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Table of Contents
Year : 2022  |  Volume : 5  |  Issue : 2  |  Page : 91-94

Medullary nephrocalcinosis: The role of genetic analysis

1 Department of Nephrology and Renal Transplant, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Nephrology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Submission03-May-2022
Date of Acceptance25-Sep-2022
Date of Web Publication31-Dec-2022

Correspondence Address:
Nidhi Gupta
Department of Nephrology and Renal Transplant, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226 014, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

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Nephrocalcinosis refers to the deposits of calcium within the renal parenchyma, usually detected on ultrasonography or computed tomography. The presence of medullary nephrocalcinosis may represent a variety of different etiologies. Early childhood onset of kidney stones and/or nephrocalcinosis often represent an inherited defect more frequently than in adults. The cases reported here highlight three different diseases that were diagnosed based on genetic analysis following presentation as medullary nephrocalcinosis in childhood.

Keywords: Autosomal recessive polycystic kidney disease, familial hypomagnesemia, kidney stones, primary hyperoxaluria

How to cite this article:
Gupta N, Dhanorkar M, Behera MR, Bhadauria D. Medullary nephrocalcinosis: The role of genetic analysis. Asian J Pediatr Nephrol 2022;5:91-4

How to cite this URL:
Gupta N, Dhanorkar M, Behera MR, Bhadauria D. Medullary nephrocalcinosis: The role of genetic analysis. Asian J Pediatr Nephrol [serial online] 2022 [cited 2023 Jun 7];5:91-4. Available from: https://www.ajpn-online.org/text.asp?2022/5/2/91/366539

  Introduction Top

Nephrocalcinosis refers to augmented calcium content within the renal parenchyma. Its pathogenesis chiefly involves hypercalciuria, which may be triggered by hypercalcemia. Other etiologies include states of increased urinary excretion of calcium, phosphate, and oxalate, and reduced urinary citrate excretion.[1] The presence of medullary nephrocalcinosis provides a window for the clinician to diagnose many vital diseases. This case series includes three cases of medullary nephrocalcinosis with different etiologies in which diagnosis was reached through a high index of suspicion and detailed etiological evaluation, including genetic testing. Informed consent was taken from all patients beforehand.

  Case Reports Top

Case 1

An 8-year-old boy presented with a history of recurrent episodes of abdominal pain for 1 year old. When evaluated at a local center, he was found to have bilateral renal calculi, for which right ureteroscopic lithotripsy was performed at 2 years of age. He was recently referred to our center due to renal impairment. The family history was unremarkable. Of his hematological parameters were within the normal limits. Blood tests revealed impaired kidney function with serum creatinine 1.7 mg/dl (estimated glomerular filtration rate, of 32 ml/min/1.73 m2, using revised bedside Schwartz formula), and elevated serum calcium (10.4 mg/dl; at upper limit of normal range), normal levels of intact parathyroid hormone [Table 1]. The level of 24-h urinary oxalate was elevated for age and sex (1.35 mmol/day; normal <0.5 mmol/day) [Table 1]. Ultrasonography revealed bilateral multiple bilateral kidney stones with right ureteric calculus and hydroureteronephrosis. Non-contrast computed tomography of the abdomen revealed extensive medullary nephrocalcinosis [Figure 1].
Figure 1: Reconstructed images of non-contrast computed tomography findings in case 1 indicating medullary nephrocalcinosis

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Table 1: Blood and urine biochemistry in the three patients

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Given the early age of onset of disease, next genetic sequencing was performed, with focus on a panel of genes including known congenital causes. Sequencing revealed a homozygous variation in AGXT (chromosome 2q37.3) which was a missense reported change (c.568G>A; p. Gly190Arg), confirming the diagnosis of primary hyperoxaluria (PH) type 1.

Case 2

A 26-year-old male was referred to our center in 2017 for the evaluation of chronic kidney disease. Past history was significant for multiple surgical interventions for kidney stones since 5 years of age, including right percutaneous nephrolithotomy when 6 year old, bilateral extracorporeal shock-wave lithotripsy when 12 year old, and bilateral percutaneous nephrolithotomy at 25-year-old. Subsequently, there was progressive decline in kidney function. The 24-h urinary levels of calcium, sodium, uric acid, oxalate and citrate were within the limits [Table 1]. While there was no evidence of primary hyperparathyroidism, there was significant hypomagnesemia. Next-generation sequencing revealed a homozygous missense variation in CLDN16 (chromosome 3q28; exon 2; c.374T>C; p. Phe 125Ser) which has been previously reported in patients with hypomagnesemia type 3, characterized by hypomagnesemia, massive renal magnesium wasting, hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive kidney failure.

Case 3

A 9-year-old girl, born out of consanguineous marriage with no significant family history, was evaluated first at 2-year-old for polyuria and polydipsia in the department of endocrinology. Based on blood gas, urine biochemistry, and results of the ammonium chloride loading test, she was diagnosed with distal renal tubular acidosis (RTA) [Table 1] and managed accordingly. At 6 years old, she presented with the recurrent episodes of pain abdomen. Ultrasonography revealed medullary nephrocalcinosis in kidneys of normal size. Intravenous pyelography showed multiple medullary cysts, whereas magnetic resonance imaging of the abdomen revealed bilateral mildly enlarged kidneys with numerous tiny cysts replacing the entire renal parenchyma. Few cysts were noted in segment VI/VII of the liver communicating with the biliary tree. A prominent central common bile duct was associated with bilobar mild intrahepatic biliary tract dilatation with a beaded appearance, suggestive of congenital hepatic fibrosis [Figure 2]. Considering the possibility of congenital cystic disease of the liver and kidney, next-generation sequencing was performed, which revealed compound heterozygous missense variations in PKHD1 (chr 6p12; c.1376_1377delinsG and c.274C>T) suggestive of autosomal recessive polycystic kidney disease (ARPKD).
Figure 2: Magnetic resonance imaging in case 3 showing bilateral mildly enlarged kidneys with multiple tiny cysts replacing almost the entire parenchyma. There were a few cysts in segments VI/VII of the liver, which were communicating with the biliary tree. The common bile duct is prominent, associated with mild, bilobar intrahepatic biliary tract dilatation with beaded appearance, consistent with hepatic fibrosis

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  Discussion Top

The case series of three patients had nephrocalcinosis in common but had three different diagnoses. Genetic testing enabled definitive diagnosis in a short span of time, for patients who were for long without a precise diagnosis.

PH is chiefly caused by autosomal recessive variants in three genes that encode enzymes involved in glyoxylate metabolism. PH type 1 is caused by the variants of AGXT as in case 1. AGXT encodes the hepatic peroxisomal enzyme alanine: glyoxylate aminotransferase, a pyridoxal 5'-phosphate-dependant enzyme, which is involved in the transamination of glyoxylate to glycine.[2],[3] This inborn error of metabolism leads to an increase in the glyoxylate pool, which is converted by lactate dehydrogenase to oxalate. As oxalate is typically excreted in the urine, the kidney is the prime target for excessive oxalate deposition, resulting in nephrocalcinosis, kidney stones, and kidney failure. The diagnosis of PH type 1 mandates combined liver and kidney transplant as the management of kidney failure; however, with the availability of miRNA-based therapies, a paradigm shift is expected in the approach to managing these patients.[3]

Pathogenic variants in CLDN16 cause a rare autosomal recessive disease, called familial hypomagnesemia with hypercalciuria and nephrocalcinosis. CLDN16 encodes the tight junction protein claudin-16, which regulates the paracellular reabsorption of magnesium and calcium in the kidney. Patients typically have renal magnesium and calcium wasting leading to nephrocalcinosis and kidney failure.

ARPKD is transmitted in an autosomal recessive fashion. In addition to kidney cysts, most patients with ARPKD also have changes in the liver, chiefly in the form of ductal plate malformation with hyperplastic biliary ducts and congenital hepatic fibrosis. Presentation of ARPKD as distal RTA has not been reported. Our patient had clinical and biochemical features of distal RTA, without any clinical or radiological findings consistent with ARPKD at initial presentation. With increasing age and added diagnostic modalities, the diagnosis of ARPKD was considered later and confirmed on genetic testing. The features of distal RTA could have represented progressive tubular dysfunction due to the increase in the number of cysts with age.

A retrospective study of 40 children from New Delhi with nephrocalcinosis, published in 2007, reported distal RTA in 50% of cases and idiopathic hypercalciuria and hyperoxaluria in 7.5% cases each. The uncommon causes included Bartter syndrome, primary hypomagnesemia with hypercalciuria, severe hypothyroidism, and Vitamin D excess. No cause was found in 12.5% of cases.[4] The contribution of monogenic disorders to the overall prevalence of kidney stone disease and nephrocalcinosis has been recently reported in a cohort of 272 genetically unresolved individuals, including 106 children and 166 adults from 268 families with nephrolithiasis (n = 256) or isolated nephrocalcinosis (n = 16). Fifty likely causative variations were detected in 14 of 30 analyzed genes, leading to a molecular diagnosis in 14.9% of all cases. The percentage of monogenic patients was notably high in both the adult (11.4%) and pediatric cohorts (20.8%).[5]

[Figure 3] and [Figure 4] presents a proposed diagnostic approach to the evaluation of children presenting with kidney stones and/or nephrocalcinosis.
Figure 3: Approach to diagnosis in a child presenting with kidney stone and/or nephrocalcinosis

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Figure 4: Diagnostic approach to the care of the pediatric patient with renal stone and nephrocalcinosis. Ca- calcium, P- phosphate, Mg- magnesium, Cl- chloride, K- potassium

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  Conclusion Top

Identifying a specific genetic etiology informs the patients and physicians on optimal management and expected outcomes, apart from throwing light on the disease pathogenesis. Genetic diagnosis often facilitates targeted therapy and cut costs associated with repeated biochemical evaluation and management of recurrent stones.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Vaidya SR, Yarrarapu SN, Aeddula NR. Nephrocalcinosis. 2021. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2022.  Back to cited text no. 1
Danpure CJ. Advances in the enzymology and molecular genetics of primary hyperoxaluria type 1. Prospects for gene therapy. Nephrol Dial Transplant 1995;10 Suppl 8:24-9.  Back to cited text no. 2
Hoppe B, Langman CB. A United States survey on diagnosis, treatment, and outcome of primary hyperoxaluria. Pediatr Nephrol 2003;18:986-91.  Back to cited text no. 3
Mantan M, Bagga A, Virdi VS, Menon S, Hari P. Etiology of nephrocalcinosis in northern Indian children. Pediatr Nephrol 2007;22:829-33.  Back to cited text no. 4
Halbritter J, Baum M, Hynes AM, Rice SJ, Thwaites DT, Gucev ZS, et al. Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis. J Am Soc Nephrol 2015;26:543-51.  Back to cited text no. 5


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1]


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