Professor of Medicine, Jersey Shore University Medical Center, 1945 NJ-33 Neptune, New Jersey, United States
Corresponding author details:
Sushil K. Mehandru, Professor of Medicine
Jersey Shore University Medical Center
New Jersey,United States
Copyright: © 2023 Mehandru SK, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 international License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
In patients with Mehandru syndrome, a recently discovered class of Pseudohypoaldosteronism (PHA-M), concomitant correction of metabolic acidosis upon lowering of serum potassium was an unexpected finding. PHA-M includes hyperkalemia, metabolic acidosis, mild hypertension in the presence of normal creatinine levels and euvolemic state. Metabolic acidosis was predominantly present in males than females, 5:1 ratio. Application of low potassium diet not only normalized serum potassium, metabolic acidosis was also corrected from bicarbonate levels of 20+2 to 25+2, a statistically significant improvement. Correction of hyperkalemia by means of low potassium diet increases ammonia generation in proximal convoluted tubule, which in turn leads to greater ammonia excretion in the collecting duct resulting in correction of metabolic acidosis. In animal studies, volume density of collecting ducts was noted to be significantly higher in females than males. The male and female kidney differs in ammonia excretion, expression of ammoniagenic enzyme, and ammonia transporter expression. Testosterone mediates many of these dimorphisms and may involve proximal tubule androgen receptor activation. Although, correction of metabolic acidosis by lowering serum potassium has been previously studied in animal models, no human study has been found in the literature.
Hyperkalemia; Hypertension; Mehandru Syndrome; Metabolic Acidosis; pseodohypoaldosteronism (PHA); Ammoniagenesis; Patiromer
Mehandru Syndrome, Metabolic Acidosis, Hyperkalemia
Acid-base homeostasis in the body is maintained by kidneys with the help of renal ammonia metabolism and transport mediation. Patients with recently published, Mehandru syndrome or Pseudohypoaldosteronism (PHA-M) were noted to present with metabolic acidosis, which got corrected upon normalization of serum potassium levels. As described by Mehandru et al. 2020, Mehandru syndrome is defined by presence of metabolic acidosis, isolated hyperkalemia, mild hypertension, normal glomerular filtration rate (GFR), normal calcium excretion and normal renin and aldosterone levels [1]. Various types of Pseudohypoaldosteronism (PHA) have been discovered in the literature, metabolic acidosis and hyperkalemia were universally present (Table1). None of these studies revealed correction of metabolic acidosis upon improvement of hyperkalemia with low potassium diet. Potassium was corrected with dietary modification as well as short term use of potassium binder, Patiromer.
Short term administration of Patiromer in some patients was necessary to normalize serum potassium levels [2]. Metabolic acidosis is generally defined by the presence of low serum bicarbonate concentration (normal levels 22-28 mEq/L) and it occurs when there is excess of acid. At the basal state, body generates about 12000 to 13000 mmol of carbon dioxide (CO2) and 1-1.5 mmol non-volatile acid per kg body weight [3]. Lowering of serum potassium in patients with PHA-M/Mehandru syndrome, with implementation of low potassium diet alone or in conjunction with short term use of potassium binders has been suggested to improve metabolic acidosis. Correction of hyperkalemia in patients with Mehandru syndrome increases proximal convoluted tubules (PCT) and collecting duct (CD) ammonia transport leading to increased ammonia excretion, inturn resulting in the correction of metabolic acidosis. Harris et al. 2018 did suggest mechanisms by which hyperkalemia can cause metabolic acidosis in the presence of normal kidney function [4]. The result of studies in mice indicated that hyperkalemia decreases ammonia excretion by means of abnormal expression of multiple proteins involved in proximal convoluted tubule ammonia generation and ammonia transport by collecting duct [4]. Excretion of ammonia from the body through urine increases elimination of acid, whereas rest of the ammonia gets metabolized in liver with the use of bicarbonate. Ammonia production and transport are regulated by a variety of factors, including extracellular pH and potassium, and by several hormones, such as mineralocorticoids, glucocorticoids, and angiotensin II [5].
A computational model of the rat proximal convoluted tubule suggested, fractional sodium reabsorption is lower in female than in male kidney. This was attributed to a smaller transport area in females as compared to males in combination with less sodium/hydrogen exchange isoform 3 (NHE3), and claudin-2 expression[6]. Sex dimorphic variations are present in many aspects of biology and involve the structure and/or function of an individual organ. Acid base homeostasis is critical for optimal health of an individual, and renal ammonia metabolism plays a major role in the maintenance of acid-base homeostasis. Several studies have suggested an important correlation between abnormal acid-base homeostasis and mortality, with both elevated and lowered serum bicarbonate predicting increased mortality in patients both with and without chronic kidney disease (CKD) [7-9]. Recent studies have also shown the sex dependent differences in renal ammonia metabolism with regards to both basal ammonia excretion and a response to an exogenous acid level [10]. The sex dysmorphisms are associated with structural changes in the proximal tubule and the collecting ducts, as well as variations in the expression of multiple proteins involved in ammonia metabolism and transport. Besides proximal tubule as the primary site for ammoniagenesis, Weiner et al. 2013 has suggested ammoniagenesis by most renal epithelial cells [5]. Renal ammoniagenesis predominantly results from glutamine metabolism, which produces 2 molecules of each, NH4+and NCO3-, from each glutamine metabolism [5].
llecting duct accounted for a significantly greater proportion of volume density in the female kidney than in the male kidney [4] (Figure 1).
Testosterone, a male sexual hormone, possibly acting through the activation of androgen receptors (AR), regulates multiple components of renal structure and ammonia metabolism. Testosterone appears to mediate several critical aspects of the sex dysmorphism in ammonia metabolism and transport. Orchiotomy-induced testosterone deficiency leads to increased ammonia excretion in male mice by about two-fold and the effects were reversed upon physiological testosterone replacement [11]. The testosterone deficiency mediated effects were not due to the dietary acid load, as food intake was not changed among the mice. This two-fold ratio between hormonally intact testosterone deficient male mice is identical to the two-fold variance between male and female mice [11]. Orchiotomy increased expression of an enzyme Phosphoenolpyruvate carboxykinase (PEPCK) and sodium-hydrogen antiporter 3 (NHE3) in the proximal tubule and NaK-Cl co-transporter (NKCC2) in thick ascending limb of loop of Henle, whereas the replacement of testosterone has reversed these side effects [11].
Thus, testosterone appears to have a major effect on ammonia metabolism and may explain much of the differences in ammonia excretion between male and female mice. However, testosteroneindependent effects of sex on ammonia metabolism have also been reported [11].
Collecting duct ammonia secretion involves Rhbg and Rhcgmediated ammonia transport [12]. Greater ammonia excretion in female mice was associated with greater expression of both Rhbg and Rhcg [13]. Hence, there are significant sex-dependent variations in several important points involved in the ammonia transport. This sex dimorphism appears to be true when applied to the humans with PHA-M/Mehandru syndrome, especially in context of males. All males exhibited metabolic acidosis with CO2less than 23 whereas all females had CO2 greater than 23.
Animal studies show that female mice excrete more urinary ammonia than male mice. This correlates with greater PEPCK, NKCC2, Rhbg,and Rhcg expression. Furthermore, these studies have identified fundamental sex differences in renal structure. In contrast, proximal tubules account for lesser percentage of the cortex in the female mice kidney than in the male kidney, whereas the opposite is true for the collecting ducts. The studies show that there are significant sex differences in basal ammonia excretion that results from sex differences in expression of multiple important proteins involved in ammonia metabolism and transport (Figure 2).
The goal of this study is to explore the relationship between hyperkalemia and metabolic acidosis in patients with PHA-M/Mehandru syndrome. Correction of hyperkalemia has shown to normalize serum bicarbonate levels. Metabolic acidosis was more predominant in males than females, however with correction of serum potassium levels, metabolic acidosis got improved in both sexes.
Patients with PHA-M were noted to have reduced CO2 levels, mostly in males. All patients were asymptomatic and with the correction of potassium, improvement in CO2 levels was seen. Serum CO2 levels were monitored along with potassium, significant rise in these was noted, achieving normal values along with correction of potassium. CO2 levels were lower in hyperkalemic state, noted with greater prevalence in males than females. Literature search shows prevalence of metabolic acidosis in male vs. females, conducted in animal studies. The results enclosed in this article provide a comprehensive look into the reasons behind these phenomena in humans (Table 2) (Figure 3).
Mild metabolic acidosis and isolated hyperkalemia has been shown to be present in several patients with PHA-M/Mehandru syndrome. In addition, mild hypertension was also noted in some cases reported with PHA-M/Mehandru syndrome. In present study, we have shown data and discussed patients with isolated hyperkalemia, metabolic acidosis with mild hypertension in the presence of euvolemia. In these patients, low potassium diet has corrected hyperkalemia, in addition correction of metabolic acidosis and mild hypertension was also observed.
Correcting the hyperkalemia would also reverse the acidosis and leads to decrease in the abnormal protein expression. In addition, as suggested by Harris et al. 2018, hyperkalemia will suppress ammonia generation and transport, and is the main factor for metabolic acidosis in type 4 RTA [4]. These findings are identical to our discoveries, most of the cases diagnosed as Type 4 RTA may indeed have newly discovered PHA-M/Mehandru syndrome. Fludrocortisone is used in RTA when hyperkalemia is associated with aldosterone deficiency [14]. Furthermore, the side effects of hypertension, heart failure, and edema were also carefully considered.
Systemic acidosis triggers the signal to reabsorb bicarbonate in the proximal convoluted tubules. Hyperkalemia has been shown to decrease proximal tubular ammonia generation and ammonia transport through the collecting ducts leading to impaired ammonia excretion that causes metabolic acidosis [4].
Kidneys are known to have two major functions in acid-base homeostasis: 1) reabsorption of filtered bicarbonate and 2) generation of new bicarbonate. In adults, kidneys typically filter about 4200 mmol/day of bicarbonate [5] and renal epithelial cells re-reabsorb almost all of this in the process called, “bicarbonate reabsorption”. Kidneys also produce new bicarbonate by means of process known as, “bicarbonate generation”, which involves both, ammonia [5] metabolisms and titratable acid secretion. Under basal conditions, ammonia metabolism, which includes net ammoniagenesis and renal epithelial cell ammonia transport leading to urinary ammonia excretion, is a quantitively greater component of new bicarbonate generation [16-19].
Acid base homeostasis is critical for the maintenance of normal health. Renal ammonia excretion is the quantitively predeterminant component of net acid excretion, both under basal conditions and in response to acid-base disturbance. The amount of ammonia that the kidneys produce and the amount of ammonia that is excreted in the urine varies dramatically in response to physiological stimuli. It has been well established that urinary ammonia excretion contributes to acid-base homeostasis and hence selective and regulated renal ammonia transport by renal epithelial cells is central to acid-base homeostasis. Both molecular forms of ammonia, NH3 and NH4+, are transported by specific proteins and regulation of these transport processes determines the eventual fate of the ammonia being generated in the body.
Early models of renal ammonia metabolism suggest that ammonia transport could be explained through the simple paradigm of NH4+ trapping and NH3 diffusion equilibrium. In this model [20], NH4+ could not be transported across plasma membranes and NH3, because it was a small and uncharged molecule, diffuses efficiently across lipid bi-layers and was in diffusion equilibrium throughout the kidneys. Based on the several studies, these aspects of the previous paradigm seems incorrect, and that specific membrane proteins have critical roles in the movement of both NH3 and NH4+ across renal epithelial cell plasma membranes.
In patients with Mehandru syndrome/PHA-M, hyperkalemia was present in all patients; metabolic acidosis was found in 34% of the cases. Several patients also exhibited mild hypertension. Metabolic acidosis was corrected in all patients upon normalization of potassium. In our study, metabolic acidosis is more prominent in males than females, ratio of 5:1. This is the first study in humans to describe sex dimorphism previously reported in animals. Further studies may coincide with our findings.
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