Kidney and urogenital abnormalities in Down syndrome: a meta-analysis

Down syndrome is likely the most recognizable genetic syndrome and occurs in approximately 1 in 600–800 live births without predilection for ethnicity or socioeconomic class. It is a common cause of intellectual disability [1‐3]. In addition, people with Down syndrome have a variety of medical conditions and malformations such as somatic growth retardation; hearing loss; obstructive sleep apnea; wheezing airway disorders; otitis media; eye disease, including cataracts and refractive errors; heart defects; gastrointestinal defects; hip dislocation; atlantoaxial instability; autoimmune diseases including hypothyroidism and, less commonly, celiac disease, juvenile idiopathic arthritis, and type 1 diabetes mellitus; and transient myeloproliferative disorder and leukaemia [4, 5].

Available reviews and guidelines on Down syndrome do not or only marginally address the issue of anomalies of the kidney and urinary tract and lower urinary tract dysfunctions [6‐10]. Since this matter has never been systematically reviewed, we performed a meta-analysis of the literature addressing these issues.

The results of the present review point out that individuals with Down syndrome have a five-fold higher risk of kidney and urogenital abnormalities and an almost 3 times higher risk of lower urinary tract dysfunctions as compared to healthy controls. Moreover, the kidney size of individuals with Down syndrome is reduced.

Current guidelines for adults with Down syndrome do not provide any recommendation on kidney and urogenital abnormalities [8]. Pediatric guidelines advise routine postnatal evaluation for kidney anomalies only in cases with prenatal abnormalities [7]. The present meta-analysis detected a 0.6% prevalence of anomalies of the kidney and urinary tract and a 50% prevalence of lower urinary tract dysfunction in Down syndrome. These data support the recommendations available for pediatric subjects. Moreover, these findings point out that a thorough medical history and a careful genital and perineal examination are important in every newborn with Down syndrome. In children, clinicians should routinely look also for symptoms of lower urinary tract dysfunction, such as incontinence, nycturia, increased daytime frequency or weak stream. In case of pathological history or examination, an ultrasound evaluation of the urinary tract and kidney morphology should be performed. Finally, since conventional ultrasound can occasionally fail to detect posterior urethral valves, a voiding cystourethrography deserves consideration in boys with recurrent urinary tract infections or in front of significant postnatal ultrasound abnormalities [21].

Both kidney and urinary tract abnormalities, and lower urinary tract dysfunction may predispose to urinary tract infections [22]. Since this diagnosis is challenging in children with intellectual disabilities, a high index of suspicion is required.

Reduced kidney size was demonstrated in 2 controlled studies. The results of the kidney size studies are supported by uncontrolled investigations, which addressed the creatinine level and the estimated glomerular filtration rate in large Down syndrome cohorts and suggest the need for specific reference values and equations to estimate glomerular filtration rate [23, 24].

In clinical nephrology, the detection of small kidneys suggests the presence of chronic kidney disease. Therefore, the finding of smaller than normal kidneys in people with Down syndrome suggests an increased tendency to develop a chronic kidney disease. An increased prevalence of immune-mediated kidney diseases may also be expected, considering that non-renal autoimmune conditions such as thyroid diseases, celiac disease, juvenile idiopathic arthritis, and type 1 diabetes mellitus are common in Down syndrome [25]. Hence, signs and symptoms consistent with chronic kidney disease should be regularly evaluated, starting from infancy, including measurement of blood pressure and assessment of kidney function. Both kidney replacement therapy [26] and transplantation [27] have been performed in end-stage renal disease patients with Down syndrome.

This study has some limitations. The main is related to the relevant heterogeneity in studies addressing malformations and lower urinary tract dysfunctions. The heterogeneity noted in the studies addressing malformations is likely caused by the different upper age limits of subjects included in the studies [14‐17]. The heterogeneity noted in studies addressing lower urinary tract dysfunctions [12] is likely due to the diagnostic criteria, which were based on history alone in 2 studies [18, 19] and more objective criteria in another study [17]. The terminology used to denote both the obstructive urinary tract malformations and the lower urinary tract dysfunctions was inconsistent, and the well-recognized role of sex on the pattern and prevalence of urinary tract malformations and lower urinary tract dysfunctions was partly disregarded in the literature. Furthermore, the quality of some papers was quite poor as well. Finally, the kidney size was evaluated only in 2 studies, thereby preventing a formal meta-analysis of this outcome.

This meta-analysis demonstrates that a variety of abnormalities of the kidney and urogenital tract, lower urinary tract dysfunctions, and a slightly reduced kidney size are more common in subjects with Down syndrome than in the general population. There is an opportunity to improve the care of children with Down syndrome by providing some specific advice on the management of kidney and urinary tract malformations and dysfunctions [28]. Future efforts should answer the question of whether the increased prevalence of urinary tract malformations translates in an increased occurrence of urinary tract infections and address the long-term nephro-urological outcome at adult age. Finally, a survey to determine the current patterns of evaluation and management of these issues pertaining to kidneys and urogenital tract among Down syndrome Clinics is recommended.