Discussion
The key finding in our study is the identification of
RMND1 deficiency as a possible genetic cause of hyporeninemic hypoaldosteronism in infancy. The evidence of
RMND1 deficiency results from the genetic findings in patient 3 and is supported by the genetic findings in patients 1 and 2 with both a pathogenic and a highly probable pathogenic mutation. Functional testing of the probable pathogenic mutation according to the technique applied by Janer [
1] was not possible due to the lack of muscle tissue or fibroblasts.
Genetic defects associated with hyporeninemic hypoaldosteronism in childhood are rare. Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal dysgenesis, clinically characterized by persistent anuria and perinatal death. Rarely, these mutations can also be present as a progressive chronic disease [
6]. Autosomal dominant tubulointerstitial kidney disease due to
REN mutation can be present in childhood [
7]. Arterial thrombosis observed in patients 1 and 2 has not been described in
RMND1 mutations. Mutations in inherited thrombophilia genes [
8,
9] factor V Leiden, prothrombin mutation, protein C deficiency, protein S deficiency, and antithrombin deficiency, however, were absent. Probably, a second hereditary defect was present, which we were unable to detect. Small ovaries observed in patient 1 can reflect a causative role of
RNMD1 mutation in Perrault syndrome [
10].
Shayota et al. [
4] commented about the clinical presentation of kidney disease including electrolyte imbalance suggesting pseudohypoaldosteronism type 1 reported in 4 patients. Ng et al. [
3] collected clinical and laboratory data from 34 patients with recessive mutations in
RMND1. Persistent hyponatremia and hyperkalemia were reported in 13 of them. In 17 patients, different stages of chronic kidney disease were present, probably using oral K + binders as in our patients in a later phase of their disease. Initial electrolyte imbalance would remain undetected. In our patients, electrolyte abnormalities were caused by a lack of sufficient aldosterone due to low renin activity. Angiotensin II infusion in patient 1 augmented plasma aldosterone concentration [
5].
Low plasma aldosterone may explain the observed electrolyte disturbances. Fine tuning of renal Na
+ and K
+ excretion occurs in the distal part of the nephron [
11,
12]. The aldosterone-sensitive distal nephron (ASDN) comprises the late distal convoluted tubule, connecting tubule, and entire collecting duct. Na
+ transport in ASDN is mediated by epithelial Na
+ (ENac). By upregulating ENac, aldosterone induces a lumen-negative transepithelial potential difference favoring K
+ secretion. In addition, activation of Na
+-K
+-ATPase promotes K
+ entry via the basolateral site into ASDN cells. Beside these effects, aldosterone directly stimulates K
+ channels apical ROMK and apical BK channels in type α intercalated cells. Aldosterone facilitates H
+ secretion via H
+-ATPase in the apical membrane of the α-intercalated cells.
A lack of stimulation by aldosterone will induce hyponatremia by urinary Na+ loss, plasma hyperkalemia, and acidosis, as was observed in our patients.
Mitochondrial disorders constitute a group of often misdiagnosed diseases with frequent multisystemic involvement especially the nervous system and muscles. Mitochondria are recognized as key players in genetic kidney disease [
13‐
15]. Renal tubular cells have very high metabolic rates and are rich in mitochondria. Proximal tubulopathy is the most common phenotype reported in mitochondrial disorders as mitochondrial aerobic respiration is required for the energy-consuming task of reabsorption of the majority of glomerular filtrate. Tubulointerstitial nephritis is rarely reported. In our patient and in all reported biopsies of
RMND1-affected patients, this tubulointerstitial damage is present. Electron microscopy in the patient reported by Gupta et al. [
16] showed mildly enlarged mitochondria with a fluffy granular matrix in tubular cells. Niaudet and Rötig [
17] reported that in their patients with tubulointerstitial nephritis due to mitochondrial defects, proximal tubular defects were absent. In our patient with pronounced symptoms of hyporeninemic hypoaldosteronism at the age of 7–12 months, a normal function of the proximal tubule and a still normal concentrating capacity were present.
Release of renin from juxtamedullary cells is precisely controlled by several well-characterized factors [
18,
19]. The major physiological pathway of this release is the macula densa mechanism. The factor(s) involved in the defective release in
RMND1 deficiency are not known. In patient 1, not only a lower plasma renin concentration but also a decrease of plasma prorenin was measured. Prorenin is produced by principal cells of the collecting duct and secreted into the tubular lumen and constitutively from the kidney [
20,
21]. It was suggested (not proven) that prorenin via active action of the prorenin receptor on the basolateral membrane of the macula densa will stimulate the [pro]renin release [
22]. Tubular sensing by the macula densa involves apical NaCl transport mechanism mainly via Na–K-2Cl cotransporter. The Na + gradient generated by basolateral Na + /K + -ATPase drives the apical transport. Adequate mitochondrial function via ATP hydrolysis supports Na + /K + -ATPase activity. When mitochondrial function is impaired in
RMND1 at this side, it will only result in an increase of renin release (see the effect of furosemide). The possible effects on renin release by the juxtaglomerular cell are numerous as is show by Schnermann and Briggs [
23].
Mitochondrial shape and function are cell-type specific. They are achieved by modulating the dynamic properties of mitochondria including fusion, fission [
24] positional tethering, and local metabolic state [
25,
26]. They will determine the selective affection of the renin-aldosterone system.
To summarize, we reveal that hyporeninemic hypoaldosteronism is a specific feature of RNMD1 deficiency allowing adequate treatment of the electrolyte disturbances. Cure of the mitochondrial defect or mitigating its deleterious effect on the interstitium will be the ultimate goal.
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