Distal RTA (Type 1)
Clinical Case Presentation 1
A 34-year-old woman presents with diffuse muscle weakness over several days. She also reports dry eyes and dry mouth over the last several months. Laboratory analysis shows the following: Na+ 141 mmol/L, K+ 2.5 mmol/L, Cl– 112 mmol/L, and HCO3– 16 mmol/L, and an arterial blood gas test shows pH 7.32 and pCO2 31 mmHg. Serum creatinine is 1.4 mg/dL and urine pH is 6.8. Ultrasound imaging shows normal sized kidneys with evidence of numerous calcifications distributed throughout both kidneys. The patient is diagnosed with type 1 RTA, thought to be secondary to underlying Sjögren’s syndrome. | |
Patients with distal (type 1) RTA are unable to acidify their urine despite severe metabolic acidosis. Distal RTA is characterized by impaired urinary acid secretion and evidence of kidney K
+ wasting with either normal or minimally reduced GFR and persistently alkaline urine pH (> 5.3; Table
1) [
10]. Patients with distal RTA often present with symptoms relating to hypokalemia, such as polydipsia and polyuria due to impaired urinary concentration ability, as well as muscle weakness, as seen in Clinical Case Presentation 1. This patient also presented with nephrolithiasis; distal RTA is a risk factor for nephrolithiasis and nephrocalcinosis due to hypercalciuria and hypocitraturia, combined with a persistently alkaline urine pH [
5,
11]. Children with distal RTA also commonly present with failure to thrive, growth retardation, and rickets [
11,
12].
Distal RTA is caused by impaired distal acidification of the urine due to a reduction in net H
+ secretion in the distal nephron, which results in impaired HCO
3– regeneration. This defect may be due to impaired H
+ secretion through decreased net activity of H
+-ATPase or H
+/K
+-ATPase (i.e., secretory defect) or increased H
+ permeability of the luminal membrane (i.e., gradient defect) [
10,
13]. Patients with distal RTA typically develop hyperchloremic, hypokalemic metabolic acidosis with a normal anion gap [
11,
14]. In general, most patients develop hypokalemia as decreased distal secretion of H
+ via H
+-ATPase or H
+/K
+-ATPase ultimately causes decreased K
+ reabsorption (i.e., renal K
+ wasting) [
13,
15]. If H
+/K
+-ATPase is primarily affected, then less K
+ will be reabsorbed. A likely greater mechanism underlying renal K
+ wasting is the effect of systemic acidosis on proximal tubular function due to defects in vacuolar H
+-ATPase. Acidemia reduces net proximal fluid reabsorption, which leads to volume contraction and activation of the renin–angiotensin–aldosterone system (RAAS), resulting in decreased proximal tubular Na
+ reabsorption and increased distal delivery of Na
+ to the cortical collecting duct. These processes, along with increased aldosterone secretion, lead to increased K
+ secretion [
13].
Impaired Na
+ reabsorption in the cortical collecting duct due to loss of H
+-ATPase function also leads to increased Na
+ delivery and urine flow to the medullary collecting duct [
10]. Increased distal Na
+ delivery stimulates expression of ENaC to promote Na
+ reabsorption, and the resultant increase in ENaC-dependent Na
+ reabsorption stimulates K
+ channel-dependent K
+ secretion [
10]. Increased urinary flow activates large conductance big K
+ channels, which further promote K
+ secretion and contribute to hypokalemia development [
16]. In contrast, renal Na
+ wasting is suspected to be caused by natriuresis due to increased levels of brain natriuretic peptide or reduced sympathetic tone in the kidneys [
17].
On the basis of the underlying defect, distal RTA may be classified as hereditary (primary) or acquired (secondary) [
5]. For example, primary distal RTA may be caused by autosomal recessive mutations in A4 (
ATP6V0A4) and B1 (
ATP6B1) subunit genes of vacuolar H
+-ATPase [
18‐
20]. Mutations in the
AE1 gene encoding the basolateral Cl
–/HCO
3– exchanger protein of α-intercalated cells are associated with autosomal dominant primary distal RTA [
21]. Acquired distal RTA may occur as a result of some medications, including amphotericin B [
22], lithium [
23], and high doses of ibuprofen [
24]. Secondary distal RTA often develops in association with systemic diseases [
7], such as Sjögren’s syndrome (as in Clinical Case Presentation 1) [
25,
26], systemic lupus erythematosus [
27], or primary sclerosing cholangitis [
28], and inherited conditions, such as sickle cell anemia [
29] and Wilson’s disease [
30].
NH
3 synthesis is normally increased in response to low pH and low serum K
+ concentrations [
5,
7]; however, the inability to acidify luminal fluid in distal RTA causes decreased NH
3 secretion in the proximal tubule [
7], which may lead to the development of elevated serum NH
3 concentrations (hyperammonemia) in some cases [
11,
31]. Furthermore, medullary transfer of NH
4+ may be impaired because of renal interstitial disease, which often occurs in association with the patient’s underlying condition or as a result of hypokalemia (i.e., kaliopenic nephropathy) or nephrocalcinosis [
7].
Distal RTA is often associated with recurrent nephrolithiasis, nephrocalcinosis, and bone disease [
32]. H
+ retention also leads to decreases in renal calcium reabsorption and increases in calcium release from bones, which causes hypercalciuria [
32]. Citrate reabsorption in the proximal tubules is elevated in distal RTA as a result of increased Na
+-dependent dicarboxylate transporter 1 activity, and this leads to hypocitraturia [
11,
32]. Hypercalciuria, hypocitraturia, and alkaline urinary pH all promote calcium phosphate precipitation [
11,
32].
Incomplete distal RTA has many clinical characteristics in common with distal RTA, including hypocitraturia and alkaline urine pH, and may also be associated with nephrolithiasis and nephrocalcinosis [
32]. However, in contrast to overt distal RTA, patients with incomplete distal RTA often have normal serum HCO
3– concentrations and NH
3 secretion is typically normal or occasionally increased [
5,
32].
Clinical Case Presentation 1 highlights some important learning points. Musculoskeletal symptoms are a common clinical manifestation of RTA and can be alleviated with the correction of hypokalemia. Secondly, patients who present with kidney stones should be screened for RTA and incomplete distal RTA should be considered in any patients with nephrocalcinosis and a persistent urine pH of at least 5.5 in the absence of urinary tract infection and normal or near-normal serum HCO3– concentrations. Early treatment of distal RTA also improves nephrocalcinosis symptoms and may prevent recurrence of kidney stones.
Proximal RTA (Type 2)
Clinical Case Presentation 2
A 65-year-old man presents with back pain and unexplained anemia. Upon evaluation, the following laboratory values are obtained: Na+ 139 mmol/L, K+ 3.4 mmol/L, HCO3– 18 mmol/L, Cl– 108 mmol/L, glucose 104 mg/dL, creatinine 2.2 mg/dL, and total protein 10.1 g/dL. An arterial blood gas test shows pH 7.35 and pCO2 33 mmHg. The urinalysis shows 1+ glucose and a urine pH of 5.5. The patient is diagnosed with multiple myeloma complicated by evidence of proximal RTA in association with generalized dysfunction of the proximal tubule (Fanconi syndrome). | |
Isolated proximal type 2 RTA is characterized by defects in the reabsorption of filtered HCO
3– in the proximal tubule without defects in the transport of other solutes (Table
1) [
33,
34]. The threshold serum concentration for HCO
3– reabsorption (normally approximately 25 mmol/L) is reduced, leading to delivery of larger quantities of filtered HCO
3– to the distal nephron (which has a low capacity for HCO
3– reabsorption) and urinary HCO
3– wastage [
33,
34]. Reductions in serum HCO
3– cause acidosis; however, the urine pH remains alkaline because of the presence of urinary HCO
3− [
34]. When serum HCO
3– concentrations decrease below the lower threshold (16–20 mmol/L), a new steady state is reached, whereby all filtered HCO
3– is reabsorbed. At this point, the urine contains no HCO
3– and is maximally acidic [
33].
A diagnosis of proximal RTA may be suspected in patients who present with hypokalemia, normal anion gap metabolic acidosis, and acidic urine (pH < 5.5) [
7]. Other signs of proximal tubular dysfunction, including hypophosphatemia, hypouricemia, euglycemic glycosuria, and proteinuria, as observed in Clinical Case Presentation 2, are also consistent with a proximal RTA diagnosis and are reflective of generalized proximal tubular dysfunction [
7]. Fractional urinary HCO
3– excretion, which is normally less than 5% of filtered HCO
3–, is usually approximately 15% in patients with proximal RTA [
35]. Isolated proximal RTA, that is decreased HCO
3– reabsorption without abnormalities in the transport of other solutes, is rare [
34]. The etiology of isolated proximal RTA may be inherited (autosomal recessive mutations in
SLC4A4, the gene encoding electrogenic NBCe1 [
36]) or acquired (e.g., due to carbonic anhydrase inhibitors [
34]). Patients with isolated proximal RTA typically present with growth retardation in early childhood [
37].
In patients with proximal RTA, hypokalemia develops as a result of the loss of proximal HCO
3– reabsorption [
7]. Increased urinary excretion of HCO
3– causes a decrease in intravascular volume, which leads to RAAS stimulation. Impaired proximal HCO
3– reabsorption also causes increased distal Na
+ delivery. The increase in RAAS activity results in elevated aldosterone levels that, combined with elevated distal Na
+ concentrations, cause an increase in urinary K
+ excretion (i.e., K
+ wasting) that leads to hypokalemia [
7].
Proximal RTA may occur as an isolated defect in HCO
3– reabsorption, but more typically occurs in association with Fanconi syndrome, characterized by a widespread proximal tubular dysfunction resulting in the loss of phosphate, glucose, uric acid, amino acids, and low molecular weight proteins, as well as HCO
3– [
33,
34]. Although proximal RTA is not associated with nephrolithiasis or nephrocalcinosis, patients with proximal RTA and Fanconi syndrome may develop skeletal abnormalities, such as osteomalacia [
38‐
41]. Skeletal abnormalities result from impaired phosphate reabsorption, which causes chronic hypophosphatemia due to renal phosphate wasting [
7,
38,
41]. Active vitamin D deficiency may be present as a result of impaired conversion of 25(OH) vitamin D
3 to 1,25 (OH)
2 vitamin D
3 in the proximal tubule [
40]. Osteopenia may also be evident as a result of acidosis-induced bone demineralization [
42].
Proximal RTA in association with Fanconi syndrome can occur following exposure to some medications, including tenofovir [
34], ifosfamide [
43], sodium valproate [
44], and topiramate [
45]. Topiramate is a carbonic anhydrase inhibitor that can cause simultaneous defects in both proximal and distal acidification mechanisms, presenting as type 3 RTA [
46]. Proximal RTA can occur secondary to metabolic diseases, such as hereditary fructose intolerance and glycogen storage disease [
47,
48]. As illustrated by Clinical Case Presentation 2, the most common cause of acquired Fanconi syndrome in adults is multiple myeloma [
49].
The clinical manifestations of anemia, hypercalcemia, and bone pain suggest a diagnosis of multiple myeloma. The patient’s condition is also complicated by proximal RTA, characterized by impaired proximal HCO3– reabsorption, hypokalemia, and variable urine pH. As the most common cause of proximal RTA in adults is multiple myeloma, this diagnosis should be excluded in all adults with proximal RTA unless another cause is found.
Hyperkalemic RTA (Type 4)
Clinical Case Presentation 3
A 55-year-old man with long-standing diabetes is referred for evaluation and treatment of diabetic nephropathy. His only medication is celecoxib 200 mg/day for treatment of mild degenerative joint disease. Physical examination is significant for a blood pressure of 146/92 mmHg and trace pedal edema. Laboratory test results show Na+ 142 mmol/L, K+ 5.7 mmol/L, Cl– 108 mmol/L, HCO3– 18 mmol/L, serum creatinine 2.0 mg/dL, protein 4.6 g/24 h, and an arterial blood gas test shows pH 7.5 and pCO2 33 mmHg. His primary care physician has been reluctant to start either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) because of increased serum K+ concentrations. | |
Hyperkalemic (type 4) RTA commonly develops in patients with diabetes or interstitial nephritis and is characterized by a disturbance in distal nephron function, leading to a reduction in the excretion of H
+ and K
+ in the cortical collecting duct that results in hyperkalemic, hyperchloremic, normal anion gap acidosis (Table
1) [
50,
51]. Patients with hyperkalemic type 4 RTA are often asymptomatic and are typically diagnosed during routine laboratory analyses. When symptomatic, manifestations may include muscle weakness or palpitations due to cardiac arrhythmias [
7,
52]. Hyperkalemic RTA may be diagnosed by the presence of hyperkalemia, normal anion gap metabolic acidosis, and abnormal serum aldosterone levels, although the GFR may be near-normal or only moderately reduced (45 to less than 60 mL/min/1.73 m
2) [
7,
8]. As illustrated by Clinical Case Presentation 3, patients usually have diabetes with mild-to-moderate decreases in GFR, a serum HCO
3– concentration of 18–22 mmol/L, and a serum K
+ concentration of 5.5–6.5 mmol/L [
7]. Other causes of hyperkalemia and normal anion gap acidosis include selective aldosterone deficiency, or defects in K
+ or H
+ secretion resulting from aldosterone resistance in the kidney (sickle cell nephropathy) [
7,
52]. Urinary obstruction can give rise to type 4 RTA [
52,
53]. In patients with obstructive uropathy and hyperkalemic metabolic acidosis, those who are unable to acidify their urine pH to less than 5.5 are thought to have a voltage-dependent defect in Na
+ transport in the distal nephron (i.e., voltage-dependent distal RTA) [
52,
53].
Type 4 RTA is typically caused by selective aldosterone deficiency or intrinsic defects in the cortical collecting duct that lead to aldosterone resistance, which causes impaired distal H
+ and K
+ secretion [
7,
52]. Hypoaldosteronism causes reduced principal cell Na
+ reabsorption and a decrease in transepithelial voltage in the cortical collecting duct, which results in diminished excretion of H
+ and K
+. Increased serum K
+ concentrations inhibit NH
3 synthesis in the proximal tubule, further reducing the kidney’s capacity to excrete acid. As described above, NH
3 availability is critical for normal distal H
+ secretion. Lack of adequate NH
3 buffer results in a drop in urine pH creating a steep pH gradient, which impedes distal H
+ secretion. Aldosterone deficiency can cause Na
+ wasting, leading to decreased plasma volume that stimulates proximal Na
+ reabsorption. The reduction in distal Na
+ delivery secondarily inhibits secretion of K
+ and H
+ in the distal nephron [
7,
52]. Hyperkalemia reduces NH
3 production in the proximal tubule and inhibits NH
4+ transport in the thick ascending limb as the high luminal K
+ concentrations compete with NH
4+ for Na
+/K
+/2Cl
– cotransporters and apical K
+ channels [
54]. Reductions in urine NH
3 can be detected by a positive urine anion gap and a failure to increase the urine osmolal gap.
In Clinical Case Presentation 3, the patient’s long history of diabetes led to an increased risk for type 4 RTA due to development of hyporeninemic hypoaldosteronism. Renin is suppressed because of salt retention, which causes volume expansion as well as atrophy and suppression of the juxtaglomerular apparatus, which leads to reduced renin secretion [
7,
51]. A reduction in renin release or development of aldosterone resistance can be caused by chronic interstitial fibrosis, which commonly develops in CKD, particularly in patients with diabetic kidney disease [
52]. Impaired cortical collecting duct function may also occur as a result of kidney structural damage due to interstitial kidney disease or obstructive uropathy [
52]. Lupus nephritis is another cause of type 4 RTA due to tubulointerstitial damage and hyporeninemic hypoaldosteronism [
55].
Patients with CKD are also at risk of developing RTA because of the progressive loss of functional kidney mass [
7]. Initially, there is an adaptive increase in NH
4+ production and acid secretion [
56]; however, as kidney impairment progresses (GFR 30–40 mL/min/1.73 m
2), this adaptive increase is unable to maintain sufficient net H
+ excretion to keep pace with endogenous acid production. Patients develop a hyperchloremic normal gap acidosis, often referred to as RTA of kidney insufficiency [
7]. In patients with more advanced CKD (GFR < 15–20 mL/min/1.73 m
2), the ability to excrete phosphate and other anions is reduced and a high anion gap metabolic acidosis develops; the acidosis at this stage is termed uremic acidosis. During this transition, patients frequently manifest features of both a normal and increased anion gap metabolic acidosis [
7]. Furthermore, patients with stage 3–5 CKD and hyperkalemia commonly develop metabolic acidosis as progressive kidney impairment leads to compromised maintenance of electrolyte and acid–base balance [
57].
Pseudohypoaldosteronism is a genetic condition associated with hyperkalemic, hyperchloremic metabolic acidosis with normal kidney function and either normal or high aldosterone levels [
52]. Type 1 pseudohypoaldosteronism may be caused by mutations in genes encoding the mineralocorticoid receptor or ENaC [
52], whereas type 2 pseudohypoaldosteronism is caused by mutations in genes encoding the with-no-lysine (WNK) family of kinases [
58]. Mutations in ENaC cause Na
+ wasting and are characterized by increased aldosterone levels, while WNK mutations give rise to Na
+ retention and either normal or low circulating aldosterone levels [
52,
58].
Hyperkalemic type 4 RTA may be caused by medications, including K
+-sparing diuretics (e.g., spironolactone, eplerenone, and amiloride), antibiotics (e.g., trimethoprim and pentamidine), nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors, ACE inhibitors, and heparin or low molecular weight heparin [
5,
59]. These agents cause hyperkalemic RTA by reducing aldosterone synthesis (ACE inhibitors), release (NSAIDs and heparin), or receptor binding (spironolactone, eplerenone), or through inhibition of ENaC (amiloride, trimethoprim, and pentamidine) [
5]. Hyperkalemic RTA may also be caused by immunosuppressant therapy with calcineurin inhibitors (e.g., tacrolimus and ciclosporin) [
60‐
62]. Calcineurin inhibitors block K
+ and H
+ secretion from the collecting duct through inhibition of basolateral Na
+/K
+-ATPase and Na
+/K
+/2Cl
– cotransporter activity [
62,
63]. Calcineurin inhibitors also suppress expression of mineralocorticoid receptors, resulting in aldosterone resistance [
64].
Clinical Case Presentation 3 highlights the need to monitor patients with diabetes for development of hyperkalemic RTA. The patient’s COX-2 inhibitor therapy potentially contributed to the development of hyperkalemia and should be discontinued. Although treatment with an ACE inhibitor or ARB was avoided because of the patient’s refractory hyperkalemia, the patient has diabetic nephropathy and would benefit from use of a RAAS inhibitor to slow the subsequent progression of CKD and to provide cardiovascular protection. Strategies for correction and minimization of hyperkalemia are discussed in the next section.