The correct answer is D

Comment: Hypokalemia is generally due to either urinary or gastrointestinal tract losses, a shift from the extracellular to intracellular fluid compartment, or in rare cases, decreased oral intake. In this patient, renal losses were thought to be most likely, given the elevated urinary potassium concentration.

Metabolic alkalosis is often classified as chloride responsive (urine chloride ≤ 20 mmol/L or less) or chloride resistant (urine chloride >20 mmol/L or more). When urine chloride excretion is greater than 20 mmol/L, the metabolic alkalosis is usually saline responsive. In metabolic alkalosis, urine chloride concentration may be a more accurate indicator of intravascular volume depletion than urine sodium concentration because bicarbonaturia in early stages of development of a chloride-depletion metabolic alkalosis results in sodium and potassium excretion in urine (as accompanying cations with bicarbonate). Thus, urine sodium and potassium concentrations may be elevated in the first 24 to 72 hours of volume depletion, and then decline subsequently. Urine chloride concentration will remain low due to ongoing sodium and chloride reabsorption in the proximal tubule due to activation of the renin–angiotensin–aldosterone axis and other factors in response to volume depletion.

This patient developed chloride-resistant metabolic alkalosis (urine chloride >20 mmol/L). Given the presence of hypertension along with urine potassium excretion greater than 20 mmol/L and low levels of both serum renin and aldosterone, the differential diagnosis includes Liddle syndrome, syndrome of apparent mineralocorticoid excess, Cushing syndrome, congenital adrenal hyperplasia, and excessive licorice use. Liddle syndrome, syndrome of apparent mineralocorticoid excess, and congenital adrenal hyperplasia were unlikely given the patient’s age. Given the patient’s elevated morning cortisol level, markedly increased 24-hour urine cortisol excretion, and high serum corticotropin (adrenocorticotropic hormone, ACTH) level, ACTH-dependent Cushing syndrome was diagnosed. ACTH-dependent Cushing syndrome could be due to either an ACTH-secreting pituitary tumor or an ectopic ACTH-secreting tumor. Findings from magnetic resonance imaging of the pituitary gland and computed tomography of the chest were unremarkable. Computed tomography of the abdomen revealed peritoneal nodules consistent with his history of recurrent carcinoid tumor. Ectopic ACTH-dependent Cushing syndrome, most likely from the active carcinoid tumor, was diagnosed. There are a few case reports that describe Cushing syndrome attributed to the presence of a carcinoid tumor.

Cortisol has the capacity to bind mineralocorticoid receptors in principal cells of the cortical collecting duct. Normally, this is limited by conversion of cortisol to cortisone, which is unable to bind to the mineralocorticoid receptor, by the enzyme 11β-hydroxysteroid dehydrogenasetype 2. Excess production of cortisol, as seen in our patient, saturates the enzyme, allowing cortisol to persist and activate mineralocorticoid receptors. This causes translocation of epithelial sodium channel proteins into the luminal membrane, increasing basolateral adenosine triphosphatase sodium/potassium pump activity and increasing renal outer medullary potassium channel activity, leading to sodium reabsorption and hypertension, hypokalemia, and metabolic alkalosis. Ideally, treatment in such patients is complete resection of the nonpituitary ACTH-secreting tumor. Unfortunately, the peritoneal carcinoid metastases were not respectable, and our patient’s metabolic alkalosis and hypertension were treated with the mineralocorticoid receptor antagonist spironolactone. After being treated with spironolactone, 50 mg, daily for 4 weeks, the patient’s blood pressure had improved to 118/77 mmHg, serum potassium concentration had increased to 3.9 mmol/L, and serum bicarbonate concentration was 25 mmol/L.

The correct answer is B

Comment: The features of polyuria, metabolic acidosis, hypokalemia, hypophosphataemia, glycosuria, and proteinuria suggest Fanconi syndrome. This diagnosis is confirmed by the demonstration of generalized aminoaciduria and tubular proteinuria and should be followed by identification of the underlying cause. In adults, the major causes of Fanconi syndrome are monoclonal gammopathies, amyloidosis, membranous nephropathy, focal segmental glomerulosclerosis, and tubulointerstitial nephritis. The other feature in this patient was photophobia. Sjögren syndrome presents classically with distal renal tubular acidosis and photophobia, although without the other abnormalities seen in Fanconi syndrome. Tubulointerstitial nephritis with uveitis also may present with proximal tubular dysfunction and photophobia, but most commonly is a diagnosis of exclusion in adolescent girls.

Photophobia with Fanconi syndrome is suggestive of cystinosis. In classic nephropathic cystinosis, Fanconi syndrome appears at 6 to 12 months of age and end-stage renal disease develops at 9 years. It accounts for 95% of reported patients. Forms with late onset, as occurred in this patient, account for 5% of all cases of cystinosis. The late-onset forms are of two phenotypes. Intermediate cystinosis, also called late-onset or juvenile cystinosis, has the same features as the nephropathic form, but patients may retain kidney function into their 30s. Ocular or non-nephropathic cystinosis, previously called benign or adult cystinosis, is characterized by only ocular findings, with all systemic manifestations lacking.

Measuring the cystine usually makes the diagnosis content of peripheral leukocytes or cultured fibroblasts. The diagnosis can also be made through recognition of cystine crystals in corneal stoma, imparting a polychromatic luster on slit-lamp examination, as in this patient. Rectangular or hexagonal cystine crystals may be found in a bone marrow or kidney biopsy specimen. Because cystine crystals are water soluble, these are not retained in tissue sections after routine histological preparation with aqueous solutions. The bone marrow biopsy specimen in this patient did not show cystine crystals. The kidney biopsy specimen included eight glomeruli. Glomeruli were of normal size with patent glomerular capillaries. There was neither thickening nor irregularity of the capillary wall. Mesangial cellularity was normal. Interstitium was edematous with lymphocytic infiltrate. Cystine crystals also were not identified in the kidney biopsy specimen. CTNS , the gene implicated in cystinosis, encodes the protein cystinos in and maps to chromosome 17p13.

Oral cysteamine therapy is recognized as the treatment of choice for patients with nephropathic cystinosis who have not undergone transplant. Cysteamine depletes lysosomal cystine by a multistep mechanism. First, it enters into the lysosomal compartment through a specific transporter and reacts with cystine to form the mixed disulfide cysteamine–cysteine; this compound in turn exits the lysosomes through an intact lysine transporter, and when in the cytoplasm, is reduced by glutathione to cysteamine and cysteine. Cysteamine has the marked odor and taste of thiols and binds to oral mucosa and dental fillings. This patient, after 9 months of treatment with cysteamine, 50 mg/kg/day, had a serum creatinine level of 1.8 mg/dL. His joint pains, rib tenderness, and proximal muscle strength have improved.

The correct answer is A

Comment: Between 12% and 20% of patients with essential hypertension have PRA greater than the upper limit of the renin-sodium profile of normotensive control patients; however, less than 30% of these patients with high-renin essential hypertension have PRA exceeding 11 ng/mL/h, independent of daily sodium excretion. Therefore one would anticipate encountering no more than 3.5% to 6% of all patients with PRA greater than this value. The persistence of unusually high PRA despite treatment with a blocker rendered the hypothesis of high-renin essential hypertension less likely in this case. High PRA may also suggest renovascular or malignant hypertension. In a recently published series of malignant hypertension, 76% of patients had PRA greater than 4.9 ng/mL/h with 25% greater than 20 ng/mL/h. However, patients with malignant hypertension usually present with a dramatic clinical picture and significant target-organ damage, including kidney damage and advanced retinopathy, neither of which was observed in our patient. Finally, the hypothesis of a renin-secreting tumor of the juxtaglomerular apparatus (TJGA) should be considered despite the rarity of this disease.

The captopril test has been used as a screening test for renovascular hypertension; however, remarkable variability exists in the diagnostic PRA cutoff values. Renal Doppler ultrasonography, computed tomography (CT), and magnetic resonance renal angiography have greater diagnostic accuracy for renovascular hypertension compared with the captopril test. Renal Doppler ultrasonography and CT renal angiography were performed in our patient and excluded renovascular disease. Abdominal CT with contrast injection also was performed for suspected Tumor of the juxtaglomerular apparatus (TJGA).

Abdominal CT identified a 2.2 cm mass at the level of the corticomedullary junction between the middle and lower third of the left kidney, with very weak contrast enhancement in the late parenchymal phase. This location and these features are consistent with TJGA. Renal CT with contrast injection has almost 100% sensitivity for the detection of TJGA. Selective renal arteriography failed to identify these tumors, which usually appear as small hypovascularare as within the renal parenchyma in approximately 60% of patients, when this procedure was performed systematically. Renal vein sampling has at best 50% to 60% sensitivity in detecting renin lateralization, possibly due to the superficial location of these tumors draining through pericapsular veins rather than the main renal veins, variable blood dilution by extra renal veins, or secretory intermittence.

The diagnosis was TJGA, and conservative surgery with tumor enucleation was performed. Serum potassium and BP values normalized within 7 days after surgery. At the 6-month follow-up, the patient remained normotensive (24-hour mean BP, 115/76 mmHg). Serum potassium level was 4.6 mEq/L, upright PRA was 0.67 ng/mL/h, aldosterone level was 9.0 ng/dL, and 24-hour proteinuria decreased to 60 mg of protein.

The correct answers are A, B, C, and D

Comment: This patient had hypertension, hypokalemia, and bilateral symmetrical muscle weakness associated with low aldosterone and renin levels. Decreased potassium intake is rarely the sole cause of hypokalemia because urinary excretion of potassium can be decreased efficiently to 15 mEq/day. Hypokalemia caused by transcellular shift is transient, as seen with thyrotoxic periodic paralysis or hypokalemic periodic paralysis. Hypokalemia is more commonly caused by either increased gastrointestinal loss or urinary loss. In our patient, gastrointestinal loss could be excluded because the patient denied diarrhea. To explore the cause of hypokalemia from urinary losses associated with hypertension, PRA will narrow the differential diagnosis: (1) increased PRA: secondary hyperaldosteronism (renovascular hypertension, diuretics, renin-secreting tumor, malignant hypertension, and coarctation of the aorta); and (2) low PRA: primary hyperaldosteronism, Cushing syndrome, exogenous mineralocorticoids, Liddle syndrome, and licorice and carbenxolone ingestion.

Plasma aldosterone levels and PRA are the most helpful laboratory tests to make the diagnosis. Both plasma aldosterone concentration and PRA were less than the reference range, which excluded the possibility of primary and secondary hyperaldosteronism. The serum cortisol level was normal; however, the increased transtubular potassium gradient suggested urinary loss of potassium. Careful history taking showed that the patient was ingesting bags of licorice, which led to this mineralocorticoid excess state.

Licorice is made from the root of Glycyrrhiza glabra. Metabolized to glycyrrhetic acid, it inhibits the enzyme 11-hydroxysteroid dehydrogenase 2 (encoded by the HSD11B2 gene), which converts active cortisol to locally inactive cortisone at the renal tubule. The accumulated cortisol has mineralocorticoid-like activity that acts on the receptor in the distal convoluted tubules, causing sodium retention and potassium wasting, and leads to a state of hypertension and hypokalemia.

The licorice-induced mineralocorticoid effect is usually reversible upon cessation of licorice ingestion. It also responds to spironolactone therapy. Dexamethasone may be considered because it suppresses endogenous cortisol production and thus decreases cortisol-mediated mineralocorticoid activity. The time required for correction of the potassium deficit after stopping licorice ingestion varies from days to weeks because of the large volume of distribution and long biological half-life of glycyrrhetinic acid. This patient was admitted to the intensive care unit, and after 3 days of receiving continuous supplements, serum potassium level normalized and clinical symptoms improved. He was discharged on oral potassium supplement therapy and advised not to eat licorice. At 2 weeks’ follow-up, blood pressure was 140/60 mmHg and chemistry test results included the following values: potassium, 4.5 mmol/L; serum creatinine, 1.0 mg/dL; and estimated glomerular filtration rate, 79.7 mL/min/1.73 m ² off potassium supplements.

The correct answer is C

Comment: This patient is both volume and potassium depleted. Thus, treatment should consist of half-isotonic saline to which 40 mmol of potassium (as KCl) should be added. Correction of volume and chloride depletion will allow the excess bicarbonate to be excreted. Thus, the anion gap between the high urine (Na ⁺ +K ⁺ ) concentration and low urine Cl ⁻ concentration is due primarily to HCO ₃ ⁻ .

Note that the urine chloride concentration is still low in this patient, indicating the need for further fluid and chloride replacement; the urine sodium concentration is not an accurate estimate of volume status in this setting because the excretion of bicarbonate obligates sodium loss.

The correct answer is A

Comment: The differential diagnosis of unexplained hypokalemia, urinary potassium wasting, and metabolic alkalosis includes surreptitious diuretic use or vomiting (during the phase of bicarbonate excretion in which both sodium and potassium excretion are increased) or some form of primary hyperaldosteronism. The normal BP in this patient excludes all of the causes of the last condition other than Bartter syndrome.

The urine chloride concentration should be measured next. A value below 25 mmol/L is highly suggestive of vomiting (which was present in this case), whereas a higher value is consistent with diuretic use or Bartter syndrome. The last two conditions can usually be distinguished by a urinary assay for diuretics.

The correct answer is A

Comment: The acidemia is due to retention of H ⁺ ions from the ketoacids; the associated anions (β-hydroxybutyrate and acetoacetate) were presumably excreted in the urine, resulting in only a minor elevation in the anion gap. The patient should be given insulin with glucose. This will correct the ketoacidosis without the risk of hypoglycemia.

The correct diagnosis is A

Comment: The differential diagnosis of unexplained hypokalemia, urinary potassium wasting, and metabolic alkalosis includes surreptitious diuretic use or vomiting during the phase of bicarbonate excretion in which both sodium and potassium excretion are increased and some form of primary hyperaldosteronism. The normal BP in this patient excludes all of the causes of the last condition other than Bartter syndrome. Viewing this as a diagnostic problem of metabolic alkalosis and measuring the urine chloride concentration can distinguish these disorders. A value below 25 mmol/L is highly suggestive of vomiting (which was present in this case), whereas a higher value is consistent with diuretic use or Bartter syndrome. The last two conditions can usually be distinguished by a urinary assay for diuretics.

The correct answer is D

Comment: Aldosterone, the most important mineralocorticoid, increases sodium reabsorption and potassium secretion in the distal nephron. Excessive secretion of mineralocorticoids or abnormal sensitivity to mineralocorticoid hormones may result in hypokalemia, suppressed plasma renin activity, and hypertension. The syndrome of apparent mineralocorticoid excess (AME) is an inherited form of hypertension in which 11-β-hydroxysteroid dehydrogenase is defective. This enzyme converts cortisol to its inactive metabolite, cortisone. Because mineralocorticoid receptors themselves have similar affinities for cortisol and aldosterone, the deficiency allows these receptors to be occupied by cortisol, which normally circulates at much higher plasma levels than aldosterone. Licorice contains glycyrrhetinic acid and mimics the hereditary syndrome because it inhibits 11-β-hydroxysteroid dehydrogenase.

The correct answer is E

Comment: Hypokalemic periodic paralysis may be familial with autosomal dominant inheritance, or it may be acquired in patients with thyrotoxicosis. Thyroid hormone increases sodium–potassium–adenosine triphosphate (ATP)ase activity on muscle cells, and excess thyroid hormone may thus increase sensitivity to the hypokalemic action of epinephrine or insulin, mediated by sodium–potassium–ATPase.

Treatment of paralytic episodes with potassium may be effective; however, this therapy may lead to post treatment hyperkalemia as potassium moves back out of the cells. Propranolol has been used to prevent acute episodes of thyrotoxic periodic paralysis and it may also be effective in acute attacks, without inducing rebound hyperkalemia.

The correct answer is C

Comment: This patient is an example of classical Bartter syndrome, characterized by early onset of metabolic alkalosis, renal potassium wasting, polyuria, and polydipsia without hypertension. Symptoms may include vomiting, constipation, salt craving, and a tendency to volume depletion. Growth retardation follows if treatment is not initiated. Unlike patients with Gitelman syndrome, their calcium excretion is elevated.

Adrenal adenoma, licorice ingestion, and Liddle syndrome are all causes of hypokalemic metabolic alkalosis, but these disorders are associated with hypertension.

The correct answer is A

Comment: The first step is the evaluation of urinary potassium excretion. A urinary potassium–creatinine ratio value exceeding 1.5 is evidence of inappropriate urinary potassium excretion in the face of hypokalemia and helps to rule out diarrhea or laxative abuse as the cause.

The correct answer is C

Comment: The urinary potassium excretion is inappropriate for someone with hypokalemia. This indicates that the likely cause is not lower gastrointestinal loss of potassium. Upper gastrointestinal loss could still be a proximate cause as the predominant mechanism for hypokalemia in that situation is renal due to secondary hyperaldosteronism and bicarbonate in the tubular fluid acting as a non-reabsorbable anion. The actual potassium loss from gastric losses is not very much, as potassium concentration is only 5 to 10 mEq/L in gastric fluid.

The correct answers are D, E, F, and G

Comment: The presence of hypertension and mild metabolic alkalosis indicates that all causes of primary and secondary hyperaldosteronism, as well as Liddle syndrome and the various forms of AME, have to be considered. Blood pressure would not be typically elevated with Bartter or Gitelman syndrome, but the abuse of diuretics in hypertensive patients should still be considered.

The correct answers are C and D

Comment: Since we are considering the causes of hypokalemia associated with metabolic alkalosis and hypertension, measurements of plasma aldosterone concentration and plasma renin activity are necessary to differentiate the various conditions.

Hypomagnesemia is not a cause of hypertension, nor is diuretic abuse. Diuretic abuse in a hypertensive patient might be a possibility, but it would be worthwhile to first document an elevated level of both renin and aldosterone. A plasma cortisol measurement may be of value later, but it should not be the initial test in trying to make this differentiation.

The correct answers are B and E

Comment: The data are clearly consistent with suppressed levels of aldosterone and renin. The differential diagnosis therefore now consists of conditions associated with no aldosterone-mediated mineralocorticoid excess.

Diuretic abuse and primary or secondary hyperaldosteronism are no longer considerations as all would have elevated levels of aldosterone.

Diuretic abuse and secondary hyperaldosteronism, renovascular hypertension, and renin-secreting tumor would also be associated with elevated plasma renin activity.

The correct answers are B and C

Comment: Two aspects of the dietary history are very important. She denies ingesting licorice, but apparently ingests large amounts of grapefruit. Acquired AME is seen with ingestion of licorice and grapefruit. Dietary flavinoids present in licorice and in grapefruit inhibit the enzyme 11-β-hydroxysteroid dehydrogenase, allowing cortisol to occupy the mineralocorticoid receptor.

The correct answer is C

Comment: The differential response to amiloride is indicative of Liddle syndrome. The mechanism of AME caused by either a genetic defect or an acquired abnormality in 11-β hydroxysteroid dehydrogenase (due to licorice or grapefruit in the latter case) is enhanced mineralocorticoid activity by virtue of occupation of the mineralocorticoid receptor by glucocorticoids. Thus, the symptoms should respond to receptor occupant ion by spironolactone. In contrast, Liddle syndrome is due to enhanced activity of the sodium channel, which is unaffected by Spironolactone, but is blocked by amiloride.

The correct answers are A and B

Comment: Genetic testing can confirm the defect in Liddle syndrome. At that point, family members should be evaluated, so that any of them with hypertension can receive appropriate treatment. Diagnosis of AME syndrome is usually done by demonstration of an excess of free urinary cortisol over free urinary cortisone in a 24-hour urine collection, although genetic testing can identify the congenital defect.

The correct answer is C

Comment: Hypokalemia can arise from a transcellular shift or increased renal and gastrointestinal losses. This patient’s metabolic abnormalities persisted despite avoidance of diuretics, lack of gastrointestinal losses, and appropriate potassium supplementation. The triad of hypertension, severe hypokalemia, and metabolic alkalosis can be seen in various conditions that can be differentiated based on the patient’s renin-angiotensin-aldosterone system profile. Suppressed plasma renin activity (PRA), increased plasma aldosterone concentration (PAC), and PAC: PRA ratio ≥ 20 is characteristic of primary hyperaldosteronism. Elevation of both PRA and PAC levels suggests secondary hyperaldosteronism (i.e., renovascular hypertension, diuretic use, or a renin-secreting tumor). Alternatively, suppression of both PRA and PAC levels should prompt investigation for alternative causes of severe hypokalemia and metabolic alkalosis, such as congenital adrenal hyperplasia, Liddle syndrome, or states of apparent mineralocorticoid excess.

This patient had suppressed PRA and PAC levels, which in the clinical context of lung cancer led to the diagnosis of ectopic adrenocorticotropic hormone (ACTH) syndrome.

Under normal conditions, excess cortisol is converted to its inactive metabolite cortisone by the kidney by the enzyme 11-β-hydroxysteroid dehydrogenase. Excessive amounts of active cortisol can overwhelm the capacity of this enzyme, resulting in cross-reactivity with renal mineralocorticoid receptors. This can lead to an acquired form of apparent mineralocorticoid excess with severe hypokalemia and metabolic alkalosis. Suppression of plasma renin and aldosterone release occurs by negative feedback inhibition. Additionally, ectopic ACTH causes increased secretion of the mineralocorticoid-like hormones, such as 11 deoxycorticosterone and corticosterone, which can potentially lead to a greater degree of hypokalemia and metabolic alkalosis compared to adrenal-limited Cushing syndrome.

The differential diagnosis of polyuria includes central or nephrogenic diabetes insipidus and psychogenic polydipsia. An osmotic load, water load, or a mix of both can drive polyuria. Osmotic diuresis is characterized by high urine osmolality (>300 mOsm/kg) and can be seen in hyperglycemia, high-protein enteral nutrition, and urea or mannitol administration. Pure water diuresis presents with low urine osmolality (<100 mOsm/kg) and results from increased free water excretion in the absence of antidiuretic hormone, reduced antidiuretic hormone responsiveness, or free water intoxication (psychogenic polydipsia). This patient’s urine osmolality of 266 mOsm/kg is most consistent with mixed polyuria. Given his normal kidney function and solute and water intake, the cause was thought to be diabetes insipidus. His severe and prolonged hypokalemia (a known cause of renal tubular dysfunction) likely resulted in defective urine concentrating ability and partial nephrogenic diabetes insipidus. Lack of brain metastases made central diabetes insipidus less likely. Of note, he had only mild hypernatremia, likely due to an intact thirst mechanism and the ability to maintain free water intake.

Complete removal of an ACTH-secreting tumor is the optimal treatment of ectopic ACTH syndrome. Because this patient had a nonresectable tumor, the hypercortisolism was treated medically with an adrenal enzyme inhibitor (ketoconazole, 200 mg, three times daily). This led to near normalization of serum cortisol levels. Additionally, given concern for hypokalemia-induced nephrogenic diabetes insipidus, he was treated with a potassium-sparing diuretic (amiloride, 5 mg/day) with subsequent improvement in all electrolyte level derangements. His urine output also improved to 1.0 L/day.

The correct answer is D

Comment: Hypokalemic paralysis, as the name implies, encompasses paralysis, muscle weakness, and is seen with severe hypokalemia. Various causes of such are mentioned above. However, the most important challenge is to differentiate between the recurrent paralyses caused by RTA, mainly the distal type, and that caused by HFPP, an entirely different condition. The latter can be caused either by hypokalemia (most commonly) or by hyperkalemia. Hypokalemia in HFPP is not due to loss of potassium as observed in distal RTA (dRTA), but to abnormalities in its redistribution between intra- and extracellular compartments. Often, the predisposing factors are strenuous exercise, high carbohydrate diet, and other triggers. They usually have normal physical growth unlike patients with dRTA. Acidosis is not a typical feature and nephrocalcinosis is not observed. Mutations in two genes encoding subunits of skeletal muscle voltage-gated calcium or sodium channels (CACNL1A3 and SCN4A) have been identified in hypokalemic HFPP. Most of the cases are hereditary, mostly autosomal dominant (AD), but acquired cases can occur with thyrotoxicosis. Management in hypokalemic HFPP involves administration of potassium supplements and/or potassium-sparing diuretic; bicarbonate is not required, as it may worsen the paralysis by redistributing potassium intracellularly. This is in opposition with hypokalemia in dRTA where both potassium and bicarbonate supplements are required.

dRTA is characterized by an impaired capacity of the distal tubules to secrete hydrogen ions and hence ammonium secretion. Urine anion gap provides a rough estimate of urinary ammonium excretion. Besides normal serum anion gap and hyperchloremic metabolic acidosis, patients with dRTA have an abnormally high urine pH (≥ 5.5) for the degree of systemic acidemia in addition to positive urine anion gap. The most common cause of dRTA in children is primary, mostly familial; it can be either autosomal dominant (AD) or recessive (AR). AD dRTA is mainly due to mutations causing defects in the kidney anion exchanger (kAE1) in the distal tubule α-intercalated cells. The AR form of dRTA is mainly due to the mutations causing defects in beta subunit of H ⁺ ATPase in the apical membrane of α-intercalated cells. Most of the children have some degree of growth failure. In adults, the dRTA can be associated with hypergammaglobulinemia, autoimmune conditions, e.g., systemic lupus erythematous, rheumatoid arthritis, etc., and drugs, e.g., lithium, amphotericin B, ifosfamide, etc. Other secondary causes of dRTA are hypercalciuric conditions, e.g., hyperparathyroidism, vitamin D intoxication, and sarcoidosis. Hypercalciuria is common in dRTA due to effects of chronic acidosis on both bone resorption and the renal tubular reabsorption of calcium. Hypercalciuria eventually leads to nephrocalcinosis and nephrolithiasis. Association of nephrocalcinosis with MSK has been described.

Our patient had a known diagnosis of MSK and also had typical features of bilateral diffuse medullary nephrocalcinosis. Patients with MSK can have medullary nephrocalcinosis along with renal tubular acidification defects, both proximal and dRTA have been described. The latter is thought to be due to tubular disruption by cysts. MSK is a congenital disorder manifested by the formation of medullary cysts secondary to dilatation of the collecting ducts in the pericalyceal region of the renal pyramids. The gold standard test to diagnose MSK is an intravenous urography. Another diagnostic modality may be a CT scan with contrast showing persistence of the contrast enhancement in the renal collecting tubules and may be as useful as an intravenous pyelogram (IVP). MSK is usually diagnosed incidentally when being worked up for some other condition. However, growth failure can be associated with it and hence may be diagnosed in patients as early as 5 or 12 years old. In fact, most cases of dRTA described in the literature in association with MSK presented with growth failure. Severe hypokalemia in dRTA has been described in association with MSK and nephrocalcinosis. Our patient had recurrent hypokalemic paralysis secondary to dRTA but presented with normal growth. Evaluation of her growth charts prior to the diagnosis of dRTA and prior to being on potassium and bicarbonate supplements revealed normal height and weight. This may suggest an incomplete dRTA; however, we do not have an ammonium chloride test to confirm this.

dRTA is commonly associated with varying degrees of hypokalemia. However, the exact mechanism of hypokalemia is not very clear. The accepted hypothesis is that when H ⁺ secretion is impaired, there is simultaneous amplification of potassium secretory mechanisms involving the potassium channel, ROMK, or the epithelial sodium channels. However, some forms of dRTA can present with normal or even high serum potassium. Also, the autosomal recessive (AR) form of dRTA usually presents with more severe hypokalemia and acidosis as compared to the AD form. The primary form of dRTA can present sporadically as in our patient (most likely), as there was no similar family history or history of consanguinity. However, we could not perform mutation analysis of the kAE1or H ⁺ ATPase, as the patient was lost to follow-up.

Transtubular potassium gradient (TTKG) is an index of potassium secretary activity in the distal tubules. There is a positive correlation between aldosterone activity and the TTKG; a high TTKG value during hypokalemia generally reflects increased aldosterone production or increased distal tubule response to aldosterone. TTKG less than six (in adults) and less than four (in children) indicates an inappropriate renal response to hyperkalemia, whereas value greater than two during hypokalemia generally points to renal loss. Hence, the expected value of the TTKG must be interpreted as per the serum concentration of potassium. Our patient had inappropriately high TTKG in the setting of hypokalemia. The possible causes of such include hyperaldosteronism or pseudohyperaldosteronism. Her serum aldosterone level was not elevated. Additionally, the CT scan of the abdomen showed no adrenal lesions. Hypokalemia in association with hyperaldosteronism secondary to adrenal tumor has been described. Causes of pseudohyperaldosteronism including Cushing’s syndrome, AME, licorice ingestion, etc., were unlikely given normal physical examination and normotension and no alkalosis.