What Can Cistanche Play in Medullary Sponge Kidney Disease?

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

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Keywords: medullary sponge kidney, chronic kidney disease

INTRODUCTION

Medullary sponge kidney disease is nephropathy characterized by the association of tubular ectasia of calyceal 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 medullary sponge kidneys 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, medullary sponge kidney prevalence is >8%.1

Patient affected by medullary sponge kidney is at risk to form recurrent renal stones, responsible for renal colic and multiple urological interventions. Nevertheless, chronic kidney disease is rarely reported. Many patients affected by medullary sponge kidney complain about chronic flank pain, even in the absence of patent renal colic.2

Click to Cistanche effects for kidney disease

It has been hypothesized that the medullary sponge kidney could have a genetic basis. Currently, only a few cases clustering in families have been reported, suggestive of incomplete penetrance. medullary sponge kidney 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.3

The GDNF, a ligand of RET, allows ureteric bud Q5 branching and invasion of the metanephric blastema with the collecting ducts and upstream kidney formation. Recently, GDNF variants have been identified in patients with medullary sponge kidneys, supporting the idea that medullary sponge kidneys might result from calyceal and collecting duct development defects.4

Considering the potential genetic origin of medullary sponge kidney, whole-exome sequencing was proposed in 2 adult patients affected by medullary sponge kidney with chronic kidney disease, an uncommon condition of medullary sponge kidney.

CASE PRESENTATION

Medical History

Case 1

A young woman had a bilateral medullary sponge kidney diagnosed in 2010 when she was 20 years old (Figure 1). There was no familial case of medullary sponge kidney. She experienced several renal colics but no stone was analyzed. She had a mild chronic kidney disease diagnosed in 2012 (serum creatinine 130 mmol/l), without urine sediment abnormality, which worsened during her first pregnancy in 2015. A renoureteroscopy was performed revealing papilla with typical medullary sponge kidney 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 Chronic kidney disease at this time.

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. medullary sponge kidney 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 chronic kidney disease: serum creatinine level was 189 mmol/l in 2019 and measured glomerular filtration rate (diethylenetriamine pentaacetatetechnetium renal clearance) was 35 ml/min per 1.73 m2. He had mild tubular proteinuria (0.16 g/l), 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 chronic kidney disease. 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 another renal disease than medullary sponge kidney, 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 the 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).

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.5 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 is associated with primary cilia and basal bodies, suggesting a role in cilia-related functions of the cells (development and maintenance of renal tubule architecture).6 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 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 the polycystic hepatorenal disease as some patients affected by ARPKD develop less severe disease with delayed chronic kidney disease.7

A link between PKHD1 mutations and medullary sponge kidney has been hypothesized by Gunay-Aygun et al.8 They performed ultrasound evaluation in 110 parents of patients affected by ARPKD.8 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 medullary sponge kidney and ARPKD, the authors hypothesized that medullary sponge kidney could be the consequence of heterozygous PKHD1 mutations. More recently, Shan et al.9 reported that heterozygous Pkhd1 mutant mice develop cystic liver disease and tubule ectasia mimicking medullary sponge kidneys.

In the 2 patients affected by PKHD1 compound heterozygous mutations, the diagnosis of medullary sponge kidney 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 medullary sponge kidney and ARPKD, affecting young adults. Both patients were affected by chronic kidney disease. Of note, the diagnosis of medullary sponge kidney is not easy because it is still based on imaging, and computed tomography scan may not perform, such as urography, in subtle medullary sponge kidney 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 Medullary sponge kidneys to evaluate the prevalence of PKHD1 mutations and whether heterozygous carriers are at risk to develop Medullary sponge kidneys or whether 2 mutations are required.

CONCLUSION

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

REFERENCES

The source is from Emmanuel Letavernier et, al on Kidney Int Rep (2021)