Medullary nephrocalcinois and primary hyperaldosteronism - A rare and under recognised association

ABSTRACT

Medullary nephrocalcinosis is an uncommon manifestation of primary hyperaldosteronism (PHA) and the exact etiology of this association is still debated. Here we report three cases of PHA with medullary nephrocalcinosis and how medullary nephrocalcinosis in one patient led to misdiagnosis as renal tubular acidosis (RTA). Although PHA and RTA can share overlapping symptoms, careful evaluation of clinical presentation, biochemical tests, and imaging studies are essential to differentiate between the two conditions and ensure appropriate management. Also, awareness of this uncommon manifestation of PHA is essential to avoid misdiagnosis as tubulopathy, as this may delay the treatment.

Introduction

Medullary nephrocalcinosis accounts for 98% of cases of renal nephrocalcinosis characterized by clusters of calcification surrounding each renal pyramid.[1] The most common conditions presenting with medullary nephrocalcinosis include primary hyperparathyroidism (PHPT), distal renal tubular acidosis (dRTA), medullary sponge kidney as well as inherited tubulopathies.[2] Primary hyperaldosteronism (PHA) is a common cause for secondary hypertension observed in 5–18% of the population who present with hypertension.[3] Medullary nephrocalcinosis has not characteristically been described in PHA and a few case reports exist of this association.[4] PHA and RTA are two distinct conditions involving the kidneys; however, they can sometimes present with overlapping symptoms, leading to misdiagnosis. Here we describe three cases of PHA with medullary nephrocalcinosis.

Case Reports

Case 1

A 35-year-old female patient presented with complaints of weakness of all four limbs. She complained of tingling and numbness in her hands and feet for 10 years with episodes of heaviness of limbs and associated muscle cramps. She was diagnosed with hypertension 10 years ago and was on two anti-hypertensives for the same. She was evaluated elsewhere and was found to have medullary nephrocalcinosis. She was suspected of having dRTA and was receiving oral sodium bicarbonate supplements along with a calcium channel blocker and diuretics. At presentation, she had normal blood pressure on two antihypertensives (cilnidipine and torsemide) and hypokalemic paralysis. Her blood investigations revealed a serum potassium of 1.1 mEq/L with metabolic alkalosis (pH-7.5, bicarbonate-32 mEq/L) and elevated creatinine (1.75 mg/dL). After correction of hypokalemia, serum renin and aldosterone levels were sent, which revealed elevated aldosterone and increased aldosterone renin ratio (ARR). Her biochemical parameters are tabulated in Table 1. Computed tomography (CT) of the abdomen revealed a 19 × 15 × 20 mm right adrenal adenoma with an absolute washout of ~60% and medullary nephrocalcinosis and she underwent curative retroperitoneal right adrenalectomy.

Table 1.

Biochemical profile of patients

Parameter	Patient 1	Patient 2	Patient 3	Range
S. Sodium (mEq/L)	145	144	146	135–145
S. Potassium (mEq/L)	1.1	3.4	1.7	3.5–5.0
S. Bicarbonate (mEq/L)	32	30	29	22–29
S. Chloride (mEq/L)	102	106	109	95–105
S. Calcium (mg/dL)	7.6	9.9	7.6	8.3–10.4
S. Phosphate (mg/dL)	3.2	4.4	2.5	2.5–4.6
Albumin (g/dL)	3.3	4.9	3.6	3.5–5.0
S. Creatinine (mg/dL)	1.75	1.0	0.94	0.5–1.4
Plasma renin	<0.5 micro IU/mL	0.02 (ng/mL/h)	1.15 micro IU/mL	<4
S. Aldosterone (pg/mL)	478	104	315	40-310
Urine calcium Creatinine ratio (spot)	0.11	-	-	<0.3
Urine calcium (24 h)	-	359 mg	162 mg	100–300

Case 2

A 17-year-old adolescent presented with a history of recurrent episodes of quadriparesis for 5 years. These episodes began with pain followed by weakness of all four limbs and required multiple hospitalizations. During one such episode, he was diagnosed with hypokalemic paralysis and was administered oral potassium supplements. He was known to have hypertension from 13 years of age with the highest blood pressure recorded being 170/100 mmHg. He was on a single antihypertensive agent (spironolactone). There was no family history of young-onset hypertension or CVA. On examination, his blood pressure was normal with all peripheral pulses well palpable. His initial blood investigations revealed metabolic alkalosis with hypokalemia. He had elevated aldosterone with suppressed renin levels, suggestive of primary hyperaldosteronism. He was noted to have hypercalciuria (6.5 mg/kg). His biochemical parameters are tabulated in Table 1. CT abdomen revealed bilaterally enlarged adrenals and medullary nephrocalcinosis. In view of bilateral adrenal hyperplasia, he was managed medically with spironolactone (aldosterone antagonist).

Case 3

A 26-year-old gentleman presented with weakness of four limbs of 2 days duration. He had a history of recurrent paralytic episodes over the last 1 year (around 6) and noticed improvement with intravenous therapy each time. He was also diagnosed with hypertension 2 years ago, however, he was not on any medication for the same. On examination, he had elevated blood pressure and hypotonia with grade 2 power in all four limbs. His preliminary blood investigations revealed hypokalemia with potassium level of 1.7 mEq/L. In the setting of hypertension with metabolic alkalosis and hypokalemia, renin and aldosterone levels were sent and ARR was found to be elevated. His biochemical parameters are tabulated in Table 1. His USG abdomen demonstrated medullary nephrocalcinosis and CT abdomen detected a right adrenal adenoma measuring 9.8 × 7.4 mm with an absolute washout of 68.3%. He was subsequently started on spironolactone and underwent curative right adrenalectomy.

Discussion

The term medullary nephrocalcinosis was coined by Fuller Albright to describe the augmented deposition of calcium phosphate and oxalate within the kidneys.[5] Although the term was originally used in primary hyperparathyroidism, it is now a well-recognized component of several diseases. Critical to its development is the presence of hypercalciuria with or without hypercalcemia.[2]

Primary hyperaldosteronism is an underdiagnosed condition, and the common presentations include young-onset hypertension, resistant hypertension and hypokalemia. Biochemical evaluation characteristically reveals metabolic alkalosis with hypokalemia, though potassium may be normal in up to 72% of individuals with primary hyperaldosteronism.[6] There have been reports of medullary nephrocalcinosis and PHA, and nephrocalcinosis is a rare and underrecognized manifestation of PHA.[4,5,7]

Although aldosterone has been postulated to cause hypercalciuria, the association of primary hyperaldosteronism with nephrocalcinosis is not well established.[8] A few case reports exist linking the same.[4,7] Several mechanisms have been postulated on how hyperaldosteronism can predispose to nephrocalcinosis. Recently, there is evidence for a bidirectional functional link between the adrenal and parathyroid glands leading to cross-talk between parathyroid hormone and aldosterone. This may lead to secondary hyperparathyroidism and further hypercalciuria.[9] Urinary calcium excretion is known to correlate positively with urinary sodium excretion. Hyperaldosteronism through volume expansion decreases proximal tubular absorption of sodium and calcium, leading to hypercalciuria.[7] Also, chronic hypokalemia causes a tubulointerstitial injury, leading to renal cyst formation and interstitial inflammation referred to as chronic kalipenic nephropathy. Medullary nephrocalcinosis has been postulated to be a manifestation of kalipenic nephropathy as it causes intracellular acidosis and further inhibition of the distal convoluted tubule calcium channels. In addition, metabolic alkalosis linked to hypokalemic states decreases calcium phosphate or oxalate solubility in alkaline urine and thus may predispose to calcinosis.[10]

However, the exact mechanism of nephrocalcinosis still remains debated. Although one of our patients did have hypercalciuria, the other two did not, suggesting that there may be other mechanisms associated with nephrocalcinosis. Nevertheless, a single measurement of urine calcium may not always be sensitive enough to detect hypercalcuria.

Medullary nephrocalcinosis is commonly associated with dRTA and PHPT, it is an uncommon manifestation of PHA. Although medullary nephrocalcinosis and hypokalemia may occur in both dRTA and PHA, the presence of hypertension in the setting of medullary nephrocalcinosis and hypokalemia should make one consider a diagnosis of PHA.

Conclusion

Medullary nephrocalcinosis can be a rare manifestation of primary hyperaldosteronism. Failure to understand this association may lead to misdiagnosis as in other tubulopathies and may delay the correct diagnosis and treatment. Although PHA and RTA can share overlapping symptoms, careful evaluation of clinical presentation, biochemical tests, imaging studies, and more importantly, the presence of hypertension and the absence of metabolic acidosis are important diagnostic clues for PHA.

Key message

Medullary nephrocalcinosis is a rare manifestation of primary hyperaldosteronism (PHA). Although medullary nephrocalcinosis is a common manifestation of distal renal tubular acidosis (dRTA) and hypokalemia is common in both dRTA and PHA, the presence of hypertension in the setting of medullary nephrocalcinosis and hypokalemia makes the diagnosis of PHA more likely.

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Conflicts of interest

There are no conflicts of interest.