Atypical Clinical Presentation of Autosomal Recessive Polycystic Kidney Mimicking Medullary Sponge Kidney Disease.

Introduction

Medullary sponge kidney (MSK) disease is a nephropathy characterized by the association of tubular ectasia of precalyceal ducts with sporadic cystic development, multiple renal stones, and/or nephrocalcinosis (calcification of renal parenchyma) and frequently tubular acidification defect. In most cases, both kidneys are affected. The prevalence of MSK in the general population is still unknown. In particular, some patients may develop tubular ectasia without recurrent kidney stone formation; thus, they can remain undiagnosed. Among kidney stone formers, a condition reaching up to 10% of the general population, MSK prevalence is >8%.

Patients affected by MSK are at risk to form recurrent renal stones, responsible for renal colic and multiple urological interventions. Nevertheless, chronic kidney disease (CKD) is rarely reported. Many patients affected by MSK complain on chronic flank pain, even in the absence of patent renal colic.

It has been hypothesized that MSK could have a genetic basis. Currently, only a few cases clustering in family have been reported, suggestive of incomplete penetrance. MSK has been associated with various malformations, such as those observed in Beckwith-Wiedemann syndrome with renal developmental defects. Hepatic diseases, such as Caroli disease, responsible for biliary duct dilation, have been described.

The GDNF, a ligand of RET, allows ureteric bud branching and invasion of the metanephric blastema with the collecting ducts and upstream kidney formation. Recently, GDNF variants have been identified in patients with MSK, supporting the idea that MSK might result from precalyceal and collecting duct development defects.

Considering the potential genetic origin of MSK, a whole-exome sequencing was proposed in 2 adult patients affected by MSK with CKD, an uncommon condition of MSK.

Case Presentation

Medical History

Case 1

A young woman had a bilateral MSK diagnosed in 2010 when she was 20 years old (Figure 1). There was no familial case of MSK. She experienced several renal colics but no stone was analyzed. She had a mild CKD diagnosed in 2012 (serum creatinine 130 μmol/l), without urine sediment abnormality, which worsened during her first pregnancy in 2015. A renoureteroscopy was performed revealing papilla with typical MSK lesions. Her renal function rapidly declined with progression toward end-stage renal failure, and she received a kidney allograft in 2019. Urine calcium excretion was normal in 2012, but the patient was already affected by CKD at this time.

Figure 1

Representative CT scan (case 1) revealing kidney tissue calcifications (arrows). CT, computed tomography.

Case 2

A man was affected by renal colics owing to recurrent kidney stones since he was 28 years old, in 1996. His brother was affected by Caroli disease. MSK was diagnosed in 1996 by i.v. urography and confirmed by computed tomography scan in 2019. His kidneys contained multiple kidney stones and tissue calcifications. He progressively developed a CKD: serum creatinine level was 189 μmol/l in 2019 and measured glomerular filtration rate (diethylenetriamine pentaacetate-technetium renal clearance) was 35 ml/min per 1.73 m2. He had a mild proteinuria (proteinuria/creatinine: 0.03 g/mmol), and urine sediment was normal. Urine biochemistry did not reveal hypercalciuria (urine calcium excretion: 2.25 mmol/d) but was performed after the onset of CKD. He had low urine citrate excretion (1.38 mmol/d) and increased urine oxalate excretion (0.61 mmol/d). No stone was analyzed.

Genetic Analyses

As renal function worsened rapidly, without other renal disease than MSK, a whole-exome sequencing was proposed to both patients. The whole-exome analysis in case 1 revealed 2 mutations of PKHD1. The first mutation was nonsense (c.7514T>A, p.Leu2505∗) with paternal origin, and the second one was missense (c.4870C>T, p.Arg1624Trp) inherited from the mother and affecting the IPT/TIG 11 domain (Figure 2).

Figure 2

Mutations discovered in case 1 and case 2. Ex., exon.

In case 2, the whole-exome analysis revealed also 2 mutations in PKHD1, which are as follows: a frameshift mutation: c.5895dup, p.Leu1966ThrfsTer4 and a missense pathogenic variant: c.5134G>A; p.Gly1712Arg in the IPT/TIG 12 domain of PKHD1 (Figure 2). No segregation analyses were performed to confirm the paternal or maternal origin of the alleles.

These mutations were reported to be pathogenic in patients affected by autosomal recessive polycystic kidney disease (ARPKD).

Discussion

More than 300 PKHD1 pathogenic mutations have been recorded, which are responsible for ARPKD. PKHD1 is a 500 kilobase gene located on chromosome 6 (6p21.1-p12) coding for polycystin. Polycystin is expressed in the kidney, in the distal part of the nephron especially in the collecting duct, the bile duct epithelium, and the pancreas. Polycystin associates with primary cilia and basal bodies, suggesting a role in cilia-related functions of the cells (development and maintenance of renal tubule architecture). Most patients are compound heterozygous, carrying 2 different alleles. ARPKD is one of the most frequent causes of genetic renal diseases, with a prevalence estimated at 1/20,000 births. A presentation occurring in utero or at birth is classic in ARPKD, associating oligohydramnios, pulmonary hypoplasia, and enlarged echogenic kidney. The kidneys are affected by cystic dilatation and ectasia of the renal collecting tubules and congenital hepatic fibrosis. The disease is extremely severe with a high mortality. For patients surviving the neonatal period, 50% will have an end-stage renal failure during the first decade. Nevertheless, the diagnosis may also be considered in young adults with polycystic hepatorenal disease as some patients affected by ARPKD develop a less severe disease with delayed CKD.

A link between PKHD1 mutations and MSK has been hypothesized by Gunay-Aygun et al. They performed ultrasound evaluation in 110 parents of patients affected by ARPKD. These parents carried a single mutation transmitted to the proband but were not affected by ARPKD. There were 6 of them who had increased medullary echogenicity and 10 who had small liver cysts. Medullary echogenicity was identified as nephrocalcinosis, and considering the common features between MSK and ARPKD, the authors hypothesized that MSK could be the consequence of heterozygous PKHD1 mutations. More recently, Shan et al. reported that heterozygous Pkhd1 mutant mice develop cystic liver disease and tubule ectasia mimicking MSK.

In the 2 patients affected by PKHD1 compound heterozygous mutations, the diagnosis of MSK was made early but the absence of (large) renal cysts did not suggest that these patients could carry PKHD1 mutations. Some PKHD1 mutations may therefore lead to an “intermediate” disease, between MSK and ARPKD, affecting young adults. Both patients were affected by CKD. Of note, the diagnosis of MSK is not easy because it is still based on imaging, and computed tomography scan may not perform, such as urography, in subtle MSK cases, and, as clearly found in these 2 cases, a similar phenotype occurs in other conditions (ARPKD, but also potentially other forms of nephrocalcinosis). These observations deserve further studies in larger cohorts of patients with MSK to evaluate the prevalence of PKHD1 mutations and whether heterozygous carriers are at risk to develop MSK or whether 2 mutations are required.

Conclusion

We describe herein that PKHD1 biallelic mutations may lead to a “hybrid” disease, between MSK and ARPKD, without multicystic phenotype and affecting adults (Table 1). Both patients were affected by CKD, with a rapid and severe progression, and clinicians should be aware that the presence of CKD in a patient diagnosed as MSK could result from PKHD1 mutations. Moreover, these observations suggest that the development of MSK could be related to impaired cilia-related functions of the tubular cells.

Table 1

Teaching points

MSK and PKHD1: most important aspects
• MSK disease prevalence is >8% among kidney stone formers (a condition affecting 10% of the general population).
• MSK may have a monogenic origin: a familial segregation was observed in some cases and mutations of GDNF were associated with MSK.
• PKHD1 biallelic mutations may be diagnosed as an atypical MSK leading to CKD in adulthood.
• PKHD1 biallelic mutations may therefore be causative for ARPKD and/or for MSK-like disease.
• The role and prevalence of mono- or bi-allelic mutations of PKHD1 in patients affected by MSK need to be addressed.

ARPKD, autosomal recessive polycystic kidney disease; CKD, chronic kidney disease; MSK, medullary sponge kidney.

Disclosure

All the authors declared no competing interests.

Patient Consent

The authors declare that they have obtained consent from the patients discussed in the report, including written consent for whole-exome sequencing.