In this population-based study we found that childless men, as compared to fathers, are more prone to show signs of renal disease as decreased eGFR and dipstick proteinuria. The likelihood of dipstick proteinuria, with or without concomitant decrease in eGFR, remained statistically significant even after adjustment for comorbidities and traits known to be linked to impaired renal function.
Research data throwing light on the association between renal disease and male infertility, are rather scarce. Using insurance claims data, Eisenberg et al. found men with an infertility diagnosis to be at a 1.6-fold increased risk of developing renal disease, with the risk-estimates being the highest in those with azoospermia2 – the most severe form of male reproductive impairment. The study did, however, not address the issue of type and severity of the over-represented renal pathologies and did not adjust for the leading causes of CKD in western countries, i.e. diabetes and hypertension. Interestingly, in our study, after adjustment for these comorbidities as well as for other components of the metabolic syndrome, a statistically significant higher likelihood of dipstick proteinuria, and decreased eGFR together with dipstick proteinuria, respectively, was still present. This could suggest a direct association between male childlessness and impaired renal function, not mediated via traditional cardiovascular and/or metabolic disturbances. It has been suggested that a significant proportion of impaired male fertility are linked to adverse environment and/or lifestyle related exposures in early fetal life8. It appears plausible, but impossible to prove in the current study set up, that such pathogenetic factors might also be responsible for development of renal disease.
Our study also found childless men to be at a twofold higher likelihood of having dipstick proteinuria, when compared to fathers. Accumulated data from nationwide population-based studies suggests that low-grade albuminuria is associated with a higher cancer-related mortality and an increased risk of cardiovascular diseases9,10. There is also an association between low eGFR and an increased cancer incidence11. As it has been shown that men with a decreased fertility potential are at an increased risk of developing the above-mentioned diseases2,12, the higher prevalence of dipstick proteinuria and decreased eGFR in those men could etiologically and/or pathogenetically be linked to these increased risk-estimates.
For infertile couples seeking fertility care, conventional semen sample analysis, as recommended by the World Health Organization, remains the staple for male fertility evaluation13. Over the last couple of years, a discussion has emerged to extend the infertility investigation by also including a clinical, endocrinological and in certain cases genetic investigations in routine work-up of subfertile men14,15. Using solely basic semen parameters to evaluate the etiology of male reproductive impairment is insufficient as unexplained infertility is present in up to 30% of infertile couples after routine evaluation16. Moreover, as previously mentioned, multiple studies have shown male reproductive impairment to have negative long-term health consequences, such as increasing the risk of metabolic, cardiovascular diseases, and certain malignancies2,3,12,17,18. As men seeking fertility evaluation, access the healthcare system at a relatively young age, this is sometimes the first, if not the only, chance for such men to undergo basal health examinations. Presence of proteinuria is usually an early manifestation of kidney impairment occurring before the evident decline in eGFR. Thus, diagnosing this condition by use of a simple test, might contribute to prevention of serious renal issues. Our finding that childless men were more likely to have dipstick proteinuria, with or without an eGFR < 60 mL/min/1.73 m2, as compared to fathers, supports the idea of implementing additional clinical measures in the population of sub-fertile men. Considering that a single measurement of dipstick proteinuria increases the 25-year risk of developing ESRD6, childless and infertile men may represent a high-risk group which would potentially benefit from having their renal status monitored simultaneously as undergoing fertility evaluation, something which is not currently recommended.
A major strength of our study is use of a large population-based cohort containing 10,000 men with robust data concerning medical history and laboratory values. Access to complete data on the baseline profile, allowed us to obtain risk-estimates for renal dysfunction adjusted for cardiovascular disease, diabetes, and other causes of CKD. There are, however, several limitations that need to be addressed. Firstly the major concern is that almost 50% of men 45 or older were categorized as being childless uring in 1980s this proportion in Sweden being reported to be in Sweden, close to 25%19. We have relied on high quality registry data, in order to classify men into fathers or childless. Although we do not have full explanation for the high percentage seen in our cohort, it could at least partially be attributed to missing fatherhood data in the STAS register before 2005. Although reporting data to the STAS has been mandatory by law, an underreporting of adopted children or those following conception with donated sperms might have occurred. The same is true for men who have achieved fatherhood outside of Sweden before or after baseline examination. However, the events described above cannot fully explain the high proportion of childless men in our study cohort. Although any misclassification leading to some fathers being categorized as childless would probably lead to bias toward the null hypothesis, our results need to be interpreted with caution.
Secondly, male childlessness is not the most robust surrogate for impaired spermatogenesis because it could be related to rather social than male biological determinants, as well as to partner´s infertility. However, we tried taking this into account by adjusting for marital and social status – parameters related to fertility potential, awareness and social aspects influencing family planning20. Nonetheless, even with such fine adjustments, presence of voluntarily childless men still could have influenced our results, but such a misclassification would also rather have underestimated than overestimated the associations identified in this study. The dipstick proteinuria parameter was evaluated by visual reading which affects the precision of the results. To minimize this, we divided the results into two groups: non-proteinuric and proteinuric. It is important to mention that measuring serum creatinine using the Jaffe method has its limitations. Although measuring renal function with cystatin C-based equations remains superior over creatinine-based estimations, this should not cause alterations in the results when it comes to comparing renal function between childless men and fathers. Though, further research on renal function among infertile men is required, preferably with more accurate renal measures such as urinary albumin-creatinine ratio, microalbuminuria, and cystatin C-based eGFR, as dipstick proteinuria assessment has low specificity and sensitivity for early kidney impairment.
In conclusion, independent of socioeconomic status, age, or traditional risk factors such as hypertension, metabolic syndrome and diabetes, childless men as compared to fathers, were at a higher likelihood of presenting with dipstick proteinuria, with or without concomitantly decreased eGFR. Men presenting with fertility issues might represent a target population which would benefit from having their kidney function investigated.
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- Source: https://www.nature.com/articles/s41598-024-58479-9