The correct answer is A

Comment: The history of chronic asthma, hyperventilation, low serum bicarbonate concentration, and a positive urine anion gap together suggest the presence of chronic respiratory alkalosis. ^,

Further, the patient’s serum bicarbonate of 16 mEq/L corresponds to a PCO ₂ of 20 to 22 mm Hg, as in chronic respiratory alkalosis, and for each 10 mm Hg drop in the pCO ₂ below 40 mm Hg, the serum bicarbonate level decreases by about 5 mEq/L.

The correct answer is C

Comment: Hyponatremia, hyperosmolality, and normovolemia in a setting of normal fractional excretion of urate (FEurate) at baseline strongly suggest the presence of reset osmostat (RO). Hyponatremia in the RO requires no therapy (option C).

Patients with the syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH) renal/cerebral salt wasting (R/CSW) and RO have similar clinical and laboratory characteristics including hyponatremia (Na <135 mEq/L), hypo-osmolality (<275 mOsm/kg), normal renal function, elevated urine osmolality (<100 mOsm/kg), and decreased serum uric acid level. All may have no clinical evidence of edema at the time of presentation. ^–

It is therefore important to distinguish these three syndromes from one another because they are treated with opposite treatment strategies.

For R/CSW, the patient is treated with fluids and sodium supplementation to restore the extracellular fluid (ECF) volume contraction. For SIADH, the patient is fluid restricted to remove the excess free water. For patients with RO, no therapy is needed because their ECF volume is intact and renal response to water and sodium is normal. ^,

The use of FEurate can accurately differentiate these three syndromes from one another. ^{, ,}

The key difference is that in SIADH, the initial FEurate is abnormally elevated (>10%) and returns to baseline value only when hyponatremia is corrected. ^–

In R/CSW, the FEurate persistently remains elevated (>10%) even after the correction of hyponatremia. ^,

In RO, unlike SIADH and R/CSW, the baseline FEurate is normal (between 4% and 10%). ^{, ,} Hyponatremia resulting from hypoaldosteronism is associated with non-gap hyperkalemic metabolic acidosis, FEurate is low (<4%), and the ECF volume is depleted. Therapy with a mineralocorticoid such as Florinef along with sodium supplements are indicated to correct hyponatremia.

The correct answer is C

Comment: The major findings in this patient were recurrent episodes of hypernatremic dehydration and absence of thirst with a plasma osmolality as high as 398 mOsm/kg H ₂ O. The patient was able to concentrate her urine (832 mOsm/kg H ₂ O). Volume expansion with water hypernatremia and hyperosmolarity and increased urine flow because of suppression of endogenous ADH.

These findings are consistent with an isolated defect in the osmoregulation of thirst as the cause of essential hypernatremia or RO (option C). ^,

The following criteria are necessary to establish this diagnosis ^, :

• A.
  

  recurrent episodes of severe hypernatremic dehydration

  
  
• B.
  

  absence of thirst

  
  
• C.
  

  normal ADH response to both osmotic and volume challenges

  
  
• D.
  

  correction of hypernatremia with fluid loading

Differentiation of reset hypernatremia from nephrogenic or central DI is important because management differs according to diagnosis. In patients with RO, vasopressin therapy is inappropriate and may lead to water intoxication.

The correct answer is A

Comment: A recent randomized, open-label, crossover controlled trial examined the efficacy and safety of adding acetazolamide into standard therapy consisting of a potassium-sparing diuretic (spironolactone), RAAS inhibitors (enalapril), and cyclooxygenase inhibitors (indomethacin) supplemented with large doses of potassium in 22 children with genetically proven Bartter syndrome resistant to the standard therapy. The study results concluded that acetazolamide in combination with standard therapy significantly improved renal responses to indomethacin plus enalapril and spironolactone without any drug-related adverse events.

The correct answer is D

Comment: The findings of hypokalemia, metabolic alkalosis, and normal BP suggest the diagnosis of secondary hyperaldosteronism caused by surreptitious vomiting, diuretic abuse, or Bartter syndrome. Measurement of urinary chloride, calcium, and magnesium is useful in the differentiation between these disorders. The urinary chloride concentration is typically less than 15 mEq/L in hypovolemia resulting from surreptitious vomiting. In contrast, a urinary chloride greater than 15 mEq/L suggests diuretic abuse, Bartter syndrome, or Gitelman syndrome. Measurement of urine calcium will help distinguish between Bartter syndrome and Gitelman syndrome. Screening urine for diuretics is indicated if surreptitious ingestion is suspected. Measurement of the urinary magnesium will help distinguish between gastrointestinal and renal losses as the major contributor.

Bartter syndrome can cause hypokalemia, metabolic alkalosis, renal magnesium wasting, and hypomagnesemia without hypertension in a manner similar to that of loop diuretics. Bartter syndrome is caused by mutations in a furosemide-sensitive ion transport mechanism in the loop of Henle and is associated with hypercalciuria. A diuretic screen is the only way to distinguish Bartter syndrome from diuretic abuse (option D). ^,

The correct answers are B, C, E, and F

Comment: Foscarnet is an antiviral drug used to treat CMV and CMV-associated ophthalmic retinitis in individuals who are unable to tolerate ganciclovir or those who have drug-resistant CMV and fail ganciclovir. It also has approval as a treatment option in immunocompromised patients with the herpes simplex virus who exhibit resistance to acyclovir, the gold-standard therapy for herpes simplex virus.

Although there are multiple adverse effects of foscarnet, the most notable are nausea associated with the infusion of the drug, electrolyte derangements, and reduced renal function. Of these three significant adverse effects, reports of renal insufficiency are relatively more common events in patients receiving this drug.

Foscarnet affects the renal tubular cells via direct cytotoxic mechanisms, and the degree of drug-induced toxicity directly correlates to the dosage administered. Along with the renal tubular damage, foscarnet can also cause crystal nephropathy with the deposition of crystals in the glomerular capillaries.

Electrolyte derangement is another adverse effect of foscarnet and often presents as hypocalcemia and hypomagnesemia. Hypocalcemia may be due to the formation of the foscarnet and calcium ion complex, or it may result from foscarnet-induced hypomagnesemia, which leads to both hypocalcemia (from a hypomagnesemia-induced hypoparathyroidism state) and hypokalemia (from excess renal potassium wasting).

The less commonly reported adverse events resulting from foscarnet administration include seizures.

The correct answers are B and C

Comment: The 24-hour urine phosphate and creatinine excretion results were 800 mg and 1250 mg, respectively. The fractional phosphate excretion was 43%.

The correct answers are D and E

Further laboratory studies revealed: serum 25 (OH) D 26 ng/mL (normal, 15–50 ng/mL); 1,25 (OH)2 D 10 pg/mL (normal, 15–60 pg/mL); PTH 3 pmol/L (normal, 1–5 pmol/L); uric acid 5 mg/dL; urine glucose negative; urine amino acid negative; and urine uric acid 50 mg/dL (normal, 10–80 mg/dL).

The correct answer is C

Comment: Oncogenic osteomalacia, referred to as tumor-induced osteomalacia (TIO), is a rare endocrine disorder in which a small bony or soft tissue mesenchymal tumor causes hypophosphatemia via secretion of fibroblast growth factor 23 (FGF23). ^, The latter causes hypophosphatemia via two mechanisms: (1) reduction of renal tubular phosphate reabsorption leading to phosphaturia and (2) impairment of hydroxylation of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, thus reducing intestinal phosphorus absorption. As a result of chronic hypophosphatemia, patients develop osteomalacia and associated insufficiency fractures.

The diagnosis of TIO should be considered in patients who have musculoskeletal pain with hypophosphatemia, with or without insufficient fractures. Diagnostic testing should include quantification of the tubular reabsorption of phosphorus, which is reduced in the presence of FGF23; additional diagnostic laboratory and imaging studies are useful for the evaluation of TIO. The differential diagnosis of hypophosphatemia includes X-linked hypophosphatemia (consider with younger age of onset, suggestive family history, and dental anomalies), proximal renal tubulopathies (consider with multiple electrolyte abnormalities; may be genetic or acquired), and dietary-related hypophosphatemia (consider in patients with low intake or refeeding syndrome).

Presence of hypocalcemia, hypokalemia, and proximal renal tubular acidosis (RTA) may suggest Fanconi syndrome.

If there is a discordance between 25 (OH) vitamin D and 1,25 (OH)2 vitamin D, this would suggest the presence of interfering FGF23, favoring the diagnosis of oncogenic osteomalacia.

Elevated PTH would result in hypophosphoremia and hypercalcemia.

The correct answers are C, D, and E

Comment: Hypocalcemia has many causes. It can result from inadequate PTH secretion, PTH resistance, vitamin D deficiency or resistance, abnormal magnesium metabolism, and extravascular deposition of calcium, which can occur in several clinical situations. ^,

The diagnostic approach to hypocalcemia involves confirming, by repeat measurement, the presence of hypocalcemia and distinguishing among the potential etiologies. The diagnosis may be obvious from the patient’s history; examples include chronic kidney disease and postsurgical hypoparathyroidism.

The correct answers are C and E

Comment: Vitamin D is a fat-soluble vitamin used by the body for normal bone development and maintenance by increasing the absorption of calcium, magnesium, and phosphate. A circulating level of 25-hydroxyvitamin D greater than 30 ng/mL is required to maintain a healthy level of vitamin D. Vitamin D deficiency can lead to an array of problems, most notably rickets in children and osteoporosis in adults.

Vitamin D deficiency is now more prevalent than ever and should be screened in high-risk populations. Many conflicting studies are now showing an association between vitamin D deficiency and cancer, cardiovascular disease, diabetes, autoimmune diseases, and depression. This section reviews the evaluation and management of vitamin D deficiency and explains the role of the interprofessional team in improving care for patients with this condition.

Certain malabsorption syndromes such as celiac disease, short bowel syndrome, gastric bypass, inflammatory bowel disease, chronic pancreatic insufficiency, and cystic fibrosis may lead to vitamin D deficiency. Lower vitamin D intake orally is more prevalent in the elderly population.

Decreased exposure to the sun as seen in individuals who have dark skin or have prolonged hospitalizations can also lead to vitamin D deficiency.

Individuals with chronic liver disease such as cirrhosis can have defective 25-hydroxylation leading to deficiency of active vitamin D. Defect in 1-alpha 25-hydroxylation can be seen in hyperparathyroidism, renal failure, and 1-alpha hydroxylase deficiency.

Medications such as phenobarbital, carbamazepine, dexamethasone, nifedipine, spironolactone, clotrimazole, and rifampin induce hepatic p450 enzymes, which activate degradation of vitamin D.

Last, end-organ resistance to vitamin D can be seen in hereditary vitamin D–resistant rickets.

Vitamin D deficiency is evaluated by the measurement of serum 25-hydroxyvitamin D. Optimal serum levels of 25-hydroxyvitamin D is still a matter of controversy.

The International Society for Clinical Densitometry and International Osteoporosis Foundation recommends minimum serum levels of 25-hydroxyvitamin D of 30 ng/mL to minimize the risk of fall and fractures in older individuals.

In patients in which vitamin D deficiency has been diagnosed, it is important to evaluate for secondary hyperparathyroidism and levels of PTH and serum calcium should be measured.

The correct answer is C

Comment: Liddle syndrome is a genetic disorder characterized by hypertension with hypokalemic metabolic alkalosis, hyporeninemia, and suppressed aldosterone secretion that often appears early in life. It results from inappropriately elevated sodium reabsorption in the distal nephron. Liddle syndrome is caused by mutations to subunits of the epithelial sodium channel (ENaC). Among other mechanisms, such mutations typically prevent ubiquitination of these subunits, slowing the rate at which they are internalized from the membrane and resulting in an elevation of channel activity. A minority of Liddle syndrome mutations, though, result in a complementary effect that also elevates activity by increasing the probability that ENaC channels within the membrane are open. Potassium-sparing diuretics such as amiloride and triamterene reduce ENaC activity, and in combination with a reduced sodium diet can restore normotension and electrolyte imbalance in Liddle syndrome patients and animal models. Liddle syndrome can be diagnosed clinically by phenotype and confirmed through genetic testing. ^,

Liddle syndrome differentiates from other genetic diseases with a similar phenotype, and what is currently known about the population-level prevalence of Liddle syndrome is discussed here. This review gives special focus to the molecular mechanisms of Liddle syndrome.

Treatment of Liddle syndrome is typically through the use of a potassium-sparing diuretic, such as amiloride or triamterene. ^, Both diuretics work by blocking the activity of ENaC, and their efficacy in Liddle syndrome cases has been shown to be enhanced with dietary salt restriction (<2 g NaCl per day). These diuretics can correct the elevated BP as well as the hypokalemic metabolic alkalosis seen in Liddle syndrome.

The correct answer is A

Comment: True (hypoosmolal) hyponatremia is associated with a reduction in serum osmolality and is further classified as euvolemic, hypervolemic, and hypovolemic.

Euvolemic hyponatremia accounts for 60% of all cases of hyponatremia. The most common cause of euvolemic hyponatremia is SIADH. ^–

The criteria necessary for a diagnosis of SIADH include:

• 1.
  

  Decreased measured serum osmolality (<275 mOsm/kg H ₂ O)

  
  
• 2.
  

  Clinical euvolemia

  
  
• 3.
  

  Urinary osmolality >100 mOsm/kg H ₂ O

  
  
• 4.
  

  Urinary Na >40 mmol/L with normal dietary sodium intake

  
  
• 5.
  

  Normal thyroid and adrenal function

  
  
• 6.
  

  Normal renal functions

  
  
• 7.
  

  Exclude use of diuretic agents within the week before evaluation

  
  
• 8.
  

  No hypokalemia

  
  
• 9.
  

  No acid-base disorders

Supporting diagnostic criteria for SIADH include serum uric acid less than 3.5 mg/dL, BUN <10 mg/dL, fractional urine sodium excretion >1%, fractional urea excretion >55%, failure to improve or worsening of hyponatremia after 0.9% saline infusion, and correction of hyponatremia with fluid restriction. ^–

The correct answers are C and D

Comment: Hyponatremia has been identified as a risk factor for increased morbidity and mortality in patients with congestive heart failure (CHF) and other edematous disorders and can lead to severe neurologic derangements. Low cardiac output and BP associated with CHF triggers a compensatory response by the body that activates several neurohormonal systems designed to preserve arterial blood volume and pressure. Hyponatremia in patients with CHF is primarily caused by increased activity of arginine vasopressin (AVP). AVP increases free-water reabsorption in the renal collecting ducts, increasing blood volume and diluting plasma sodium concentrations. Hyponatremia may also be triggered by diuretic therapy used in the management of symptoms of CHF.

At an early stage of CHF, retention of sodium and water causes expansion of extracellular fluid volume and peripheral edema, but not hyponatremia. However, at late-stage CHF, patients exhibit an impairment in the renal excretion of water (aquaresis or water diuresis), predisposing them to the development of hyponatremia. An increase in the antidiuretic hormone in this late stage imposes an aquaretic defect, which, in combination with the use of potent diuretics and severe salt restriction, frequently leads to dilutional hyponatremia. ^,

The correct answer is A

Comment: SIADH involves the continued secretion or action of AVP despite normal or increased plasma volume. The resulting impairment of water secretion and consequent water retention produce the hyponatremia (i.e., serum Na ⁺ <135 mmol/L) with concomitant hypo-osmolality (serum osmolality <280 mOsm/kg) and high urine osmolality that are the hallmarks of SIADH.

The key to understanding the pathophysiology, signs, symptoms, and treatment of SIADH is the awareness that hyponatremia results from an excess of water rather than a deficiency of sodium.

Differentiating SIADH from reset hyponatremia renal salt wasting (RSW) has been extremely difficult to accomplish, in part because of significant overlapping clinical findings between both syndromes. All three syndromes are associated with intracranial diseases; have normal renal, thyroid, and adrenal function; are hyponatremic and hypouricemic; and have concentrated urines, with high urinary sodium >40 mEq/L. The baseline fractional excretion of urate is also high in SIADH and RSW, but normal in reset hyponatremia. ^–

The only clinical difference is the state of the patient’s ECV, being euvolemic or hypervolemic in SIADH, hypovolemic in RSW, and euvolemic in reset hyponatremia.

This diagnostic dilemma between SIADH and RSW can be resolved by repeating the fractional excretion of urate after correction of hyponatremia. In SIADH the fractional urate excretion returns to normal value (<10%), whereas in RSW, it remains persistently high (>11%). ^,

The correct answers are C and E

Comment: Hyponatremia is the most common electrolyte abnormality seen in hospitalized patients, with 15% to 20% of patients having a sodium level <135 mmol/L. The differential diagnosis for hyponatremia is broad, and a systematic and logical approach is needed to identify the cause.

RO is an uncommon and underrecognized cause of hyponatremia that does not require any treatment. This diagnosis needs to be considered when the hyponatremia workup suggests SIADH, but the hyponatremia is not amenable to fluid restriction, salt administration, or diuretic treatment. ^–

Diagnosing RO is a diagnosis of exclusion. Individuals must be euvolemic, and a thorough exclusion of other causes of euvolemic hyponatremia (e.g., hypothyroidism, cortisol deficiency, medications) must take place. A key feature of RO is that individuals should be able to concentrate and dilute the urine appropriately. Thus, a water challenge should result in dilute urine (e.g., <100 mOsm/kg) and a water deprivation test should result in concentrated urine. Sometimes, a patient given a diagnosis of SIADH will be proven to reset the osmostat when it becomes apparent that fluid restriction does not successfully raise the serum sodium level.

RO classically occurs in neurologic conditions such as epilepsy and paraplegia, in addition to pregnancy, malignancy, and malnutrition. It has also been observed in healthy individuals.

Hyponatremia in the SIADH results from ADH-induced retention of ingested or infused water. Although water excretion is impaired, sodium handling is intact because there is no abnormality in volume-regulating mechanisms such as the renin-angiotensin-aldosterone system or atrial natriuretic peptide.

The correct answer is C

Comment: The constellation of high blood pH, high serum bicarbonate concentration, and pCO ₂ above 40 mm Hg suggests the presence of a mixed metabolic and respiratory alkalosis. Metabolic alkalosis is caused by persistent vomiting over the past 48 hours. Respiratory alkalosis is likely from hyperventilation as a result of shortness of breath secondary to chest pain.

The correct answer is C

Comment: The acid-base diagnosis is uncomplicated hyperchloremic acidosis resulting from severe diarrhea. This would allow you to estimate her pCO ₂ from the Winter formula, which applies only when simple (uncomplicated) metabolic acidosis is present.

The expected fall can be estimated using the following equation:

Then, the predicted pCO ₂ compensation can be estimated as the difference between normal pCO ₂ and the expected fall in pCO ₂ [normal pCO ₂ (40)] – delta [pCO ₂ (12)] or 28 mm Hg.

The H ⁺ can then be calculated with the modified Henderson-Hasselbach equation:

The H ⁺ value obtained is 45 mEq/L, which is equivalent to a pH of 7.35 (every 0.1 fall in pH is equivalent to 10 mEq/L rise in plasma H ⁺ concentration).

The correct answer is D

Comment: Hypokalemia is generally from 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 because of ongoing sodium and chloride reabsorption in the proximal tubule from 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 >20 mmol/L and low levels of both serum renin and aldosterone, the differential diagnosis includes Liddle syndrome, syndrome of AME, Cushing syndrome, congenital adrenal hyperplasia, and excessive licorice use. ^– Liddle syndrome, syndrome of AME, 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 (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 MRI of the pituitary gland and CT 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 11b-hydroxysteroid dehydrogenase type 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 resectable, 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 mm Hg, 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, hypophosphatemia, 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 nonnephropathic 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. The 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 cystinosis and maps to chromosome 17p13. ^,

Oral cysteamine therapy is recognized as the treatment of choice for patients with nephropathic cystinosis who have not undergone a 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, 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 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 hypovascular area 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 because of the superficial location of these tumors draining through pericapsular veins rather than the main renal veins, variable blood dilution by extrarenal 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 mm Hg). 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 carbenoxolone 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 on 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 an oral potassium supplement therapy and advised not to eat licorice. At 2 weeks’ follow-up, his BP was 140/60 mm Hg, and chemistry test results included the following values: potassium, 4.5 mmol/L; serum creatinine, 1.0 mg/dL; and estimated GFR, 79.7 mL/min/1.73 m ² off potassium supplements.

The correct answer is A

Comment: The acidemia is due to retention of H ⁺ ions from ketoacidosis; the associated anions (b-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 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 <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 AME is an inherited form of hypertension in which 11-b-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-b-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-ATPase 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 posttreatment 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. ^,

Correct answer is C

Comment: This patient is an example of classic 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 in patients with Gitelman syndrome, 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 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. The upper gastrointestinal loss could still be a proximate cause because the predominant mechanism for hypokalemia in that situation is renal from secondary hyperaldosteronism and bicarbonate in the tubular fluid acting as a nonabsorbable anion. The actual potassium loss from gastric losses is not very much, as potassium concentration is only 5 mEq/L to 10 mEq/L in gastric fluid. ^,

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: Because 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 because all would have elevated levels of aldosterone.

Diuretic abuse and secondary hyperaldosteronism, renovascular hypertension, and renin-secreting tumors 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 flavonoids present in licorice and in grapefruit inhibit the enzyme 11-b-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-b hydroxysteroid dehydrogenase (resulting from 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 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 PRA, increased plasma aldosterone concentration (PAC), and PAC:PRA ratio 20³ 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 AME.

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

Under normal conditions, excess cortisol is converted to its inactive metabolite cortisone by the kidney by the enzyme 11-b-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 AME 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 DI. 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 from 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 DI, 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 previously. However, the most important challenge is to differentiate between the recurrent paralyzes 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 because it may worsen the paralysis by redistributing potassium intracellularly. This is in opposition to 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 5.5³ 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 AD or autosomal recessive. AD dRTA is mainly due to mutations causing defects in the kidney anion exchanger (kAE1) in the distal tubule a-intercalated cells. The autosomal recessive form of dRTA is mainly the result of mutations causing defects in beta subunit of H+ ATPase in the apical membrane of a-intercalated cells. Most of the children have some degree of growth failure. In adults, dRTA can be associated with hypergammaglobulinemia, autoimmune conditions (e.g., systemic lupus erythematous, rheumatoid arthritis), and drugs (e.g., lithium, amphotericin B, ifosfamide). Other secondary causes of dRTA are hypercalciuric conditions (e.g., hyperparathyroidism, vitamin D intoxication, sarcoidosis). Hypercalciuria is common in dRTA because of 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 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. MSK is usually diagnosed incidentally when being worked up for another condition. However, growth failure can be associated with it and hence may be diagnosed in patients as early as age 5 or 12 years. 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 before the diagnosis of dRTA and before 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 form of dRTA usually presents with more severe hypokalemia and acidosis compared with the AD form. The primary form of dRTA can present sporadically as in our patient (most likely) because there was no similar family history or history of consanguinity. However, we could not perform mutation analysis of the kAE1 or H+ ATPase because the patient was lost to follow-up.

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 lower than 6 (in adults) and lower than 4 (in children) indicates an inappropriate renal response to hyperkalemia, whereas value greater than 2 during hypokalemia generally points to renal loss. Hence, the expected value of the TTKG must be interpreted per the serum concentration of potassium. Our patient had inappropriately high TTKG in the setting of hypokalemia. The possible causes 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 syndrome, AME, or licorice ingestion were unlikely given normal physical examination and normotension and no alkalosis. ^–

The correct answer is A

The correct answer is B

Comment: The patient was initially prescribed a furosemide loading dose of 80 mg IV to rapidly achieve a therapeutic serum level, followed by a maintenance dose of 5 mg/h (120 mg/day) IV to maintain a steady state; this management strategy has effectively achieved decongestion. This dose is equivalent to 240 mg/day orally, which should be given as 120 mg twice daily to avoid postdiuretic sodium reabsorption. However, because this patient’s signs and symptoms of acute decompensated heart failure and AKI resolved and 2.4 L/day urine output is no longer necessary, a lower oral dose of furosemide, such as 80 mg twice daily, may be appropriate. Furosemide 120 mg twice daily with metolazone 10 mg/day would further increase diuresis and could cause hypovolemia and/or hypokalemia. Similarly, bumetanide 4 mg orally twice daily, which is equivalent to furosemide 160 mg IV twice daily or 320 mg orally twice daily, would also risk hypovolemia. Unless sodium intake can be severely restricted, neither furosemide nor bumetanide should be dosed once daily.

The correct answer is A

Comment: Hypokalemia is likely secondary to reversible type 1 renal tubular acidosis, likely from ibuprofen use.

A systematic approach to hypokalemia can help narrow the differential diagnosis in this case.

Hypokalemia can result from shifts of potassium from the extracellular to the intracellular space (internal balance) or from potassium depletion resulting from losses into the gastrointestinal tract or urine (external balance). Severe hypokalemia with paralysis from an intracellular potassium shift can be due to hypokalemic periodic paralysis (hereditary or thyrotoxic) or exogenous insulin or catecholamines. In our patient, the relatively high urinary potassium excretion, the need for large doses of potassium during replacement, and the clinical course made us conclude that he was potassium depleted. The causes of potassium depletion include vomiting, diarrhea, RTA, toluene toxicity, diuretic use, Bartter and Gitelman syndromes, and acquired or hereditary hypertensive renal potassium wasting disorders.

The expected renal response to hypokalemia would be to limit urinary potassium excretion. A patient has abnormal urinary losses during hypokalemia if potassium excretion surpasses 30 mEq in a 24-hour urine collection or a random urine potassium-creatinine ratio is >13 mEq/g. Our patient had 30 mEq of potassium per gram of creatinine in the urine on admission and 112 mEq of potassium in the 24-hour urine collection (while getting potassium repletion). Urinalysis was normal with a pH of 7.0.

The cause of renal potassium wasting can be determined from the associated acid–base disturbance and blood pressure. Our patient had a normal anion gap metabolic acidosis. Therefore, we need not consider the various causes of hypertensive or normotensive renal potassium wasting with metabolic alkalosis.

Normal anion gap metabolic acidosis and potassium wasting could be caused by RTA, toluene toxicity, or diarrhea. RTA with hypokalemia can be seen in type 1 (distal) or type 2 (proximal) RTA. Proximal RTA typically has mild hypokalemia, an acid urine pH (unless treated), and other proximal tubular abnormalities (Fanconi syndrome) that were absent in our patient. Severe hypokalemia and alkaline urine pH are features of distal RTA. Inhaling solvent fumes, such as glue sniffing or paint huffing, results in systemic absorption of toluene, which is oxidized to benzoic acid and then conjugated with glycine to form hippuric acid. These hippurate anions are then secreted into the tubular lumen with sodium and potassium (along with ammonium, which raises the urine pH), causing a very similar picture to distal RTA. In addition to urine potassium and pH, other relevant urine parameters include the urinary osmoles (sodium, potassium, urea, and glucose), which enable us to calculate the urinary osmolar gap, the difference between measured urine osmolarity and calculated urine osmolarity (2 × [Na + K]) + [urea] + [glucose]), which serves as a surrogate of ammonium excretion.

A normal anion gap metabolic acidosis caused by diarrhea or solvent abuse is associated with high rates of urine ammonium excretion; the rate of urine ammonium excretion is not high in RTA. Urine ammonium is not routinely measured by clinical laboratory tests, but it can be estimated from the gap between measured and calculated urine osmolality; urine ammonium excretion is approximately equal to half the urine osmolar gap. In our patient, the 24-hour urine osmolar gap was not high, and hippuric acid was not found in urine. The elevated urine pH without an increase in urinary osmolar gap is consistent with a diagnosis of dRTA.

The acute onset of dRTA without nephrocalcinosis makes an acquired rather than a congenital form more likely. Autoimmune disease, most often Sjögren syndrome, is the most common cause of acquired dRTA. Serologic testing was negative for autoimmune causes, so we considered additional causes. Although ibuprofen has typically been associated with hyperkalemia, there have been several case reports of severe hypokalemia and transient distal RTA resulting from abuse of a combination drug containing ibuprofen and codeine. The pathogenesis is unclear but inhibition of carbonic anhydrase, which is present in the proximal and distal tubules, has been suggested.

Consistent with the suspicion of ibuprofen being the etiologic agent, after the patient stopped treatment with the medication, his serum potassium level increased dramatically and renal losses decreased. He was discharged with a normal potassium level, and normal carbon dioxide level, and had no subsequent recurrences.

The correct answer is A

Comment: This girl with a solitary kidney had urinary incontinence and constipation since birth along with recurrent UTIs, resulting in the development of CKD stage IV (estimated GFR 22 mL/min/1.73 m ² by modified Schwartz formula). She was underweight with short stature and had hypertension, anemia, metabolic acidosis, vitamin D deficiency, and hyperparathyroidism, which are manifestations of CKD. The solitary right kidney did not show compensatory hypertrophy and had loss of corticomedullary differentiation with hydroureteronephrosis in the absence of vesicoureteric reflux. These findings and increased bladder wall thickness on ultrasound suggested presence of concomitant bladder dysfunction probably because of anatomical or functional obstruction. A patulous anus and characteristic “Christmas tree” appearance of the urinary bladder with irregular contours were suggestive of a neurogenic bladder. Both ovaries and uterus were absent. Because the patient was phenotypically female, this prompted us to consider 46, XY disorders of sexual development such as androgen insensitivity syndrome (OMIM 300068). She was in her early adolescence; hence, we could not comment on the development of secondary sexual characteristics. Patients with androgen insensitivity syndrome usually do not have extragenital anomalies. The presence of genitourinary abnormalities, abnormal thumb of the left hand with loss of thenar prominence, and probable neurogenic bladder raised the suspicion of multisystem structural involvement. Patients with Kallmann syndrome may rarely have solitary kidneys with genital and skeletal abnormalities but they have associated anosmia and a family history of delayed or absent puberty. Hence, we revisited our differential diagnosis to a syndrome that involved Müllerian duct agenesis, congenital anomalies of the kidney and urinary tract, and the skeletal system. We further evaluated the patient for Mayer-Rokitansky-Küster-Hauser syndrome.

The correct answer is C

Comment: The clinical picture described in this patient is consistent with SIADH. SIADH observed in this patient is attributed to the increased serum levels of valproic acid (VPA) that exceeded the therapeutic range. Restricting daily fluid intake and decreasing the dose of VPA to obtain a therapeutic level was our first management strategy. After 1 week of dose adjustment, the patient’s serum level of VPA decreased to 90 µg/dL (50–100 µg/dL) and sodium level increased to 137 mEq/L.

SIADH is a well-known cause of euvolemic hyponatremia and is characterized by the presence of hypo-osmolality and inappropriately increased urine osmolality (>120 mOsm/kg) in the absence of abnormal kidney function, glucocorticoid deficiency, hypothyroidism, and decreased arterial blood volume. The hallmark of the activity of ADH is considered to be inappropriate in this disorder because no exact osmotic or hemodynamic stimulus is detected for its action. ^, Water excretion is impaired despite the hypo-osmolality of plasma. ^, There is a variety of etiological causes in SIADH, such as central nervous system disorders (infection, trauma, malignancies, intracranial hemorrhage), pulmonary diseases (infections, malignancy, cystic fibrosis), and neoplasia (leukemia, lymphoma). A number of drugs have also been associated with this syndrome such as cyclophosphamide, vincristine, amitriptyline, and desipramine. Among antiepileptic drugs, carbamazepine and oxcarbazepine are more commonly reported to cause SIADH. ^, VPA is extremely rarely reported as a cause of SIADH and all of the reported cases are in adults. ^{, ,}

Our patient was diagnosed with SIADH because of euvolemic hyponatremia and elevated urine osmolality despite low plasma osmolality, normal kidney function, and the absence of thyroid deficiency. There was no obvious clinical or laboratory evidence of malignancies or pulmonary disorders, so these possible etiological causes of SIADH were excluded. Intracranial tumors and/or hemorrhage were excluded by cranial CT. She did not have fever, vomiting, altered consciousness, or meningeal irritation signs, so meningitis was also ruled out. Although we did not obtain serum cortisol levels, we believed that adrenal insufficiency was unlikely in this patient because she was asymptomatic, her volume status and blood pressure were normal, she did not have hyperpigmentation, and she had no significant abnormality on laboratory examination other than hyponatremia. After all possible causes were excluded as described, the underlying etiology of SIADH was attributed to VPA. The concomitant use of clonazepam in our patient may raise the question of whether this drug may also be the cause of hyponatremia.

The correct answer is E

Comment: The differential diagnosis in patients presenting with unilateral multicystic renal lesions is multilocular cystic nephroma, unilateral renal cystic disease, segmental multicystic dysplastic kidney disease, and cystic renal cell carcinoma. The therapy for multilocular cystic nephroma is radical nephrectomy because it cannot be differentiated from more aggressive neoplasms such as the cystic variant of Wilms tumor and cystic renal cell carcinoma, which makes it crucial for us to carefully consider other diagnoses first.

The lack of suspect lymph nodes and homogeneous tumor mass as well as the presence of cysts in other areas of the affected kidney in our patient made the diagnosis of cystic nephroma less likely. Unilateral renal cystic disease is a less well-known entity reported that is nonfamilial and nonprogressive. Segmental multicystic dysplastic kidney disease was unlikely in our patient because on the CT scan there was normal contrast enhancement in the renal tissue adjacent to the cysts.

The correct answer is B

Comment: Chronic diarrhea and the absence of polyuria/polydipsia are untypical for patients with Bartter syndrome and cystic fibrosis of the pancreas. The findings of normal BP also rule out hyperaldosteronism.

CLD is a rare autosomal recessive disease occurring mainly in people in Arabian countries, Finland, and Poland. ^– It is characterized by unremitting watery diarrhea with high fecal losses of chloride, failure to thrive, and renal impairment in older children and adults if the disease is left untreated. Prenatal symptoms include polyhydramnios and dilated intestinal loops; birth is often premature, and postnatal mortality rates are high because of severe dehydration and electrolyte imbalances. The disease is caused by a defective anion exchange protein, an epithelial chloride/bicarbonate (Cl ^– /HCO ₃ ^– ) exchanger located in the brush border of the ileum and colon, resulting in defective intestinal chloride absorption and secretion of HCO ₃ ^– , with a secondary defect in sodium/hydrogen (Na ⁺ /H ⁺ ) transport, altogether leading to intestinal losses of both sodium and water, hypochloremia, hyponatremia, and metabolic alkalosis.

Some of the clinical features of CLD may resemble Bartter syndrome, which had been suspected in this case, namely, polyhydramnios, failure to thrive, and hypochloremic metabolic alkalosis. However, all forms of Bartter syndrome are characterized by high urinary losses of Na, potassium (K), and Cl because of defective tubular reabsorption. Thus, a simple spot urine measurement may rule out Bartter, as in this case. Urinary concentrations of Na and Cl were 14 mmol/L and 15 mmol/L, respectively. However, misdiagnosis of batter syndrome in CLD patients has been described in a number of cases. Differential diagnosis further includes cystic fibrosis, which (especially in hot climates) may result in high Cl losses, hypochloremic metabolic alkalosis, gastrointestinal symptoms, and failure to thrive and should be ruled out by a sweat chloride test (normal in this case).

Measuring chloride in stool is a simple clinical test to confirm the clinical diagnosis of CLD. Cl concentrations of >90 mmol/L are reportedly diagnostic for the disease. In this case, the value was 89 mmol/L (after rehydration and chloride substitution). However, genetic testing is now available in specialized laboratories to establish the definitive diagnosis.

Patients with CLD harbor mutations in both copies of the SLC26A3 (solute carrier family 26, member 3, or DRA) gene on chromosome 7q31. Altogether, 36 different mutations distributed within exons 3 through 19 of the gene have been identified in patients with CLD. ^, However, certain founder mutations are particularly frequent in patients in Arabian countries, Finland, and Poland, and account for the majority of CLD cases. No genotype-phenotype correlation has emerged. Direct sequencing of the SLC26A3 gene detects point and splice-site mutations and small insertions and deletions, with an overall mutation detection rate of >95%. In this case, both parents were found to harbor the heterozygous mutation c.559G>T (p. G187X), resulting in a homozygous mutation of the patient at this locus. This mutation results either in severe protein truncation or in nonsense-mediated RNA decay, with no protein produced at all. This mutation has been described in patients from Saudi Arabia and Kuwait ; it represents the Arab founder mutation and has apparently spread to Libya as well.

Our patient was treated with placement of a percutaneous endoscopic gastrostomy, resulting in dramatic improvement of fluid and caloric intake and instantaneous weight gain. Intravenously administered alimentation was discontinued, and at discharge from the hospital, the child needed substitution with 6 mEq/kD per day of KCl to maintain normal potassium, chloride, and bicarbonate serum levels.

The correct answer is C

Comment: The child has presented in infancy with hyperkalemia associated with a hyperchloremic metabolic acidosis and a normal anion gap of 11 (normal, 10–14). His estimated GFR is normal. Hyperkalemia in the presence of estimated GFR >15 mL/min/1.73 m ² is generally from an aldosterone deficiency or aldosterone resistance in the distal nephron.

The action of aldosterone on the distal nephron can be quantified using the TTKG.

TTKG = [Urine K ⁺ × Plasma osmolarity/Urine osmolarity × Plasma K ⁺

A low TTKG suggests aldosterone deficiency or insensitivity. A high TTKG suggests a dietary excess of potassium. Our patient had a reduced TTKG of 2.7 in the presence of hyperkalemia (normal range in infants, 4.9–15.5), suggesting aldosterone deficiency or end-organ resistance. The differential diagnosis would thus include congenital adrenal hyperplasia or hypoplasia, hypoaldosteronism, or insensitivity to aldosterone. The presence of a normal serum aldosterone in our patient makes end-organ resistance to this mineralocorticoid the most likely cause.

There are many conditions in which aldosterone levels are normal and the primary defect resides at the level of the renal tubule, including hereditary pseudohypoaldosteronism type I (in infants) and type II (in children and adult), systemic lupus erythematosus, amyloidosis, obstructive uropathy, sickle cell nephropathy, or drugs (spironolactone, triamterene, amiloride, trimethoprim, and pentamidine).

In view of the early presentation and that the infant was not on any medication, the most likely cause of his phenotype is hereditary PHA. PHA describes conditions of apparent hypoaldosteronism despite normal-to-high circulating levels of aldosterone. There are two separate clinical syndromes of PHA.

Type I PHA reflects the apparent lack of aldosterone effect on sodium reabsorption and potassium secretion and thus features hypotension and hyperkalemia. These children have renal salt wasting and often have hyponatremia. Plasma renin levels are elevated, as are plasma levels of aldosterone. The latter finding, as well as the lack of response to mineralocorticoid replacement therapy, differentiates them from infants with selective aldosterone deficiency who otherwise have a similar constellation of clinical findings. There are autosomal dominant and autosomal recessive forms of this disease, caused by mutations of the mineralocorticoid receptor and ENaC, respectively. Therapy with salt supplementation is effective in treating both the salt depletion and the hyperkalemia. As in other instances of mineralocorticoid deficiency, volume contraction with decreased distal delivery of salt and water appears necessary for overt hyperkalemia to develop. Spontaneous recovery usually occurs by the age of 2 years, although episodic hyperkalemia may still occur during episodes of acute illness.

PHA type II (Gordon syndrome or familial hypertension with hyperkalemia) exhibits an autosomal dominant mode of transmission and is usually seen in late childhood or adulthood. These patients also have hyperkalemia and hyperchloremic metabolic acidosis but do not exhibit renal salt wasting, have low plasma renin levels, and are usually hypertensive. Aldosterone levels are normal or high and most of these patients have a normal estimated GFR. This syndrome is also characterized by short stature, intellectual impairment, dental abnormalities, and muscle weakness. ^, Recent positional cloning has linked mutations of WNK1 (on chromosome 12p) and WNK4 (on chromosome 17q21) to type II PHA. With-no-lysine [K] (WNK) kinases are a new family of large serine-threonine protein kinases with an atypical placement of the catalytic lysine. Wild-type WNK1 and WNK4 inhibit the thiazide-sensitive sodium chloride cotransporter in the distal tubule. Mutations of these proteins are associated with gain of function and increased cotransporter activity, excessive chloride and sodium reabsorption, and volume expansion. Hyperkalemia, another hallmark of this syndrome, might be a function of diminished sodium delivery to the cortical collecting tubule. Sodium reabsorption provides the driving force for potassium excretion, which is mediated by the ROMK. Alternatively, the same mutations in WNK4 that result in a gain of function of the Na-Cl cotransporter might inhibit ROMK activity, resulting in hyperkalemia. Treatment consists of either a low-salt diet or thiazide diuretics, aimed at decreasing chloride intake and blocking Na-Cl cotransporter activity, respectively.

The presence of hyperkalemia in association with hyperchloremic metabolic acidosis, a low serum renin, normal serum aldosterone, and an adequate GFR in this child makes PHA type II the most likely diagnosis. In this syndrome, hypertension tends to develop in the third decade, so its absence in our patient does not exclude the diagnosis. Because the condition is inherited in an autosomal dominant pattern, we proceeded to screen the child’s father, who was 28 years old and asymptomatic. He was hypertensive with a BP reading of 160/90 mm Hg. His serum potassium was elevated at 6.4 mmol/L. His renal function and acid-base status were normal. The father and the infant were commenced on chlorothiazide, which led to normalization of the serum potassium (and BP in the father) and eliminated the need for dietary restriction of potassium. Initial genetic screening for WNK1 and WNK4 gene mutations in our patient was negative. However, further mutation studies are ongoing.

The correct answer is B

Comment: This 15-year-old girl presented with hypokalemic paralysis, which can result from HypoPP resulting from an acute K ⁺ shift into cells or non-HypoPP from a large total body K ⁺ deficit. Measurements of urinary K ⁺ excretion and blood acid–base status can help in the differential diagnosis. Her high urinary K ⁺ excretion, reflected by an elevated TTKG, suggested renal K ⁺ wasting and non-HypoPP. Her concurrent hyperchloremic metabolic acidosis suggested a condition with both K ⁺ depletion and direct or indirect bicarbonate loss (renal tubular acidosis). The assessment of urine NH4 ⁺ excretion by urine anion gap and/or urine osmolality gap separates RTA from non-RTA. A positive urine anion gap indicated defective NH4 ⁺ excretion associated with RTA. Her persistently alkaline urine (pH >7.0) pointed to a diagnosis of distal RTA. In fact, hypokalemia is a common finding in distal RTA and results from the combination of renal Na ⁺ wasting, secondary hyperaldosteronism, and bicarbonaturia.

Nevertheless, the underlying cause of distal RTA must be identified. On review of her history, she had been experiencing dry mouth for the past 3 months despite a normal Schirmer test for dry eye. An exhaustive workup demonstrated elevated anti-Ro antibody, rheumatoid factor, antinuclear antibody (>1:1280), polyclonal immunoglobulin G, typical delayed salivary secretion on salivary scintigraphy, and sialo duct ectasia and typical periductal lymphocytic infiltration (focus score 3) in the salivary gland biopsy. Renal histology showed chronic tubulointerstitial nephritis with predominant lymphocytic infiltration. After ruling out other autoimmune diseases, such as systemic lupus erythematosus or juvenile arthritis, primary Sjögren syndrome (SS) was diagnosed.

SS is a chronic autoimmune disease characterized by progressive lymphocytic infiltration of exocrine glands with typical features of keratoconjunctivitis, sicca, and xerostomia. Various degrees of extraglandular involvement, such as arthritis, RTA, and lymphoma, may develop before or after glandular damage. SS is most prevalent in women in their fourth and fifth decades and uncommon in children or adolescents. The clinical presentations of juvenile SS are diverse. Dry eye and dry mouth sensation are the most common presenting complaints in adults, but usually develop later in juveniles, reflecting the atypical presentations of juvenile SS at the outset. The nonspecific clinical picture and lack of universal diagnostic criteria mean that most patients are underdiagnosed until they experience complications. Profound hypokalemia with paralysis is a rare primary manifestation of SS in children. To the best of our knowledge, only nine cases, including ours, have been reported in the literature. ^– All of the affected children were girls between the ages of 8 and 17 years. Of note, extraglandular involvement with distal RTA causing non-HypoPP preceded the typical sicca symptoms in these patients.

The criteria for diagnosing adult SS may be not applicable to juvenile SS because of sensitivity as low as 39%. Recurrent enlargement of bilateral parotid glands, antinuclear antibody, rheumatoid factor, serum amylase, leukopenia, polyclonal hypergammaglobulinemia, erythrocyte sedimentation rate, and RTA have been introduced as new parameters to enhance the diagnosis of juvenile SS. However, the inclusion of these factors has only increased the sensitivity to 76%. The insensitive criteria, combined with atypical presentations, frequently result in delayed recognition of juvenile SS. In fact, many patients with juvenile SS are not diagnosed until they experience severe glandular or extraglandular sequelae, as clearly illustrated in this and other cases. ^–

Impaired distal tubular H ⁺ secretion is by far the most common renal manifestation of SS. It takes time to progress from impaired distal tubular H ⁺ secretion to full-blown RTA. Therefore, defective renal acidification (pH > 5.5) in response to the acid-load test and low urine citrate excretion are the earliest indices to suggest renal involvement in SS. The impaired ability to concentrate (hyposthenuria) is also another marker of early primary SS.

Hypokalemia and nephrocalcinosis (or nephrolithiasis) are common but late manifestations in distal RTA because they are nearly asymptomatic (>90%) in the early stages. The combination of renal Na ⁺ wasting, secondary hyperaldosteronism, and bicarbonaturia in distal RTA contribute to hypokalemia. ^, Metabolic acidosis, per se, can induce bone resorption and reduce renal tubular calcium and phosphate reabsorption, leading to increased urine calcium and phosphate excretion. This, in combination with hypocitraturia, as a result of metabolic acidosis and hypokalemia, precipitates the formation of nephrocalcinosis or nephrolithiasis.

With respect to therapy, K ⁺ citrate must be used to correct hypokalemia and metabolic acidosis and prevent further nephrocalcinosis. Care for oral involvement includes mechanical stimulation of the salivary glands, diet modification, regular oral hygiene, and topical fluoride. Prompt recognition and management of SS achieves a good prognosis by preventing glandular and extraglandular complications. Corticosteroids are the drugs of choice for SS with visceral involvement. In life-threatening cases, mycophenolate mofetil and novel biological therapies like rituximab and infliximab can be attempted.

The correct answer is C

Comment: Our patient presented with failure to thrive, excessive irritability, recent-onset polyuria, polydipsia, and severe hypercalcemia of uncertain etiology. The child was evaluated for causes of hypercalcemia. Undetectable PTH and normal serum phosphorus levels ruled out a diagnosis of primary hyperparathyroidism. Despite there being a history of failure to gain weight for the past 3 months, counts were normal, and there was no lymphadenopathy or hepatosplenomegaly. Hence, malignancy as a cause of such as like neuroblastoma and hepatoblastoma, among others. No abdominal mass was detected during the clinical examination, and ultrasonography of the abdomen also did not reveal any such abnormality. Moreover, 1,25(OH) vitamin D and PTH-related protein levels were subsequently reported to be normal. There was no contact history of tuberculosis, and a chest x-ray did not reveal any evidence of sarcoidosis or tuberculosis.

There was no family history of kidney stones or disease. The patient had hypercalciuria and low PTH levels, thereby eliminating the possibility of familial hypocalciuric hypercalcemia because this is an autosomal dominant condition with a mutation in the calcium-sensing receptor gene ( CASR ) and the patients were found to have normal or increased PTH with a low urine calcium:creatinine ratio. Within 4 days of admission, laboratory test results for vitamin D, A, and E levels became available. Vitamin A and E levels were normal, but 25(OH) vitamin D levels were markedly elevated (>450 ng/mL), suggesting that the child had probably received intramuscular vitamin D injections followed by oral calcium and vitamin D supplements, which was confirmed later. Based on the medical history and clinical and biochemical evidence, the child was diagnosed with hypervitaminosis D. The parents were instructed to restrict dairy products and use sunscreen. Intravenous hydrocortisone was replaced by oral prednisolone at a dose of 1.5 mg/kg/day. The dose was tapered gradually and stopped after 3 weeks of treatment. At discharge, his 25(OH) vitamin D level was 454 ng/mL and his total calcium concentration was 10.8 mg/dL.

The cause of nephrogenic DI in hypervitaminosis D is hypercalcemia. Two underlying mechanisms leading to nephrogenic DI have been proposed. First, calcium-sensing receptors (CaSR) expressed on the basolateral (blood) side of the thick ascending limb cells indirectly inhibits the NKCC2 cotransporter BSC1 and impairs the generation of a medullary concentration gradient. Second, this receptor is also expressed on the luminal side of the collecting duct cells and decreases aquaporin-2 expression on the apical membrane.

Computed tomography of the abdomen on day 5 confirmed a left renal calculus of dense limey bile layered in the dependent portion of the gallbladder and a few calculi in the lumen, as well as calcification in the head of the pancreas. Gallstones in patients with primary hyperparathyroidism are well known, but vitamin D intoxication leading to gallstone disease has not been reported. Unlike primary hyperparathyroidism, in which both hypercalcemia and high PTH levels are known to play roles in pathogenesis, ^, vitamin D intoxication causes hypercalcemia, thus favoring a lithogenic milieu.

Vitamin D interplays with PTH to maintain normal serum levels of calcium. Both PTH and calcitriol increase serum calcium levels by activating osteoclastic bone resorption and increasing renal absorption of filtered calcium. Calcitriol also causes increased absorption of calcium from the intestine. Normal serum levels of calcium are 8.8 to 10.3 mg/dL during childhood. An overdose of vitamin D leads to hypercalcemia, hyperphosphatemia, and high calcium/phosphorus product-associated complications. Following the administration of an excess of vitamin D, the vitamin can be found in the circulation for several months because it is stored in fatty tissues. Treatment of vitamin D intoxication includes removal of the exogenous source, forced diuresis by adequate hydration and loop diuretics, and the use of glucocorticoids, which decrease the production of 1,25 (OH)2 vitamin D3 and thereby decrease intestinal reabsorption of calcium. In patients with alarmingly high levels of hypercalcemia refractory to conventional therapy, intravenous pamidronate in doses of 0.5 to 1 mg/kg, or even lower doses of 0.35 mg/kg are used. There have been reports of the use of oral alendronate in children with vitamin D toxicity. ^,

The correct answer is A

Comment: Our patient symptoms of polyuria and polydipsia result from decreased concentrating ability, which occurs secondary to any cause of hypercalcemia. The patient had a raised serum angiotensin-converting enzyme level at 225 U/L and a biopsy of one of the enlarged inguinal lymph nodes revealed multiple noncaseating epithelioid cell granulomata, which is consistent with the diagnosis of sarcoidosis.

Initial saline hyperhydration with 0.9 % NaCl and diuresis with frusemide failed to significantly reduce the total serum and ionized calcium levels over 48 hours. Commencement of steroid treatment (prednisolone 2 mg/kg/day) led to a progressive fall in calcium levels; normalizing after 11 days of treatment.

Hypercalcemia results when the entry of calcium into the circulation exceeds its excretion into the urine or deposition into bone. This can occur when there is accelerated bone resorption, excessive gastrointestinal absorption, decreased renal excretion of calcium, or in some disorders, a combination. It is often a clue to an underlying disease process. The differential diagnoses for hypercalcemia in children are wide and include primary and familial hyperparathyroidism, familial isolated hyperparathyroidism, hypercalcemia of malignancy, vitamin D intoxication, vitamin A intoxication, chronic granulomatous disorders, medications (thiazide diuretics, lithium, theophylline), hyperthyroidism, acromegaly, pheochromocytoma, adrenal insufficiency, immobilization, parenteral nutrition, and milk alkali syndrome.

In our 12-year-old patient with lymphadenopathy and hepato-splenomegaly, the hypercalcemia is likely secondary to malignancy or chronic granulomatous disease. The diagnosis of sarcoidosis was confirmed with the finding of a normal bone marrow biopsy, coupled with a raised serum angiotensin-converting enzyme level and lymph node biopsy showing multiple noncaseating epithelioid cell granulomata. Supporting this is that hypercalcemia in our patient was associated with a suppressed serum PTH and PTH-related protein, increased fractional excretion of calcium, and a high 1,25-dihydroxycholecalciferol level. His presentation with polyuria is attributable to a concentrating defect secondary to hypercalcemia, which in turn led to the increased sensation of thirst. The coordinated function between the Na ⁺ /K ⁺ 2 Cl cotransporter (NKCC2), the inward-rectifier potassium channel (ROMK), and chloride channels (CLC-KB) found in the cells of the thick ascending limb (TAL) of the loop of Henle is critical for salt absorption. A gradient for sodium entry across apical membranes (in which most occur through the NKCC2) is generated by the Na ⁺ /K ⁺ /ATPase. ^, Sodium and chloride ions entering the apical cell surface via the NKCC2 leave the cell through the Na ⁺ /K ⁺ /ATPase and CLC-KB, respectively, at the basolateral membrane. Potassium recycling via ROMK ensures that K ⁺ concentration in the TAL remains constant to allow proper functioning of the NKCC2. In addition, the lumen-positive voltage of the TAL resulting from potassium recycling drives absorption of a second cation (Na ⁺ , Ca ²⁺ , Mg ²⁺ ) through the paracellular pathway. Calcium regulates salt transport by interacting with CaSR expressed on the basolateral membrane of cells of the TAL. Activation of CaSR by calcium increases 20-hydroxyeicosatetraenoic acid, which potently inhibits the NKCC2, ROMK, and Na ⁺ /K ⁺ /ATPase, thereby disrupting NaCl absorption. ^, Additionally, CaSR stimulation leads to the generation of prostaglandin E2, which contributes further to inhibition of NKCC2. This is compounded by a reduced responsiveness to antidiuretic hormone secondary to downregulation of AQP2 expression caused by activation of CaSR on the luminal surface of cells in the inner medullary collecting ducts in the setting of increased distal calcium delivery. ^,

Sarcoidosis, the etiology of which remains unknown, is a systemic, granulomatous disease. It most commonly affects patients between 10 and 40 years of age in 70% to 90% of cases and is three to four times more common in Blacks. The most common presentation in adults is with hilar lymphadenopathy, pulmonary infiltrates, and ocular and cutaneous lesions. Symptomatic sarcoidosis is rare in children. In infants and children younger than age 4 years, the most common presentation is with the triad of skin, joint, and eye involvement without the typical pulmonary disease, whereas in older children, involvement of the lungs, lymph nodes, and eyes predominates. In a series of Danish children with sarcoidosis, the most common presenting features were erythema nodosum and iridocyclitis. Other features of sarcoidosis include fatigue, malaise, fever, and weight loss. . Although the lungs are the most frequently affected organ, the disease can affect any organ system in the body. Up to 30% of patients present with extrapulmonary disease; the most prominent sites involve the skin, eyes, reticuloendothelial system, musculoskeletal system, exocrine glands, heart, kidney, and central nervous system. ^– Abnormalities related to calcium metabolism are the most common renal and electrolyte abnormality observed in patients with sarcoidosis. It is due to extrarenal production of activated vitamin D (1, 25-dihydroxycholecalciferol) by activated macrophages, which leads to increased intestinal calcium absorption, which in turn leads to hypercalcemia leading to hypercalciuria and nephrocalcinosis. This is due to a markedly enhanced production of 1-alpha hydroxylase (the enzyme that converts 25-hydroxycholecalciferol to the activated form) and a lack of feedback inhibition, which would normally limit enzyme expression. ^, Hypovolemia resulting from hypercalcemia-induced urinary salt wasting exacerbates hypercalcemia by impairing the renal clearance of calcium. Saline hyperhydration expands the extracellular fluid volume and increases the GFR leading to increased excretion of calcium in the urine. Saline administration alone can control hypercalcemia in some patients but requires careful monitoring because it can lead to fluid overload in patients who fail to excrete the administered salt and water from impaired renal function. Administration of a loop diuretic can be initiated once fluid repletion is achieved to further increase urinary calcium excretion but this approach often involves intensive administration of frusemide (1–2 mg/kg every 1–2 hours) with aggressive fluid hydration (up to 10 L daily). Other renal complications of sarcoidosis include membranous nephropathy, proliferative or crescentic glomerulonephritis, focal segmental glomerulosclerosis, granulomatous interstitial nephritis, polyuria, hypertension, and a variety of tubular defects. ^, Treatment with glucocorticoids, which decreases inflammatory activity, leading to a reduction of calcitriol synthesis, improves calcium metabolism and lowers plasma creatinine concentration. Concurrent treatment with bisphosphonates with or without calcitonin can be used to treat severe hypercalcemia. ^, Rarely, patients with sarcoidosis develop end-stage renal disease (most often from hypercalcemic nephropathy rather than granulomatous nephritis or glomerulopathy) requiring renal replacement therapy. The outcome of renal transplantation is not well documented. A retrospective review of 18 patients from eight French centers, with a median follow-up of 4 years, showed patient and death-censored graft survival of 94%. Sarcoidosis recurred in five patients at a median of 13 months after transplantation.

The correct answer is A

Comment: Our patient had metabolic alkalosis, hypokalemia, high urinary chloride, and hypertension. Because her urinary chloride was high, and she had severe hypertension with hypokalemic metabolic alkalosis in the presence of rounded facies, we clinically suspected Cushing syndrome (CS) as a possible etiology, and she underwent estimation of serum cortisol along with plasma ACTH. The history was reviewed, and she denied any history of intake of steroids or medications containing steroids. The plasma renin activity (0.2 ng/mL/h) and plasma aldosterone level (3 ng/dL) were low (reference values: plasma renin activity, 0.9–6.6 ng/mL/h; plasma aldosterone level, 6.5–29.5 ng/dL). This led to a clinical suspicion of endogenous CS as a potential explanation for the constellation of clinical and laboratory findings encountered in this patient.

In view of a clinical suspicion of CS, she underwent estimation of serum cortisol (at 8 a.m.) along with plasma ACTH. The levels of these were found to be >75 µg/dL (reference value, 4.3–22.4 µg/dL) and 363 pg/mL (reference value, 10–60 pg/mL), respectively. This led to a diagnosis of ACTH-dependent CS. MRI of the cranium showed no evidence of pituitary or hypothalamic lesions. A contrast-enhanced CT scan of the thorax and abdomen was performed for further evaluation of the etiology of endogenous CS. This showed evidence of a tumor in the tail of the pancreas, para-aortic and celiac lymphadenopathy, evidence of metastasis to the liver, and bilateral adrenal hyperplasia. Subsequently, the patient underwent distal pancreatectomy, bilateral adrenalectomy with nodal sampling, and liver nodule excision biopsy. Histopathological examination of the excised pancreatic specimen showed monomorphic tumor cells arranged in nests and sheets that showed moderate cytoplasm, fine stippled chromatin, and moderate degree of nuclear atypia. These cells were diffusely positive for immunohistochemistry with synaptophysin and chromogranin. The Ki-67 index was 40%. Hence, the final histopathology was suggestive of a well-differentiated pancreatic neuroendocrine tumor (NET) (World Health Organization grade 3) with metastasis to celiac lymph node and liver nodule.

To summarize, she had a pancreatic NET producing ACTH, leading to endogenous CS. Postoperatively, she requires amlodipine (being tapered) and hydrocortisone. Stress dose of hydrocortisone was initiated. After a multidisciplinary tumor board discussion, oral capecitabine and temozolamide chemotherapy were initiated.

The mechanisms of hypertension in endogenous CS are multifactorial. The primary mechanism is the mineralocorticoid action exerted by supraphysiological levels of serum cortisol. Serum cortisol is known to bind to both glucocorticoid and mineralocorticoid receptors. The plasma levels of cortisol in humans are 100- to 1000-fold higher than that of aldosterone, which implies that mineralocorticoid receptor (MR) can be chiefly activated by cortisol. However, this is kept in check by 11β-hydroxy steroid dehydrogenase (11β-HSD), which modulates the effect of cortisol at the tissue level. There are two isoforms of the 11β-HSD enzyme. The first isoform 11β-HSD1 catalyzes both dehydrogenation and reduction reactions and is responsible for the interconversion of cortisol and cortisone. In vivo, it predominantly functions as a reductase, converting inactive cortisone to active cortisol. It is abundantly expressed in the liver and adipose tissue. The second isoform 11β-HSD2 is active at very low cortisol concentrations and has mainly dehydrogenase activity that inactivates cortisol to cortisone. It is highly expressed in mineralocorticoid target tissues such as the renal cortex, colon, salivary, and sweat glands. This enzyme prevents cortisol from binding to MR in mineralocorticoid target tissues under physiological concentrations of cortisol. However, in cortisol excess states, the levels of cortisol would exceed the capacity of 11β-HSD to inactivate it to cortisone, thus making it available to bind to MR, mimicking excess aldosterone. This MR activation in turn results in increased renal tubular sodium reabsorption and intravascular volume expansion. Mineralocorticoid-induced hypertension is due to overactivity of epithelial Na+ (ENac). MR activity also leads to ROMK channel and H+K+ATPase stimulation in the distal nephron, leading to hypokalemia and metabolic alkalosis, respectively.

There are other mechanisms involved in glucocorticoid-induced hypertension. Endothelin-1, the most potent vasoconstrictor peptide, with marked hypertensive, mitogenic, and atherogenic effects, is significantly elevated in patients with untreated active CS; an action mediated by glucocorticoids. Nitric oxide is a vasodilator that is produced by the enzyme NO synthase (NOS). Glucocorticoids inhibit NOS synthesis and may lead to increased BP by reduction in peripheral vasodilation. Yet another mechanism of hypertension in high cortisol states is the upregulation of sympathetic nervous system through the accentuation of the action of catecholamines. Though the catecholamine levels are normal, adrenergic receptor sensitivity towards catecholamines is increased, thereby causing an increase in vascular tone. Finally, insulin resistance results from chronic glucocorticoid exposure, which culminates in sodium and water retention, causing volume expansion. It also causes increased sympathetic activity, renin-angiotensin-aldosterone system activation, and vascular hypertrophy, which results in vascular resistance and hypertension. Although endogenous CS is characterized by low plasma renin activity and low aldosterone levels, this is a state of apparent mineralocorticoid excess, which leads to a partial response to spironolactone. As spironolactone is an MR blocker, it leads to control of hypertension and as well as resolution of hypokalemia.

Polyuria in our index case is probably from hypokalemia, which resolved after its correction. In hypokalemia, the urinary concentrating ability of the kidney is impaired because of defective activation of renal adenylate cyclase, which further prevents antidiuretic hormone-stimulated urinary concentration.

Nevertheless, the patient finally required distal pancreatectomy and bilateral adrenalectomy, which led to resolution of hypertension and the hypokalemic metabolic alkalosis.

We describe here a rare case of ACTH-dependent CS (endogenous CS) resulting from pancreatic NET (producing ACTH) leading to severe hypertension associated with hypokalemic metabolic alkalosis in a 14-year-old girl. Although pediatric nephrologists often encounter etiologies such as renovascular hypertension, and rarely other entities such as Liddle syndrome, syndrome of apparent mineralocorticoid excess in a clinical setting of severe hypertension with hypokalemic metabolic alkalosis, it is important not to miss other rare and occasional causes that may be complicated by similar metabolic disturbances. The presence of rounded facies (cushingoid facies) in our patient led to a clinical suspicion of CS as an explanation for her clinical and laboratory findings.

CS is an endocrine disorder caused by a prolonged exposure to elevated cortisol. The most common form of CS results from exogenous administration of steroids. Endogenous CS is rare. Cushing disease (CD) is the most common etiology of endogenous CS. CD is caused by ACTH-secreting pituitary tumors (microadenomas or macroadenomas). ^– There are a few population-based studies that have evaluated etiologies of endogenous CS. ^– The overall incidence of endogenous CS is 0.7 to 2.4 million people/year. In children older than 7 years of age, CD is the leading cause of CS (75–90% of all cases). CD is less common in children younger than 7 years of age. Adrenal causes of CS are more common in this age group (<7 years) and include adrenal adenoma, adrenal carcinoma, and bilateral adrenal hyperplasia. The incidence of ectopic ACTH-producing conditions leading to endogenous CS is less than 1%, which include small cell carcinoma of the lung, carcinoid tumors of the pancreas, bronchus, thymus, gut, medullary carcinoma of thyroid, pheochromocyomas, and NETs, especially of the pancreas.

NETs are rare in children (0.75 cases per 100,000 children and adolescents per year). Although the majority of these tumors is a benign or low-grade malignancy, about 10% of NETs in children are highly malignant. Less than 2% of NETs are of pancreatic origin. The usual age of presentation of these tumors is older than 10 years in majority of the children. Almost 90% of pancreatic NETs are hormonally inactive and are diagnosed incidentally in the majority. Hence, the diagnosis is often delayed by an estimated period of 8 to 10 years from the time of first symptom to time of confirmed diagnosis, leading to poor prognosis. Pancreatic NETs may rarely secrete ACTH, growth hormone–releasing hormone, PTH-related peptide, serotonin, and cholecystokinin, leading to the respective clinical syndromes. Our index case is an ACTH-secreting pancreatic NET. These ectopic ACTH-secreting tumors result in higher amounts of serum cortisol and are supraphysiological in nature, leading to excessive apparent mineralocorticoid activity. This led to severe hypertension and hypokalemic metabolic alkalosis in our case. The positivity of histological markers (chromogranin and synaptophysin) as seen in our patient is known in NETs. The Ki-67 index is an important prognostic marker in pancreatic NETs and helps in choosing an optimal therapeutic approach as well as preoperative assessment of pancreatic NETs. Ki-67 index >2% is associated with poor prognosis with increased mortality compared with Ki-67 index <2%. It is noteworthy that our patient had a Ki-67 index of 40%, implying very poor prognosis. New pathological classifications help in prognostication and the 5-year survival rates of grades I, II, and III tumors are mentioned as 96%, 73%, and 28%, respectively. ^– Approximately 60% of malignant pancreatic NETs have metastases to the liver and 10% to 20% of the cases can have distant metastases at the time of diagnosis. Treatment of pancreatic NETs includes chemotherapy and surgical resection. Although surgery is the frontline treatment for pancreatic NETs in localized tumors, there is a significant expansion in systemic treatment options in metastatic tumors. Chemotherapy with capecitabine and temozolamide (which was used in our patient) has shown prolongation of progression-free survival.

To summarize, endogenous CS is predominantly of pituitary or adrenal origin; and ectopic ACTH-dependent tumors contribute to <1% of endogenous CS cases in children and adolescents. The present case represents an exceedingly rare cause of endogenous CS. Through this case, the authors wish to create awareness regarding endogenous CS as a rare cause of severe hypertension with hypokalemic metabolic alkalosis.