered by gavage for 40 consecutive days.

After the experimental period, animals were euthanized by overdose of sodium thiopental (Thiopentax 1 g, Cristália, Itapira, SP, Brazil). Immediately after death, blood was collected by cardiac puncture and centrifuged, and isolated serum was preserved at -20°C. In addition, both kidneys were collected and fixed in 4% buffered formaldehyde.

Serum creatinine and urea levels were measured with kits (kinetic creatinine and enzyme urea; Bioclin, Belo Horizonte, MG, Brazil).

Kidneys were weighed and their volumes measured by Scherle’s method1313 Marchon RG, Ribeiro CT, Costa WS, Sampaio FJB, Pereira-Sampaio MA, de Souza DB. Immediate and late effects of stress on kidneys of prepubertal and adult rats. Kidney Blood Press Res. 2018;43:1919-26. https://doi.org/10.1159/000496004
https://doi.org/10.1159/000496004...
,1414 Damasceno-Ferreira JA, Bechara GR, Costa WS, Pereira-Sampaio MA, Sampaio FJB, Souza DB. The relationship between renal warm ischemia time and glomerular loss. An experimental study in a pig model. Acta Cir Bras. 2017;32:334-41. https://doi.org/10.1590/s0102-865020170050000002
https://doi.org/10.1590/s0102-8650201700...
. Left kidneys, transversely sliced at a thickness of 2 mm into sequential sections, were used for determining the cortical-medullar ratio using Cavalieri’s principle1515 Abreu L, Damasceno-Ferreira JA, Costa WS, Pereira-Sampaio MA, Sampaio FJB, de Souza DB. Glomerular loss after renal radiofrequency ablation are comparable to 30 minutes of warm ischemia. J Endourol. 2017;31:517-21. https://doi.org/10.1089/end.2016.0899
https://doi.org/10.1089/end.2016.0899...
,1616 Souza DB, Costa WS, Cardoso LE, Benchimol M, Pereira-Sampaio MA, Sampaio FJ. Does prolonged pneumoperitoneum affect the kidney? Oxidative stress, stereological and electron microscopy study in a rat model. Int Braz J Urol. 2013;39:30-6. https://doi.org/10.1590/S1677-5538.IBJU.2013.01.05
https://doi.org/10.1590/S1677-5538.IBJU....
. The absolute cortical volume (CV) was calculated by multiplying the cortical-medullary ratio by the renal volume1313 Marchon RG, Ribeiro CT, Costa WS, Sampaio FJB, Pereira-Sampaio MA, de Souza DB. Immediate and late effects of stress on kidneys of prepubertal and adult rats. Kidney Blood Press Res. 2018;43:1919-26. https://doi.org/10.1159/000496004
https://doi.org/10.1159/000496004...
.

Fragments from the right kidneys were collected and routinely processed for paraffin embedding. Sections of 5-µm thickness were obtained and stained with hematoxylin and eosin. Twenty-five randomly selected histological fields of the cortex of each kidney were analyzed. These fields were photographed using a digital camera (DP70, Olympus, Tokyo, Japan) coupled with a microscope (BX51, Olympus, Tokyo, Japan) under 200× magnification.

Glomerular volumetric density (Vv[glom]), which indicates the proportional volume occupied by the glomeruli in the cortex, was estimated by the point-counting technique with an M42 test system1717 Benchimol de Souza D, Silva D, Marinho Costa Silva C, Barcellos Sampaio FJ, Silva Costa W, Martins Cortez C. Effects of immobilization stress on kidneys of Wistar male rats: a morphometrical and stereological analysis. Kidney Blood Press Res. 2011;34:424-9. https://doi.org/10.1159/000328331
https://doi.org/10.1159/000328331...
,1818 Bechara GR, Damasceno-Ferreira JA, Abreu LAS, Costa WS, Sampaio FJB, Pereira-Sampaio MA, De Souza DB. Glomerular morphology and renal function after warm ischemia by main artery or selective clamping in a porcine model. Urol Int. 2017;99:262-6. https://doi.org/10.1159/000458762
https://doi.org/10.1159/000458762...
. Volume-weighted glomerular volume (VWGV), which indicates the mean volume of the glomeruli, was estimated by the point-sampled intercepts method by analyzing 50 glomeruli per animal1515 Abreu L, Damasceno-Ferreira JA, Costa WS, Pereira-Sampaio MA, Sampaio FJB, de Souza DB. Glomerular loss after renal radiofrequency ablation are comparable to 30 minutes of warm ischemia. J Endourol. 2017;31:517-21. https://doi.org/10.1089/end.2016.0899
https://doi.org/10.1089/end.2016.0899...
,1717 Benchimol de Souza D, Silva D, Marinho Costa Silva C, Barcellos Sampaio FJ, Silva Costa W, Martins Cortez C. Effects of immobilization stress on kidneys of Wistar male rats: a morphometrical and stereological analysis. Kidney Blood Press Res. 2011;34:424-9. https://doi.org/10.1159/000328331
https://doi.org/10.1159/000328331...
,1818 Bechara GR, Damasceno-Ferreira JA, Abreu LAS, Costa WS, Sampaio FJB, Pereira-Sampaio MA, De Souza DB. Glomerular morphology and renal function after warm ischemia by main artery or selective clamping in a porcine model. Urol Int. 2017;99:262-6. https://doi.org/10.1159/000458762
https://doi.org/10.1159/000458762...
. Quantitative analyses of Vv[glom] and VWGV were performed using the ImageJ software (version 1.46r, National Institutes of Health, Bethesda, United States). The total number of glomeruli per kidney was estimated by dividing the product of the cortical volume and Vv[glom] by VWGV1313 Marchon RG, Ribeiro CT, Costa WS, Sampaio FJB, Pereira-Sampaio MA, de Souza DB. Immediate and late effects of stress on kidneys of prepubertal and adult rats. Kidney Blood Press Res. 2018;43:1919-26. https://doi.org/10.1159/000496004
https://doi.org/10.1159/000496004...
,1717 Benchimol de Souza D, Silva D, Marinho Costa Silva C, Barcellos Sampaio FJ, Silva Costa W, Martins Cortez C. Effects of immobilization stress on kidneys of Wistar male rats: a morphometrical and stereological analysis. Kidney Blood Press Res. 2011;34:424-9. https://doi.org/10.1159/000328331
https://doi.org/10.1159/000328331...
,1818 Bechara GR, Damasceno-Ferreira JA, Abreu LAS, Costa WS, Sampaio FJB, Pereira-Sampaio MA, De Souza DB. Glomerular morphology and renal function after warm ischemia by main artery or selective clamping in a porcine model. Urol Int. 2017;99:262-6. https://doi.org/10.1159/000458762
https://doi.org/10.1159/000458762...
.

One-way analysis of variance (ANOVA) with Bonferroni’s post-hoc test was used to compare mean values, with the significance level set at p<0.05. All analyses were performed using the GraphPad Prism software (version 5.0, San Diego, CA, United States).

Results

Urea serum levels increased by 152.5% in the Dut group and 81.7% in the Fin group compared with those in the Ctrl group. Creatinine serum levels were also increased by 166.3% in Dut group and by 124.4% in Fin group compared with those in Ctrl group. All numerical data are presented in Table 1.

Table 1
Serological and renal morphological data of rats receiving dutasteride or finasteride vs. control*.

Kidney weights in the Dut and Fin groups decreased by 14.5 and 23.1%, whereas kidney volumes decreased by 14.8 and 24.3%, respectively, compared with those in the Ctrl group.

Cortical-medullary ratio decreased by 32.9% in the Dut group and by 8% in the Fin group compared with that in the Ctrl group. Regarding the absolute cortical volume, the Dut group had a decrease of 41.2% and the Fin group had a decrease of 29.9% compared with the Ctrl group.

In addition, Vv[Glom] and VWGV were reduced in both Dut and Fin groups compared with the ones in the Ctrl group. Animals receiving dutasteride had 36.7% reduction in Vv[Glom] and 21.1% reduction in VWGV. Rats from the Fin group showed 29.7% reduction in Vv[Glom] and 31.2% reduction in VWGV. Figure 1 shows representative images of renal cortex from the groups.

Figure 1
Photomicrographs of renal cortex from the experimental groups: (a) control group, composed of Wistar Kyoto rats that received distilled water; (b) dutasteride group, composed of rats that received dutasteride; (c) finasteride group, composed of rats that received finasteride hematoxylin and eosin, 200x.

Finally, the number of glomeruli per kidney was reduced by 51.6% in the Dut group and 26.8% in the Fin group compared to the Ctrl group. This represents a loss of approximately 49.200 and 25.600 glomeruli per kidney, caused by the treatment with dutasteride and finasteride, respectively.

Discussion

The present study is the first to demonstrate that 5-ARIs treatment induces reduction in the number of glomeruli in rats. It is well known that the treatment of BPH or alopecia with 5-ARIs may be associated with side effects. These side effects are mainly seen in the penis and characterized by morphological alterations in the corpora cavernosum and transient or permanent erectile disfunction55 Da Silva MHA, Costa WS, FJ BS, De Souza DB. The corpus cavernosum after treatment with dutasteride or finasteride: a histomorphometric study in a benign prostatic hyperplasia rodent model. Asian J Androl. 2018;20:505-10. https://doi.org/10.4103/aja.aja_28_18
https://doi.org/10.4103/aja.aja_28_18...

6 Da Silva MHA, Medeiros JL, Jr., Costa WS, Sampaio FJB, De Souza DB. Effects of the dutasteride and sildenafil association in the penis of a benign prostatic hyperplasia animal model. Aging Male. 2019;20:1-7. https://doi.org/10.1080/13685538.2019.1653839
https://doi.org/10.1080/13685538.2019.16...
-77 Pinsky MR, Gur S, Tracey AJ, Harbin A, Hellstrom WJ. The effects of chronic 5-alpha-reductase inhibitor (dutasteride) treatment on rat erectile function. J Sex Med. 2011;8:3066-74. https://doi.org/10.1111/j.1743-6109.2011.02425.x
https://doi.org/10.1111/j.1743-6109.2011...
. However, information regarding side effects in other organs is scarce, especially in tissues not typically recognized as androgen-dependent.

Several conditions can lead to reduction in the number of glomeruli, including stress, renal ischemia, radiofrequency ablation, hypertension, and diabetes1313 Marchon RG, Ribeiro CT, Costa WS, Sampaio FJB, Pereira-Sampaio MA, de Souza DB. Immediate and late effects of stress on kidneys of prepubertal and adult rats. Kidney Blood Press Res. 2018;43:1919-26. https://doi.org/10.1159/000496004
https://doi.org/10.1159/000496004...

14 Damasceno-Ferreira JA, Bechara GR, Costa WS, Pereira-Sampaio MA, Sampaio FJB, Souza DB. The relationship between renal warm ischemia time and glomerular loss. An experimental study in a pig model. Acta Cir Bras. 2017;32:334-41. https://doi.org/10.1590/s0102-865020170050000002
https://doi.org/10.1590/s0102-8650201700...
-1515 Abreu L, Damasceno-Ferreira JA, Costa WS, Pereira-Sampaio MA, Sampaio FJB, de Souza DB. Glomerular loss after renal radiofrequency ablation are comparable to 30 minutes of warm ischemia. J Endourol. 2017;31:517-21. https://doi.org/10.1089/end.2016.0899
https://doi.org/10.1089/end.2016.0899...
,1717 Benchimol de Souza D, Silva D, Marinho Costa Silva C, Barcellos Sampaio FJ, Silva Costa W, Martins Cortez C. Effects of immobilization stress on kidneys of Wistar male rats: a morphometrical and stereological analysis. Kidney Blood Press Res. 2011;34:424-9. https://doi.org/10.1159/000328331
https://doi.org/10.1159/000328331...

18 Bechara GR, Damasceno-Ferreira JA, Abreu LAS, Costa WS, Sampaio FJB, Pereira-Sampaio MA, De Souza DB. Glomerular morphology and renal function after warm ischemia by main artery or selective clamping in a porcine model. Urol Int. 2017;99:262-6. https://doi.org/10.1159/000458762
https://doi.org/10.1159/000458762...

19 Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE. Human nephron number: implications for health and disease. Pediatr Nephrol. 2011;26:1529-33. https://doi.org/10.1007/s00467-011-1843-8
https://doi.org/10.1007/s00467-011-1843-...
-2020 Turoni CM, Reynoso HA, Marañón RO, Coviello A, Peral de Bruno M: Structural changes in the renal vasculature in streptozotocin-induced diabetic rats without hypertension. Nephron Physiol. 2005;99:50-7. https://doi.org/10.1159/000083136
https://doi.org/10.1159/000083136...
. All these conditions are associated with an increased risk of chronic kidney disease. Moreover, the relationship between decreased glomeruli and decreased glomerular filtration rate is well known2121 Viggiano D, Nigro M, Sessa F, Vignolini G, Campi R, Serni S, Pollastro RM, Vallone G, Gigliotti G, Capasso G. The number of nephrons in different glomerular diseases. Peer J. 2019;7:e7640. https://doi.org/10.7717/peerj.7640
https://doi.org/10.7717/peerj.7640...
. Thus, the quantification of the number of glomeruli, which corresponds to the number of nephrons, becomes a useful and sensitive method to morphologically evaluate possible damage to renal function.

Renal function is not always immediately impaired by glomerular loss. Previous studies have demonstrated considerable loss of glomeruli without changes in serum levels of urea or creatinine2222 de Souza DB, de Oliveira LL, da Cruz MC, Abílio EJ, Costa WS, Pereira-Sampaio MA, Sampaio FJB. Laparoscopic partial nephrectomy under warm ischemia reduces the glomerular density in a pig model. J Endourol. 2012;26:706-10. https://doi.org/10.1089/end.2011.0412
https://doi.org/10.1089/end.2011.0412...
,2323 Damasceno-Ferreira JA, Abreu LAS, Bechara GR, Costa WS, Pereira-Sampaio MA, Sampaio FJB, De Souza DB. Mannitol reduces nephron loss after warm renal ischemia in a porcine model. BMC Urol. 2018;18:16. https://doi.org/10.1186/s12894-018-0328-5
https://doi.org/10.1186/s12894-018-0328-...
. Although the loss of glomeruli is irreversible1919 Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE. Human nephron number: implications for health and disease. Pediatr Nephrol. 2011;26:1529-33. https://doi.org/10.1007/s00467-011-1843-8
https://doi.org/10.1007/s00467-011-1843-...
,2424 Meyrier A. Mechanisms of disease: focal segmental glomerulosclerosis. Nat Clin Pract Nephrol. 2005;1:44-54. https://doi.org/10.1038/ncpneph0025
https://doi.org/10.1038/ncpneph0025...
, unaffected glomeruli can increase their filtration rate, thus keeping the renal biomarkers at a normal level2525 Deen WM, Maddox DA, Robertson CR, Brenner BM. Dynamics of glomerular ultrafiltration in the rat. VII. Response to reduced renal mass. Am J Physiol. 1974;227:556-62. https://doi.org/10.1152/ajplegacy.1974.227.3.556
https://doi.org/10.1152/ajplegacy.1974.2...
. In the present study, an increase in serum urea and in creatinine levels was observed, indicating that renal damage caused by 5-ARIs was greater than the hyperfiltration capacity of the remaining glomeruli.

Some studies have shown that treatment with 5-ARIs causes decrease in VEGF expression, an increase in collagen in the renal medullar zone, and renal cell apoptosis99 Haggstrom S, Torring N, Moller K, Jensen E, Lund L, Nielsen JE, Bergh A, Damber J-E. Effects of finasteride on vascular endothelial growth factor. Scand J Urol Nephrol. 2002;36:182-7. https://doi.org/10.1080/003655902320131848
https://doi.org/10.1080/0036559023201318...

10 Baig MS, Kolasa-Wolosiuk A, Pilutin A, Safranow K, Baranowska-Bosiacka I, Kabat-Koperska J, Wiszniewska B. Finasteride-induced inhibition of 5alpha-reductase type 2 could lead to kidney damage-animal, experimental study. Int J Environ Res Public Health. 2019;16:16. https://doi.org/10.3390/ijerph16101726
https://doi.org/10.3390/ijerph16101726...
-1111 Tian HL, Zhao CX, Wu HY, Xu ZX, Wei LS, Zhao RT, Jin D. Finasteride reduces microvessel density and expression of vascular endothelial growth factor in renal tissue of diabetic rats. Am J Med Sci. 2015;349:516-20. https://doi.org/10.1097/MAJ.0000000000000451
https://doi.org/10.1097/MAJ.000000000000...
. DHT is known to regulate several functions in androgen-dependent organs, and the deprivation of this hormone (which is inhibited by 5-ARIs) can promote changes in the urogenital system22 Da Silva MHA, De Souza DB. Current evidence for the involvement of sex steroid receptors and sex hormones in benign prostatic hyperplasia. Res Rep Urol. 2019;11:1-8. https://doi.org/10.2147/RRU.S155609
https://doi.org/10.2147/RRU.S155609...
,55 Da Silva MHA, Costa WS, FJ BS, De Souza DB. The corpus cavernosum after treatment with dutasteride or finasteride: a histomorphometric study in a benign prostatic hyperplasia rodent model. Asian J Androl. 2018;20:505-10. https://doi.org/10.4103/aja.aja_28_18
https://doi.org/10.4103/aja.aja_28_18...

6 Da Silva MHA, Medeiros JL, Jr., Costa WS, Sampaio FJB, De Souza DB. Effects of the dutasteride and sildenafil association in the penis of a benign prostatic hyperplasia animal model. Aging Male. 2019;20:1-7. https://doi.org/10.1080/13685538.2019.1653839
https://doi.org/10.1080/13685538.2019.16...
-77 Pinsky MR, Gur S, Tracey AJ, Harbin A, Hellstrom WJ. The effects of chronic 5-alpha-reductase inhibitor (dutasteride) treatment on rat erectile function. J Sex Med. 2011;8:3066-74. https://doi.org/10.1111/j.1743-6109.2011.02425.x
https://doi.org/10.1111/j.1743-6109.2011...
. In addition, it has previously been shown that DHT reduction affects both angiogenesis and VEGF levels in the prostate2626 Pareek G, Shevchuk M, Armenakas NA, Vasovic L, Hochberg DA, Basillote JB, Fracchia JA. The effect of finasteride on the expression of vascular endothelial growth factor and microvessel density: a possible mechanism for decreased prostatic bleeding in treated patients. J Urol. 2003;169:20-3. https://doi.org/10.1097/01.ju.0000039923.75777.91
https://doi.org/10.1097/01.ju.0000039923...

27 Steers WD. 5alpha-reductase activity in the prostate. Urology. 2001;58:17-24. https://doi.org/10.1016/s0090-4295(01)01299-7
https://doi.org/10.1016/s0090-4295(01)01...
-2828 Marshall S, Narayan P. Treatment of prostatic bleeding: suppression of angiogenesis by androgen deprivation. J Urol. 1993;149:1553-4. https://doi.org/10.1016/s0022-5347(17)36446-7
https://doi.org/10.1016/s0022-5347(17)36...
. Future studies that add insight into the mechanisms underlying DHT and 5-ARI activity in renal tissue are warranted.

In our study, we observed that the number of glomeruli decreased in animals treated either with dutasteride or finasteride, with a greater reduction seen in the animals treated with dutasteride. The fact that this drug acts on more isoforms of the 5-alpha-reductase enzyme22 Da Silva MHA, De Souza DB. Current evidence for the involvement of sex steroid receptors and sex hormones in benign prostatic hyperplasia. Res Rep Urol. 2019;11:1-8. https://doi.org/10.2147/RRU.S155609
https://doi.org/10.2147/RRU.S155609...
,55 Da Silva MHA, Costa WS, FJ BS, De Souza DB. The corpus cavernosum after treatment with dutasteride or finasteride: a histomorphometric study in a benign prostatic hyperplasia rodent model. Asian J Androl. 2018;20:505-10. https://doi.org/10.4103/aja.aja_28_18
https://doi.org/10.4103/aja.aja_28_18...
may explain the greater renal damage observed in the present study. Thus, in patients whose renal function is an important aspect to be considered, the use of finasteride may be preferred over dutasteride. The use of alpha-1 blockers may also be a good option in these cases. However, there is evidence that this class of drugs promotes various adverse effects, including renal adverse ones2929 Mori Y, Matsubara H, Nose A, Shibasaki Y, Masaki H, Kosaki A, Okigaki M, Fujiyama S, Tanaka-Uchiyama Y, Hasegawa T, Iba O, Tateishi E, Amano K, Iwasaka T. Safety and availability of doxazosin in treating hypertensive patients with chronic renal failure. Hypertens Res. 2001;24:359-63. https://doi.org/10.1291/hypres.24.359
https://doi.org/10.1291/hypres.24.359...
,3030 Koski RR, Zufall WH: Efficacy and safety of alpha-blockers for kidney stones in adults. J Pharm Technol. 2018;34:54-61. https://doi.org/10.1177/8755122517750398
https://doi.org/10.1177/8755122517750398...
.

Although rodents are widely used, the use of an animal model can be considered a limitation of the present study, as the results cannot be directly extrapolated to humans. Future clinical studies that add knowledge regarding the possible kidney damage caused by 5-ARIs are warranted. Furthermore, studies with longer follow-up periods are required to better understand the long-term renal effects of finasteride and dutasteride.

Conclusions

The 5-ARIs finasteride and dutasteride promote morphological modifications in the kidneys with biomarker alterations in a rodent model. Dutasteride showed more severe modifications than finasteride. If confirmed in humans, these findings should be considered when choosing BPH treatment, especially in patients with a history of renal disease.

Acknowledgments

Not applicable.

  • Research performed at Urogenital Research Unit, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro (RJ), Brazil.
  • Data availability statement

    Data will be available upon request.
  • Funding

    Fundação Carlos Chagas Filho de Amparo Pesquisa do Estado do Rio de Janeiro
    Grant no. E26/202.662/2018
    Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
    Grant no. 88882.450716/2019-01
    Conselho Nacional de Desenvolvimento Científico e Tecnológico
    Grant no. 2915901470564504

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Publication Dates

  • Publication in this collection
    15 Sept 2021
  • Date of issue
    2021

History

  • Received
    09 Apr 2021
  • Reviewed
    11 June 2021
  • Accepted
    08 July 2021
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