Successful management of pseudohypoaldosteronism secondary to urinary tract malformation with urinary tract infection and gastrointestinal co-infection in an infant male: a case report

Introduction

Pseudohypoaldosteronism (PHA) is a rare syndrome of mineralocorticoid resistance. PHA has been classified into two distinct forms: PHA1, a genetic condition that consists of systemic (autosomal recessive primary PHA) or renal (autosomal dominant primary PHA) mineralocorticoid resistance, and PHA2, an autosomal dominant PHA also known as Gordon syndrome, responsible for familiar hyperkalemic hypertension (1-3). Transient PHA—also named secondary type 1 PHA (S-PHA) or PHA3—is generally induced by renal diseases [urinary tract infection (UTI) and/or malformation (UTM)], intestinal pathologies (e.g., major intestinal resection), sweat glands conditions (e.g., cystic fibrosis), sickle cell nephropathy or systemic lupus erythematosus (4-7).

In S-PHA there is a tubular impairment of sodium reabsorption, due to tubular mineralocorticoid resistance, that cause hyponatremia with renal sodium loss, moderate hyperkalemia and metabolic acidosis (4,8). Renin and aldosterone levels in serum are increased reflecting physiologically renin-angiotensin-aldosterone system (RAAS) response to lower sodium levels. The renal mechanism of resistance to aldosterone and the hyponatremia secondary to UTI/UTM are not fully explained, but it is believed that tubular and renal immaturity may contribute to the development of the disease (4,5,8).

We describe a case of severe hyponatremia due to PHA with UTM, worsened by an intercurrent UTI and also by a Salmonella enteritis that is a further non-renal cause of salt loss. PHA can be a relative unknown condition in general pediatrics. This case report highlights the importance of evaluation of renal and non-renal causes of sodium loss, as well as the possibility of genetic investigations in selected cases. We present this article in accordance with the CARE reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-24-19/rc).

Case presentation

An 8-month-old Caucasian boy was admitted to our pediatric unit in June 2022 (Figure 1) because of severe hyponatremia [113 mmol/L, normal value (n.v.) 136–145 mmol/L] with hyperkalemia (6.0 mmol/L, n.v. 3.5–5.1 mmol/L) and hypochloremia (81 mmol/L, n.v. 98–107 mmol/L) in a compensated metabolic acidosis [pH 7.4, pCO₂ 31 mmHg, HCO₃⁻ 19.1 mmol/L, base excess (BE) −6.5]. In the 2 weeks before hospitalization he had been variably irritable and drowsy, with a stunted growth and a weight loss of about 700 g. He had a variable bowel movement (without history of diarrhea or vomiting) and the diuresis was slightly concentrated with cloudy urine. On admission, the child was alert and responsive, sometimes drowsy; he was apyretic with normal vital parameters (heart rate 138 bpm, blood pressure 93/65 mmHg, respiration rate 44 bpm) but mildly dehydrated (capillary refill time 2 seconds, n.v. <2 seconds, dry lips, depressed bregmatic fontanelle and dark circles under eyes). Creatinine and urea blood levels were normal (creatinine: 0.26 mg/dL, n.v. 0.17–0.42 mg/dL); urea 15.0 mg/dL, n.v. <50 mg/dL). Other serum parameters were normal (no neutrophil leukocytosis and C-reactive protein or erythrocyte sedimentation rate elevation). Intravenous rehydration with physiological saline solution (0.9% NaCl) was started to achieve slow and progressive normalization of electrolytes.

Figure 1 Visual timeline of case report. VCUG, voiding cystourethrography; UVJ, ureterovesical junction; MAG3 scintigraphy, mercaptoacetyltriglycine scintigraphy.

Among the possible causes of hyponatremia, we excluded gastrointestinal losses (no history of vomiting or profuse diarrhea) and cystic fibrosis (negative sweat and genetic tests). Glucocorticoid deficiency or hypothyroidism were also excluded nevertheless aldosterone (6,360 ng/L, n.v. 12–240 ng/L) and renin (>2,500 mUI/L, n.v. 2.8–39.0 mUI/L) plasma concentrations were significantly increased. Furthermore, urinary electrolytes level showed a renal salt loss (NaU 20 mmol/L, KU 6 mmol/L) with a calculated fractional excretion of sodium (FENa) of 13.2% (Na 128 mEq/L, serum creatinine 0.22 mg/dL, urinary creatinine 0.22 mg/dL) plus the urinary osmolarity was not higher than plasma osmolarity (Posm 264 mOsm/kg, n.v. 275–300 mOsm/kg; Uosm 206 mOsm/kg, n.v. 300–800 mOsm/kg).

Urinalysis showed significant leukocyturia [white blood cell (WBC) 500 cells/mm³] and microscopic hematuria with a negative urine culture. Abdominal ultrasound (Figure 2A) showed a left IV–V grade hydroureteronephrosis (not previously known) with markedly dilated ureter and tortuous course up to the renal pelvis (pelvis anterior-posterior diameter of 13 mm and pre-vesical ureter of 20 mm). Amoxicillin-clavulanate treatment was prescribed (90 mg/kg/die, TID, 10 days).

Figure 2 Main findings in imaging diagnostic tests. (A) Renal ultrasonography showing severe hydroureteronephrosis (arrow) with dilated renal pelvis and calyces (asterisks). (B) Renal scintigraphy with MAG3 confirming the urinary tract malformation and decreased left kidney function. ERPF, effective renal plasma flow; LT, left; RT, right; BKG, background.

In consideration of the high aldosterone level associated with hyponatremia and hyperkalemia, we hypothesized a diagnosis of transient PHA secondary to obstructive uropathy and/or UTI. While plasma sodium gradually normalized, diarrheal stools appeared, and a Salmonella E-group was isolated. Due to intravenous rehydration (0.9% NaCl followed by a 0.9% NaCl + 5% glucose solution during all the hospitalization) and progressive resolution of diarrhea, child’s conditions improved, he started to gain weight (8.33 kg on admission, 9.63 kg 1 month later), natremia and other electrolytes values normalized (normal natremia of 136 mmol/L was reached in 5 days from the admission; 1 month later, the sodium value was stable, 138 mmol/L; at the time of discharge, the remaining electrolytes were also within the normal range: K⁺ 4.5 mmol/L, Cl⁻ 106 mmol/L). After 11 days, the patient was discharged in good general conditions.

After 3 weeks, in July 2022, patient presented a further episode of oliguria and turbid urine with a positive urine culture for multidrug-resistant Enterobacter cloacae ESBL successfully treated with gentamycin therapy (6 mg/kg/die, BID, 5 days).

To better investigate the nature of the previously unknown megaureter, a voiding cystourethrography (VCUG) was performed which excluded the presence of ureteral reflux. A renal scintigraphy with MAG3 showed an impairment drainage from left ureter, leading to the urological diagnosis of left ureterovesical junction (UVJ) obstruction (Figure 2B). The patient underwent cystoscopy for the procedure of hydrostatic dilation of the megaureter. However, during the cystoscopy, a left para-ureteral diverticulum and kinking of the left ureter were observed, making difficult the placing of the left ureteral stent. Given the technical difficulty that prevented the safe and effectiveness execution of the procedure, it was decided to suspend it and proceed directly to surgical intervention. In March 2023, the patient underwent a left ureteral reimplantation surgery (Cohen technique) and left para-ureteral diverticulum removal without post-operative UTIs nor complications.

After the treatment of UTI and the surgical correction of obstructive megaureter, the patient has never experienced further hyponatremia episodes. Plasma aldosterone and renin were evaluated on follow-up (1 month after surgery) and remained stable (aldosterone 143 ng/L, n.v. 12–240 ng/L, renin 64.6 mUI/L, n.v. 2.80–39.00 mUI/L). No adverse and unanticipated events were presented during the follow-up.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient’s parents for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

In the infant we described, severe hyponatremia was the main concern at presentation: weight loss and a mild increase of capillary refill time oriented us to hypovolemic hyponatremia. The most common cause of hypovolemic hyponatremia in children is diarrhea because of gastroenteritis. Other causes of extrarenal salt losses arise from skin, due to sweating (cystic fibrosis) or burns, or third-space losses. On the other hand, renal sodium loss may occur in a variety of situations: use of diuretics, hereditary kidney diseases, tubulointerstitial nephritis and, among other causes, lack of aldosterone effect. Aldosterone may be absent (21-hydroxylase deficiency) or alternatively, there may be a genetic or transient mineralocorticoid resistance (PHA or S-PHA) (9).

In our patient, different causes of kidney salt loss were investigated: salt-wasting crises due to congenital adrenal hyperplasia and other aldosterone synthesis defects were excluded, due to neonatal screening negativity and normal 17 hydroxyprogesterone level. Raised plasma renin and aldosterone levels, together with hyponatremia, hyperkalemia and metabolic acidosis suggested an impaired aldosterone effect and a PHA diagnosis. Abdominal ultrasound showed a severe hydroureteronephrosis of the left kidney; renal scintigraphy with MAG3 confirmed the urinary tract malformation (UTM) thus suggesting the hypothesis of PHA secondary to UTI/UTM.

PHA secondary to uropathy is mainly linked to UTM with concomitant infection, rather than to UTM or UTI alone (80% vs. 11.7% vs. 8.3%, respectively). Presentation is generally under the age of 7 months, with a peak before 3 months suggesting that the immaturity of renal tubular responsiveness in infants plays a key role in the development of secondary PHA (5,8). According to some authors, onset of hyponatremia during UTI may not be so rare (10). Similar alterations of sodium levels can be observed in different infectious diseases such as gastroenteritis, respiratory tract infections or meningitis (10,11).

From an etiopathogenetic perspective, we know that aldosterone binds the mineralocorticoid receptor of the distal renal tubule and of the cortical collecting duct activating the basolateral sodium-potassium pump, the luminal expression of the epithelial sodium channel, and the luminal renal outer medullary potassium channels. These lead to the reabsorption of sodium and the excretion of potassium, therefore, an aldosterone resistance is linked to hyponatremia, hyperkalemia, metabolic acidosis and hypovolemia (12) with a decrease in the glomerular filtration rate (1).

Resistance to aldosterone may be induced by some cytokines, such as TGF-beta, that are increased in many infections and reduce sensitivity of mineralocorticoid receptors (5). Other cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), impair the expression of sodium channels at the apical epithelial level and reduce sodium ATPase at the basolateral level. There is also an augmented antidiuretic hormone (ADH) activity caused by IL-1b, IL-6 and TNF (10,11,13). ADH binds to the vasopressin-2 receptors in the renal collecting duct and stimulates the insertion of preformed aquaporin-2 water channels into the apical plasma membrane resulting in transcellular movement of water (11).

In UTIs the pathogenetic mechanism underlying hyponatremia may be more complex than in other infections. In uropathy, hyponatremia can be caused by cytokines production, increased anterograde pressure in renal tubules and the involvement of renal parenchyma with a mild impairment of the maximal urinary concentrating ability due to bacterial invasion of the renal medulla (13,14). According to Kuhnle (15), in association with obstructive uropathy there can be also a decrease in the number—and not only a resistance—of aldosterone receptors. A different mechanism in inflammatory-infectious kidney disease could be the increase of prostaglandin and nitric oxide that downregulate the epithelial sodium channel and ATPase gene expression (10). The decrease in caloric and water intake and frequent regurgitation or vomiting episodes can be adjuvant conditions for hyponatremia (10,12). Finally, breast milk contains low sodium concentrations: if sodium losses and circulatory volume depletion occur, renin-angiotensin-aldosterone (RAA) system is activated, the resistance to aldosterone leads to hyponatremia and the release of ADH further exacerbates the hyponatremia (16).

In S-PHA, normal saline solution (0.9% NaCl) is the best choice aiming to progressive normalization of sodium values and correction of hyperkalemia and metabolic acidosis. Other treatments such as sodium bicarbonate, fludrocortisone or cation exchangers are mostly unnecessary. A slow increase in plasmatic sodium level (less than 6 mEq/L NaCl daily correction) is recommended to avoid the risk of central pontine myelinolysis (17).

In our patient, additionally to correction of electrolytes, we started antibiotic treatment, despite the initial negative urine culture, because of the ultrasound finding of hydronephrosis associated with particulate urine in the bladder, combined with a chemical-physical urine examination strongly suggestive of a UTI (presence of many leukocytes, 500/µL, and abundant mucus). Furthermore, 1 month prior, two urine tests were performed by the primary care pediatrician and these tests had shown clearly positive results (leukocyte esterase 3+, leukocytes 872/µL) but the patient was not treated.

Finally, we wondered about the role of Salmonella infection in S-PHA. Diarrhea has been described in the symptomatologic context of PHA and hyponatremia (9,18) but, at the best of our knowledge, there are no reports of PHA and Salmonella co-infection. Salmonella spp. infection may result in a secretory imbalance of intestinal ion transport with consequent hyponatremia (19). So, in our patient, gastroenteritis might have contributed to the imbalance of water and electrolyte, worsening a situation of precarious stability, or it could have been only a casual finding.

After correcting the infection and malformation, as there were no recurrences of hyponatremia and electrolyte imbalance, we did not consider it necessary to proceed with genetic investigations for the suspected, albeit rare, co-occurrence of primary PHA. At least in one study, after the therapy, the infant’s condition did not completely improve, aldosterone remained elevated, and feeding difficulties persisted. Eventually, in this infant and his mother, the molecular evaluation by chromosomal microarray analysis revealed autosomal dominant PHA due to a deletion in the NR3C2 gene (20).

In conclusion, our case is noteworthy because it describes a secondary PHA due to a UTM, likely precipitated by an intercurrent UTI, but also by a non-renal cause of salt loss, the Salmonella enteritis. Correction of the underlying structural and infectious causes of the pathology, in the absence of disease recurrence, allowed us to exclude a possible genetic disease.

Conclusions

Secondary PHA may not be a rare complication of uropathy or UTI. In an otherwise unexplained hyponatremia, it is important to obtain a urine culture and an urinary tract ultrasound to rule out UTM or UTI. In case of lack of clinical improvement or normalization of laboratory parameters, genetic causes should be excluded. In severe hyponatremia, treatment consists of correction of ion imbalance with prudent saline infusion while investigating for the etiology. Sodium correction must comply with recommended rates to avoid severe neurological sequelae.

Strengths and limitation of the study

This case report documenting an unusual clinical presentation, contributes to the existing literature and aids in the identification and management of similar cases in the future. The description of clinical and laboratory findings offers a useful educational tool for clinicians and trainees. The findings described are based on a single patient, limiting the generalizability of the observations, despite being integrated and supported by the literature. We did not explore possible genetic causes because of the patient quick recover, otherwise it would had been interesting evaluate the presence of genomic alterations.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-24-19/rc

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-24-19/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient’s parents for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

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