Introduction

Down syndrome (DS) is the most common chromosomal abnormality, with a prevalence of 1–2 cases per 1,000 births. DS has many manifestations that can affect multiple organ systems, but kidney disease has not been typically considered a frequent complication. Reports of patients with renal diseases are increasing, partially due to increased survival [1]. A variety of urological abnormalities have been described such as ureteropelvic junction obstruction [2], vesicoureteral reflux [3], renal hypoplasia [4], obstructive uropathy or posterior urethral valves [5]. Glomerulopathies have also been reported, including membranoproliferative glomerulonephritis [6], immunoctactoid (amyloid-like glomerular deposits) glomerulopathy [7], focal and segmental sclerosis or hypercalcemia with medullary calcinosis [8]. A growing number of patients with DS who develop chronic renal failure (CRF) requiring renal transplantation or replacement therapy has been reported [9].

The aim of this study was to study the incidence of renal disease in a series of patients with DS followed up at a pediatric genetics department of a tertiary pediatric care center and to describe the main pathological findings.

Patients and methods

A cross-sectional study was carried out in patients with DS followed-up in a pediatric genetics unit of a tertiary hospital. All families were properly informed and gave their consent for participation. Children were referred to the division of pediatric nephrology for evaluation. Medical records were reviewed for age, gender, perinatal events and associated malformations. Families were instructed to collect a 24-h urine specimen. A blood sample was obtained at the completion of the urine collection; height, weight and blood pressure were measured. Hypertension was defined if systolic or diastolic blood pressure values exceeded the p95 of the reference values for each patient’s age, length and sex [10]. Kidney and urinary tract structures were evaluated by ultrasonography. Glomerular filtration rate (GFR) was estimated by the Schwartz formula [11] in girls and children younger than 14 years and by the Cockroft method in the adult patients [12]. CRF was defined as creatinine clearance below 70 ml/min/1.73 m2. Fractional excretion of sodium and potassium, tubular reabsortion of phosphate, urinary excretion of calcium, magnesium, uric acid and proteinuria were also determined and compared with reference values for the general population [13]. Hypercalciuria was defined as urine calcium excretion higher than 4 mg/kg/day. Uric acid excretion higher than 800 mg/day/1.73 m2 was considered as hyperuricosuria. Pathological proteinuria was defined by values higher than 4 mg/m2/h. All statistical analyses were performed using SPSS Software Package (SPSS, Chicago, Ill.).

Results

Sixty nine patients (37 boys, 32 girls) aged 12 months to 24 years (median 9.7 years) were recruited. Eighteen patients (26%) had congenital heart defects, all of them acyanotic.

Clinical findings

Five patients (four boys and a girl) had enuresis, a 7.5-year-old boy had sporadic urinary incontinence and a girl had pollakiuria. One patient (1.8%), a 7-year-old girl with normal renal function and no obesity, presented with hypertension.

Analytical data

GFR was determined in 66 patients, and three patients (4.5%) had CRF (Table 1), with no clinical symptoms and normal ultrasound. Eight patients (11.6%) presented with asymptomatic hyperuricemia.

Table 1 Patients with Down syndrome and chronic renal failure. GFR glomerular filtration rate, EFD endocardial fusion defects, VFD ventricular fusion defects
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Urinalysis revealed microscopic hematuria in two boys and mild proteinuria in three patients (all of them with normal renal function), whose clinical findings are explained in Table 2. Eighteen patients were found to have hyperuricosuria (24.2%). Four patients had asymptomatic hypercalciuria (two of them also had high urate excretion). No abnormalities in the fractional excretion of sodium, potassium and phosphate were found.

Table 2 Ultrasound abnormalities and laboratory findings. GFR glomerular filtration rate. *Proteinuria expressed as mg/m2/h
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Only minor radiological abnormalities were detected in five patients (7.3%): bladder hypertrophy in a male with microscopic hematuria, medullary hyperechogenicity as the only finding in a case of asymptomatic hypercalciuria, ectopic left kidney, small kidney associated with pollakiuria and right kidney pyelectasia in a 7-year-old boy with nocturnal enuresis (Table 2).

Discussion

Down syndrome can affect multiple organ systems, although renal disease has been thought to be quite rare. In 1960, Berg et al. [2] described the first cases of DS with renal and urological malformations. Since them, published data concerning this issue have generally been restricted to sporadic case reports; only a descriptive study of DS patients with congenital heart disease focusing on kidney disease [14] and a review of the literature [15] have been reported previously. The incidence of renal and urological anomalies has been estimated as 3.5–21.4% [2, 4]. A variety of urological abnormalities have been described, including ureteropelvic junction obstruction, vesicoureteral reflux [3], renal hypoplasia [15], obstructive uropathy [4] and posterior urethral valves [5]. We have found a single case of asymptomatic renal pelvic dilatation and a patient with left kidney ectopia and no other clinical findings. Benaccerraf et al. [16] suggested that fetal pyelectasis could be associated with DS, but results are controversial; the risk of DS in isolated pyelectasis in a low risk population has been estimated as less than 1 in 340 [17]. Some authors suggest that the incidence of renal and urological anomalies in DS is high enough to encourage systematic screening [5, 15]. Thus, ultrasound should be performed in these infants early in life and, if abnormal, a voiding cystourethrogram to rule out any urological abnormality should also be performed.

To our knowledge, our study includes the largest population of young DS patients specifically investigated for renal disease. Urinalysis revealed five cases of hematuria and mild proteinuria as the only possible hint of glomerulopathy, and all of them had normal GFR. Pathological proteinuria was defined by a value higher than 4 mg/m2/h in a 24-h urine sample, but a postural element could have been present. We think that no specific glomerulopathy is associated with DS. Some autopsy studies in DS patients have reported “typical” histological findings, including glomerular microcysts, tubular dilatation and immature glomeruli [4, 18]. Ariel et al. [4] found 30 patients with cysts in the autopsy of urinary systems in 97 DS patients. Lo et al. [19] reported that cystic dilatation of Bowman’s space was more frequent than in the general population, and these findings were more common after the 1st decade of life. Acquired glomerulopathies have also been reported in DS patients, including membranoproliferative glomerulonephritis [6], inmunoctactoid glomerulopathy [7], focal and segmental sclerosis [19], amyloidosis [20] and hemolytic-uremic syndrome [9]. In addition, it has been reported that DS patients with autoimmune diseases (celiac disease, alopecia or hypothyroidism) may also present with primary glomerulonephritis [21], including two cases of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis [22, 23]. It remains unclear, however, whether the coexistence of DS, autoimmune disorders and renal disease is somehow associated or whether it is just a coincidence due to their relatively common respective prevalence.

Four patients with asymptomatic hypercalciuria were detected. All of them had normal ultrasonographic findings, with the exception of one case of medullary hyperechogenicity with normal GFR. We think that these findings are different from previous reports of several patients with DS, hypercalcemia, hypercalciuria and medullary nephrocalcinosis [8, 24, 25] who progressed to renal insufficiency. A possible genetic predisposition to excessive dietary calcium absorption or a tubular disorder has been postulated to explain these cases [24].

Hyperuricemia and hyperuricosuria were the most frequent findings in our population. Increased serum uric acid level [26, 27] and the eventual development of gout [28, 29] have been previously documented. This could be explained by a decreased urinary clearance of uric acid [27] added to a decreased fractional excretion in DS patients [26]. Despite the relatively high frequency of uric acid disturbances observed, none of our patients developed gout.

We did not find malignant degeneration. Renal tumors in DS are extremely uncommon, and only four cases have ever been published: one malignant renal cancer of unstated histology [30], two nephroblastomas [31, 32] and one case of nephroblastomatosis [33].

Some DS patients develop end-stage renal disease, and we have found a CRF prevalence of 4.5% in our study, with unclear etiology. Two of our three patients with CRF are in their late teens, as are the majority of cases previously reported [9]. Two of these patients had acyanotic congenital heart defects (a 22-year-old female with an endocardial fusion defect and a 2.5-year-old boy with a ventricular septal defect), but we think there is no higher risk of CRF in patients presenting with these cardiovascular problems. Subrahmanyam et al. [14] have previously reported the results of 54 patients (40 of whom had congenital heart disease) and concluded that children with DS do not have a higher incidence of clinically significant renal anomalies compared to the general population.

CRF was defined by estimated GFR, using the Cockroft or Schwartz criteria, depending on age. Although it could be suggested, that this method is inaccurate as a sole indicator of impaired renal function, we think it could be enough as a screening test and regular follow-up should be carried out. Our patients have a mild impairment with GFR, and thus, conservative treatment was carried out and no biopsy performed. Renal transplantation is found to be a reasonable option in end-stage renal failure treatment for DS patients [34], and it seems to be the preferred treatment modality, although a few pediatric cases of DS on dialysis have been reported [35]. Nonetheless, the absence of other serious medical problems, level of psychomotor development and family support also must be taken into account in order to choose the best treatment option when the patient develops end-stage renal disease [36].

It is well known that DS patients are at a risk for infections, but we did not find a higher incidence of urinary tract infections compared with the general population.

Our population had an incidence of clinical symptoms of about 11.5%, mostly related to voiding disturbances, as others authors have previously noted [3]. According to our data, the incidence of renal anomalies in DS patients does not appear to be different when compared to the general population. We found that there are several signs and symptoms, most of them minor pathologies (hematuria, proteinuria or hypertension) that would require no treatment but rather follow-up. We consider that systematic follow-up of DS patients should be recommended: we suggest including a first evaluation (including ultrasound examination) and periodical urinalysis and serum creatinine levels determinations, synchronized with other regular blood analysis in DS patients.

In conclusion, renal disease in patients with DS is not very common, yet not rare, and it presents with a wide spectrum of findings. According to the variety of pathological findings, and in order to detect early CRF, it seems reasonable to perform regular monitoring of renal function in these patients.