Pseudohypoaldosteronism (PHA) type II (PHA2) is a genetic disorder that leads to volume overload and hyperkalemic metabolic acidosis. PHA2 and PHA type I (PHA1) have been considered to be genetic and pediatric counterparts to type IV renal tubular acidosis (RTA). Type IV RTA is frequently found in adults with chronic kidney disease and is characterized by hyperchloremic hyperkalemic acidosis with normal anion gap (AG). However, we recently observed that PHA1 was not always identical to type IV RTA. In this study, we focused on the acid-base balance in PHA2. Through a literature search published between 2008–2020, 46 molecularly diagnosed cases with PHA2 were identified (median age of 14 years). They comprised 11 sets of familial and 16 sporadic cases and the pathology was associated with mutations in WNK 4 (n = 1), KLHL3 (n = 17), and CUL3 (n = 9). The mean potassium (K⁺) level was 6.2 ± 0.9 mEq/L (n = 46, range 4.0–8.6 mEq/L), whereas that of chloride (Cl^–) was 110 ± 3.5 mEq/L (n = 41, 100–119 mEq/L), with 28 of 41 cases identified as hyperchloremic. More than half of the cases (18/35) presented with metabolic acidosis. Although AG data was obtained only in 16 cases, all but one cases were within normal AG range. Both Cl^– and HCO3^– levels showed significant correlations with K⁺ levels, which suggested that the degree of hyperchloremia and acidosis reflect the clinical severity, and is closely related to the fundamental pathophysiology of PHA2. In conclusion, our study confirmed that PHA2 is compatible with type IV RTA based on laboratory findings.

PSEUDOHYPOALDOSTERONISM (PHA) TYPE II (PHA2, also referred to as Gordon syndrome) is a genetic disorder characterized by hypertension due to volume overload, hyperkalemia, and metabolic acidosis [1-4]. This nomenclature is derived from the inability of exogenous mineralocorticoids to increase potassium (K⁺) excretion [5, 6]. The basic pathophysiology of PHA2 is unrestrained sodium (Na⁺) reabsorption across the Na⁺-chloride (Cl^–) co-transporter (NCC) localized at the apical surface along the distal convoluted tubules (DCTs) [1-4]. Genetic heterogeneity exists in PHA2; mutations in WNK4, WNK1, KLHL3, and CUL3 cause PHA2B (OMIM # 614491), PHA2C (# 614492), PHA2D (# 614495), and PHA2E (# 614496), respectively [7-9]. These genes encode constituent proteins of the machinery responsible for the phosphorylation or ubiquitination of NCC and their aberrations lead to the overexpression and hyperfunction of NCC [3]. Thiazide, an inhibitor of NCC, effectively ameliorates hypertension and hyperkalemia in most patients with PHA2 [1-4].

On the other hand, PHA type I (PHA1) is a genetic disease characterized by aldosterone unresponsiveness in the distal nephron; it is caused by mutations in either NR3C2—that encodes the mineralocorticoid receptor expressed in the aldosterone-sensitive distal nephron (PHA1A, OMIM # 177735)—or in one of the three genes (SCNN1A, SCNN1B, or SCNN1G) that encode each subunit of the epithelial Na⁺ channel (ENaC) located in the connecting tubules (CNTs) and collecting ducts (CDs) (PHA1B; OMIM # 264350, # 620125, and # 620126, respectively) [1, 10, 11]. The clinical hallmark of PHA1 is salt-wasting crisis with volume depletion, which contrasts with the volume overload observed in PHA2.

Type IV renal tubular acidosis (RTA) represents a form of acid-base imbalance that often develops in adults with mild-to-moderate chronic kidney disease and is characterized by hyperchloremic hyperkalemic metabolic acidosis with a normal anion gap (AG) [12-14]. Type IV RTA is frequently presented in adults with diabetes or interstitial nephritis; this condition is also referred to as hyporeninemic hypoaldosteronism [12, 15, 16], where decreased aldosterone action is considered crucial for acidosis formation. Type IV RTA can also develop in adults with a variety of conditions, including obstructive uropathy [12, 17] and post-kidney transplantation [18]; this type of RTA is also referred to as voltage-dependent RTA, where failure to achieve a lumen-negative potential difference in the distal nephron is critical for the development of acidosis.

PHA, including both PHA1 and PHA2, has been considered a genetic and pediatric counterpart to type IV RTA. As a result, the association of PHA with hyperchloremic metabolic acidosis with normal AG is prevalent in the textbooks and medical reviews [4, 12, 13, 19-21]. However, the connection between PHA and type IV RTA appears to be derived from the similarity in the nomenclature—pseudohypoaldosteronism and hyporeninemic hypoaldosteronism, respectively—and remains to be verified.

Recently, we found that the nature of acidosis in PHA1 was not always identical to that in type IV RTA; hypochloremia, not hyperchloremia, and increased AG were found in a substantial portion of the patients with PHA1 [22]. In this study, we conducted an extensive literature search focusing on the acid-base imbalance in PHA2 and attempted to verify the concept that PHA2 presents with type IV RTA.

A literature search was conducted using PubMed and Google Scholar with the single query “pseudohypoaldosteronism,” between August and October 2020 (Fig. 1). Only studies written in English and those that included clinical information on cases with PHA2 were selected. Since the mid-1980s, the laboratory methodology for Cl^– measurement has changed from a colorimetric method to the use of ion-selective electrodes; the Cl^– levels obtained using the latter can be substantially higher than those obtained using the former [23]. Therefore, to eliminate this bias as much as possible, studies published before 2008 were omitted. In addition, only cases with delineated mutations in WNK4, WNK1, KLHL3, or CUL3 were included. For the following reasons, we excluded cases older than 40 years. The major reason was to avoid the effect of age-related kidney damage, which may be facilitated in cases with PHA2 because of early-onset hypertension. The second reason was to exclude the mildly affected or asymptomatic cases who are frequently identified via family searches. Lastly, because our previous study on PHA1 comprised exclusively pediatric cases, exclusion of older cases may allow for the comparison between PHA1 and PHA2. For each case, only laboratory data obtained prior to fluid infusion or drug administration were used for the analysis. We defined normal Cl^– levels those within the range 98–108 mEq/L, which corresponds to 2 standard deviations (SD) of the mean data obtained from 29,490 adult patients with normal renal function and electrolyte levels [24]. The definition of acidosis was arbitrarily set as either a pH value lower than 7.30 or a bicarbonate (HCO3^–) level lower than 20 mEq/L [22]. AG was calculated using the following equation: AG = [Na⁺] + [K⁺] – [Cl^–] – [HCO3^–]. AG levels greater than 20.8 mEq/L were considered increased, based on the results of the same study used to obtain the normal Cl^– levels [24].

Fig. 1

The flow of the present study

Each value is presented as the mean ± SD. The Student’s t-test was used to compare K⁺, Cl^–, and HCO3^– levels between the cases with KLHL3 mutations and those with CUL3 mutations. The correlations between K⁺ levels and Cl^– or HCO3^– levels were tested using Pearson’s product-moment correlation coefficient. Statistical analyses were performed using the International Business Machine (IBM) Statistical Package for the Social Sciences (SPSS) version 24 (IBM Corp., Armonk, NY, USA). Statistical significance was set at p < 0.05.

Through a literature search, we collected 18 studies written in English, in which clinical information regarding 92 PHA2 cases was fully described. All 18 studies are listed in the Supplementary Table. After excluding cases that did not meet the inclusion criteria, 46 cases were subjected to the following analysis (Fig. 1).

The age of the 46 cases (24 males) ranged between 2 months and 39 years, with a median of 14 years. The cases included in the analysis consisted of 10 sets of familial cases and 17 sporadic cases. The responsible mutations were found in WNK4 in one case, in KLHL3 in 17 cases/families, and in CUL3 in nine cases/families (Fig. 1).

As shown in Table 1, mean blood pressure in adults (>18y) was above the global reference for hypertension of 140/90 mmHg [25]. Also, mean blood pressure in each pediatric age group exceeded the screening values requiring further evaluation suggested by American Academy of Pediatrics [26]. Data on K⁺ levels were available for all 46 cases, and the mean K⁺ level was 6.2 ± 0.9 mEq/L (range 4.0–8.6 mEq/L). Information on Na⁺ levels was available in nearly half of the cases, and the mean Na⁺ level was 139 ± 2.2 mEq/L. Cl^– levels, which were reported in 41 out of 46 cases, ranged between 100 and 119 mEq/L, with a mean value of 110 ± 3.5 mEq/L. Whereas 28 of 41 cases (68%) were categorized as having hyperchloremia, hypochloremia was not observed in any case.

Information on acid-base balance, namely on either HCO3^– or pH, was available for 35 cases. According to our definition, 18 of the 35 eligible cases (51%) were judged to have acidosis. AG could be calculated in 16 cases; in all but one case AG values fell within the normal range.

Fig. 2 depicts the significant correlations found between K⁺ and Cl^– levels (obtained from 41 cases) and between K⁺ and HCO3^– levels (n = 35). The correlations remained significant after excluding infantile cases, considering the high K⁺ and low HCO3^– levels during infancy (data not shown). As also shown in Fig. 2, the cases with CUL3 mutations had significantly higher K⁺ levels compared to those with KLHL3 mutations [7.1 ± 0.83 (n = 12) vs. 5.9 ± 0.73 (n = 33), p < 0.01]. Similar results were observed both for Cl^– [112.6 ± 3.0 (n = 10) vs. 108.9 ± 3.2 (n = 30), p < 0.01] and HCO3^– levels [15.5 ± 2.9 (n = 11) vs. 21.3 ± 3.4 (n = 23), p < 0.01].

Fig. 2

Scatter plots of the potassium (K⁺) and chloride (Cl^–) levels (top) and K⁺ and bicarbonate (HCO3^–) levels (bottom) in the reported cases of pseudohypoaldosteronism type II (PHA2). Simultaneous measurements of K⁺ and Cl^– and of K⁺ and HCO3^– were available for 41 and 35 cases, respectively. A significant correlation (p < 0.01) was observed between K⁺ levels and Cl^– and HCO3^– levels. Both correlations remained significant after removing infantile cases (data not shown).

Filled circles, PHA2 cases with KLHL3 mutations; open circles, cases with CUL3 mutations; gray circle, a case with WNK4 mutation.

To the best of our knowledge, this is the first study to delineate the nature of acid-base imbalance observed in patients with PHA2. Our results showed that PHA2 can be classified as type IV RTA. The mean Cl^– level found in untreated cases with PHA2 was 110 ± 3.5 mEq/L, which was above the reference range of 98–108 mEq/L. Hyperchloremia was ascertained in 28 of 41 cases (68%). In addition, metabolic acidosis was found in 18 of 35 cases (51%). Although AG levels were reported infrequently, their range fell within normal values in all but one case (15 of 16 cases, 94%). These findings, namely hyperkalemic and hyperchloremic metabolic acidosis with normal AG, are consistent with the definition of type IV RTA.

Further, significant correlations between K⁺ levels and Cl^– and HCO3^– levels (Fig. 2) indicate that both hyperchloremia and acidosis are closely related to the fundamental pathophysiology of PHA2. The results of the genotypic analysis also support this notion. We observed that the cases with CUL3 mutations showed a significantly higher degree of hyperkalemia compared to those with KLHL3; this finding is in accordance with a previous observation that patients with CUL3 mutations display a more severe phenotype in terms of age of onset, degree of hypertension, and degree of electrolyte abnormality [27]. In the present study, CUL3 mutations were associated with a higher degree of hyperchloremia and acidosis. Taken together, our results show that hyperchloremic acidosis does not exist in isolation, but is closely related to NCC hyperfunction.

The precise mechanism for the development of PHA2 to type IV RTA is not fully understood; however, the widely accepted mechanism is depicted in Fig. 3. Hyperchloremia may directly result from increased Na⁺-coupled Cl^– absorption at DCT through NCC (the upper part of Fig. 3). In addition, increased paracellular Cl^– transport may be involved [28]. The development of hyperkalemia and acidosis has been elucidated as follows [1-4]. First, unsuppressed Na⁺ absorption at DCT will impair downstream Na⁺ delivery, and Na⁺ absorption via ENaC located from CNT to CD will decrease. Inadequate Na⁺ absorption fails to generate a lumen-negative potential difference, which is indispensable for the excretion of K⁺ and protons (H⁺) [the middle part of Fig. 3]. Theoretically, hyperkalemia-induced impairment of ammonia formation at the proximal tubules may worsen the degree of acidosis [1]. Besides the above-mentioned mechanisms, tubular remodeling, namely, increased DCT mass and decreased CNT mass, has been suggested as another cause for K⁺ retention in PHA2 [29]; however, this has not been ascertained in humans. Recently, the pathogenic role of the Cl^–/HCO3^– exchanger pendrin, which is expressed in β-intercalated cells in CD, was revealed (the lower part of Fig. 3). Pendrin, in collaboration with the Na⁺-driven Cl^–/2HCO3^– exchanger (NDCBE), is thiazide-sensitive, is upregulated by WNK signaling, and mediates Na⁺ absorption and HCO3^– excretion [30]. Therefore, increased pendrin activity, as a result of increased WNK signaling, will lead to volume overload with metabolic acidosis. López-Cayuqueo et al. found that, in a PHA2 mouse model (TgWnk4^PHAII), acidosis was fully reversed by pendrin ablation; the authors suggested that acidosis in PHA2 is mainly caused by pendrin hyperactivity and this mechanism should be referred to as “type 5” RTA [31]. Therefore, PHA2, which is not associated with the overproduction of any nonvolatile acid, will present with hyperchloremic, hyperkalemic metabolic acidosis with normal AG, namely type IV RTA. From this viewpoint, acidosis in PHA2 may be another example of voltage-dependent RTA and may differ from hyporeninemic hypoaldosteronism.

Fig. 3

Schematic presentation of the main pathophysiological events in pseudohypoaldosteronism (PHA) type II (PHA2), illustrating the differences with PHA type I (PHA1). The basic event in PHA2 is unrestrained sodium (Na⁺) and chloride (Cl^–) ion reabsorption via the Na⁺-Cl^– co-transporter at the distal convoluted tubules (DCTs). This leads to decreased Na⁺ delivery to the connecting tubules (CNTs) and collecting ducts (CDs), which will fail to generate a lumen-negative potential difference. Thus, the excretion of potassium (K⁺) ion and proton (H⁺) is impaired. In addition, in β-intercalated cells, increased Na⁺ reabsorption and bicarbonate (HCO3^–) excretion via pendrin has been suggested. On the other hand, the basic pathophysiological event in PHA type I (PHA1) is impaired Na⁺ reabsorption in CNT/CD, which leads to insufficient lumen negativity. A compensated Na⁺ reabsorption in DCT has been suggested in PHA1 [32]. PHA1 and PHA2 share the pathology of insufficient lumen negativity, which is the cause for the hyperkalemic acidosis found in both of them. On the other hand, the fundamental Na⁺ kinetics is in the opposite direction in both forms of PHA, which may be responsible for the difference in the chloride levels between PHA1 (hypochloremic) and PHA2 (hyperchloremic).

Black rectangles indicate the main pathology, while light blue rectangles denote secondary changes.

In contrast to the present results, our previous study on PHA1 found that the phenotype was inconsistent with typical hyperchloremic type IV RTA [22]; analysis of data related to seven times well-documented salt-wasting crises experienced by our PHA1B patient between 3 and 7 years of age revealed that most of the crises were accompanied by hypochloremia and elevated AG levels. In addition, analysis of 106 PHA1 cases collected through a literature search found that hypochloremia was present in 69% (9 of 13) of PHA1A and 54% (7 of 13) of PHA1B cases at the time of salt-wasting. Elevated AG levels were found in 44% (4 of 9) of PHA1B cases.

It is not surprising, however, that PHA1 and PHA2 differ greatly in terms of acid-base imbalance, considering the substantial difference in the clinical picture between these disorders. The hallmark of PHA1 is salt wasting with volume depletion, resulting from either impaired aldosterone action (PHA1A) or ENaC malfunction (PHA1B) [10, 11]. In addition, because patients with PHA1, especially those with PHA1B, present with repetitive salt-wasting crises, they are usually normokalemic and develop hyperkalemia only periodically. In contrast, PHA2 is characterized by volume overload due to increased Na⁺ absorption via NCC, with resultant hypertension [1-4]. Patients with PHA2 show chronic hyperkalemia until any intervention is initiated. Thus, PHA1 and PHA2 have opposite characteristics in their humoral status and acute-chronic mode. Basic pathophysiology of PHA1 is schematically shown in Fig. 3, illustrating the difference to that of PHA2. PHA1 and PHA2 share the impaired K⁺ and H⁺ excretion due to the insufficient lumen-negativity in the distal nephron, which is the direct cause for hyperkalemic acidosis found in both forms. However, whereas the primary event in PHA2 is unrestrained Na⁺ reabsorption at DCT and CD, that in PHA1 is Na⁺ loss at CNT–CD. This fundamental difference in Na⁺ kinetics will cause the opposite direction in the chloride levels between PHA1 (hypochloremic) and PHA2 (hyperchloremic). As we speculate before, an elevated AG found in PHA1 may derive from hyperlacticemia caused by severe volume depletion [22]. Considering that aldosterone unresponsiveness is not the main factor in the pathogenesis of PHA2, it may be thoughtful to treat PHA1 and PHA2 as completely different entities, despite their nomenclature.

As a retrospective literature review that included only one case of our own (ref. 12 in Supplementary Table), this study had some limitations. First, we must consider that cases with atypical manifestation may be under-reported. Second, the methods for obtaining laboratory data were seldom mentioned in the literature and may be diverse. Third, the accuracy of the reported data could not be verified. Lastly, some data were missing in the surveyed papers. In particular, because information on HCO3^– levels was often lacking, AG levels could be determined only in a limited number of cases.

In conclusion, our study confirmed that PHA2, unlike PHA1, is highly characterized by hyperchloremic hyperkalemic acidosis with normal AG and can be classified as type IV RTA.

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