Multicystic Kidney Disease in a Family With Tuberous Sclerosis Complex

ABSTRACT

Tuberous sclerosis complex (TSC) is a multisystem condition associated with disease‐causing variants of either TSC1 or TSC2 genes. Significant kidney involvement in TSC is most often due to development of angiomyolipomas (AMLs) and occurs more frequently in people with TSC2 variants. Kidney cysts are also commonly seen; however, these are usually small and not recognised as problematic. A subset of patients has a severe polycystic kidney disease due to a contiguous gene deletion involving PKD1 and TSC2 on chromosome 16. End‐stage kidney disease (ESKD) occurs commonly in patients with TSC2/PKD1 deletions but is otherwise rare. We report a family with a TSC1 variant. The father, a 34‐year‐old male, presented with chronic kidney disease with eGFR 31 mL/min, proteinuria 1.2 g/day and hypertension. Ultrasound showed small cystic kidneys. Coincidentally, his 2‐year‐old daughter presented with seizures and had skin lesions and neurological signs consistent with TSC. Her 1‐year‐old brother also met TSC diagnostic criteria. Further investigations of the father showed typical skin lesions and cerebral tubers. Genetic testing identified a variant in TSC1. The father progressed to ESKD and subsequently received a kidney transplant. His two children have similar renal ultrasounds with multiple cysts; now aged 18 and 16 years, they have normal eGFR and no proteinuria. This family manifests a rarely described multicystic phenotype and TSC1 variant. The father's case demonstrates the risk of progressive kidney disease in TSC, even in the absence of AMLs or TSC2/PKD1 contiguous deletion, and highlights the importance of renal monitoring of all adults with TSC.

1. Introduction

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder affecting 1 in 6000 to 10 000 individuals [1]. It arises from disease‐causing variants in TSC1 or TSC2, encoding the proteins hamartin and tuberin respectively. Loss of function variants in TSC1 and TSC2 result in overactivity of the mechanistic target of rapamycin (mTOR) pathway, leading to abnormal tissue proliferation and the formation of characteristic hamartomas, most commonly in the brain, kidneys, heart, skin and lungs [2, 3].

Kidney involvement in TSC is an important cause of morbidity and mortality, characterised by the progressive occurrence and growth of angiomyolipomas (AMLs), cysts and, less commonly, renal cell carinomas [4, 5]. Large or multiple AMLs can replace normal renal parenchyma, resulting in declining kidney function and chronic kidney disease (CKD). Further kidney function decline can be caused by haemorrhage or loss of nephrons following endovascular or surgical intervention [6]. CKD has been reported in 40% of TSC patients over the age of 50 years [6] although end‐stage kidney disease (ESKD) is uncommon, reported in only 1%–3% of patients [4, 7].

Cystic kidney disease is seen in approximately 50% of TSC patients and can range in phenotype, from benign cortical cysts, microscopic glomerulocystic to a polycystic phenotype identical to autosomal dominant polycystic kidney disease (ADPKD) [6]. Variants in TSC2 are typically associated with more severe disease manifestations, including higher numbers and more aggressive growth of both AMLs and renal cysts, and a higher rate of complications including haemorrhage [5, 8, 9]. Approximately 2%–3% of patients with TSC2 have a contiguous gene deletion that extends into the adjacent PKD1 gene on chromosome 16, which encodes polycystin‐1 (one of two genes associated with ADPKD). Although it is well known that these patients have severe and early‐onset polycystic kidney disease which often progresses to ESKD in early adulthood, disease progression in other forms of TSC‐associated cystic kidney disease is highly variable and poorly understood.

In this report, we present a family with TSC secondary to a pathogenic variant in TSC1. The father presented in early adulthood with elevated serum creatinine, proteinuria and renal cysts, with a multicystic pattern on imaging. Unusually for TSC1 variants, he progressed to ESKD requiring a kidney transplant. His two children were diagnosed concurrently and have developed similar cystic changes.

2. Case Presentation

A 34‐year‐old male was referred after investigations for lethargy showed a serum creatinine of 214 μmol/L (eGFR of 31 mL/min). He had 1.2 g/day of proteinuria and an elevated blood pressure of 141/95 mmHg. A renal ultrasound showed small kidneys: a 9.6 cm right kidney and a 9.2 cm left kidney, with irregular outlines, thin cortex and multiple cysts (Figure 1). In the right kidney, there were cysts up to 3 cm, and up to 2.5 cm in the left kidney. There was no evidence of AMLs on ultrasound or CT (Figure 1). His medical history was largely unremarkable. There was no history of hypertension, diabetes or urinary tract infections. The man denied frequent use of NSAIDs and was on no regular medications. He did report use of a proton‐pump‐inhibitor in the past, but this was ceased over 2 years ago. He did not have a history of epileptic seizures or intellectual disability.

FIGURE 1.

Renal imaging of 34‐year‐old male with TSC and multicystic kidneys. (A and B) Renal ultrasound demonstrating multiple cysts of varying size in both kidneys with echogenic parenchyma. (C) Abdominal CT scan demonstrating small atrophic kidneys with numerous exophytic cysts.

There was no reported family history of renal disease. However, around the same time that he first presented, his then 2‐year‐old daughter was being investigated for focal epileptic seizures and was found to have hypomelanotic skin macules and cerebral MRI changes showing cortical tubers and subependymal nodules, consistent with TSC. Her 1‐year‐old brother was also found to have numerous hypomelanotic skin macules and, around the same time, developed focal epileptic seizures. He had similar cerebral MRI changes, including small cortical tubers and a subependymal nodule, also meeting the diagnostic criteria for TSC. Further investigations of the adult male showed typical skin lesions including hypomelanotic macules and angiofibromas, and a cerebral CT revealed cortical tubers and a small subependymal nodule.

Genetic testing was performed on the father, and he was sequenced in 2010 via Sanger sequencing of all coding exons of the TSC1 and TSC2 genes. Multiplex ligation‐dependent probe amplification (MLPA) of both genes, including the TSC2/PKD1 contiguous deletion region, was also performed. Other genes associated with cystic kidney disease were not covered. This revealed a pathogenic variant in TSC1 (NM_000368.5:c.2689C>T, p.(Gln897*)). The children did not undergo genetic testing, but as they both meet diagnostic criteria for TSC, they are assumed to carry the same variant. This variant has not been previously reported to cause ESKD.

The father was prescribed ramipril with an initial improvement in proteinuria to 750 mg/day. However, he progressed to ESKD over the following 3 years. He was commenced on peritoneal dialysis then underwent a successful deceased donor kidney transplant 2 years later. Currently 8 years post‐transplant, he has stable graft function.

His daughter has had annual renal imaging since age 2 years. Small kidney cysts were first seen at 9 years of age; now aged 18 years, she has several cysts with the largest being 17 mm (Figure 2). The son had a single cyst identified by 7 years of age. Now aged 16 years, he has developed small AMLs and several cysts, with the largest being 23 mm in diameter (Figure 2). Both children have normal eGFR, normal blood pressure and no proteinuria.

FIGURE 2.

Renal MRIs of two siblings with TSC and multicystic kidneys. (A) T2 weighted MRI of an 18‐year‐old girl showing multiple cysts in both kidneys, and the largest in the left lower pole. (B) T2 weighted MRI of a 16‐year‐old boy showing multiple cysts in both kidneys, and the largest in the left lower pole.

3. Discussion

There is a growing awareness of the diverse renal phenotypes seen in people with TSC and this case highlights a particular multicystic phenotype that can be associated with progressive CKD. Whilst in general the clinical manifestations of TSC tend to be more severe in people with TSC2 variants compared to those with TSC1 variants [5, 9, 10], this case also demonstrates that ESKD can occur as a consequence of TSC1 variants, even when other clinical manifestations are relatively mild.

Renal cysts are frequently identified in young children with TSC2 variants, and except for those with contiguous TSC2/PKD1 deletions, do not usually portend progressive kidney disease. When children were evaluated at 2 years of age in the EPISTOP study, multiple kidney cysts were not observed in participants with TSC1 (0%, 0 of 19) in that paediatric cohort, compared to TSC2 (34%, 20 of 59) [9]. In an international study of 224 patients with TSC, patients with TSC2 developed renal cysts earlier (13.8 years of age vs. 26.3 years of age for TSC1 variants), had more severe cystic kidney disease, as well as a higher frequency and grade of renal AMLs [10]. None of the patients with TSC1 variants had significant renal involvement; all had either no or minimal renal cysts and AMLs. The course of the two children described herein at first appears to follow this pattern for TSC1 variants, with cysts not seen before 7 years of age; however, by 16 years, both had developed more and larger cysts, raising the possibility that their clinical course could mirror their father's.

When patients with TSC are considered as a whole, regardless of genotype, there is strong evidence to show a risk of CKD during adulthood. Whilst impaired renal function was infrequent in the international TOSCA cohort, being reported in 39/2211 (3.8%) with no clear association with genotype, most study participants were younger than 18 years of age [5]. By comparison, of the 223 participants enrolled in the EXIST‐1 and EXIST‐2 clinical trials of everolimus, 37% had reduced GFR (CKD 2–4) at baseline, with an association seen between both age and a history of previous surgical intervention for AMLs [11].

When examined from the standpoint of ESKD registries, patients with TSC who develop ESKD tend to commence renal replacement therapy (RRT) in the fourth or fifth decade of life. Ninety‐nine patients with TSC were identified in the French Renal Epidemiology and Information Network (REIN) registry as having undergone RRT between 2002 and 2016 at a mean ± standard deviation age of 48.4 ± 16.4 years [12]. Only 14 patients had undergone genetic testing, with 9 patients having TSC1 variants and 5 having TSC2 variants. As was seen in the EXIST trials, prior nephrectomy or embolization for AML was the leading cause of ESKD, and 27.9% of the cohort had PKD. Of their cohort, 54 patients (54.5%) underwent kidney transplant, with a graft survival rate of 92.5% at 5 years, and 70.2% at 10 years. The recently published study from the United Network for Organ Sharing (UNOS) database included 200 patients with TSC‐associated ESKD waitlisted for a kidney transplant between 1987 and 2000 [13]. The mean age at waitlisting was 38 ± 13.8 years, (range 7–75 years), and 140 patients (70%) received a kidney transplant during the follow‐up period. They reported comparable 1‐year patient and allograft survival to the general transplant population, with 91% of recipients surviving with a functioning allograft at 1‐year. Janssens et al. followed 80 patients from two centres in Belgium who had TSC diagnosed in childhood; 6 (7.5%) developed ESKD at a median age of 42 years (23–64) [7].

As seen in the studies cited above, the two best characterised risk factors for CKD in TSC are surgical intervention for AMLs and coexistent PKD. However, as the current case illustrates, ESKD can occur without either and apparently due to a multicystic kidney disease. The multicystic phenotype was proposed by Bissler and Christopher Kingswood who described five distinct phenotypes of TSC‐associated cystic disease [6]. Two phenotypes were associated with less risk of disease progression and the development of CKD: focal cystic disease and cortical cystic disease. Three phenotypes were associated with poor outcomes: microcystic, polycystic and multicystic kidney disease. Microcystic kidney disease causes subtle changes that may be missed on ultrasound and is associated with a rapid decline in renal function in the second or third decade of life. TSC‐associated polycystic kidney disease has been well described, affecting approximately 2% of TSC patients, and caused by the TSC2/PKD1 contiguous gene deletion. These patients develop significant cystic disease and hypertension early in childhood. Patients with the multicystic phenotype also have cysts of varying size throughout cortical and medullary tissue and associated CKD but are due to either TSC1 or TSC2 variants. Our patient displayed this multicystic phenotype and progressed to ESKD in the fourth decade of life. Bissler and Christopher Kingswood also developed a clinical scoring system based on phenotype, that although not yet validated, may aid in monitoring and managing patients with TSC‐associated cystic kidney disease in the future.

mTOR inhibition is now established as first line treatment of asymptomatic AMLs in TSC; however, there are no clear guidelines for the treatment of cystic kidney disease. ACE inhibitors or angiotensin receptor blockers are recommended to treat the modifiable risk factors seen frequently and early in patients with TSC, including hypertension, proteinuria and hyperfiltration [14]. There are a small number of case series that suggest mTOR inhibitors may be beneficial in TSC‐related cystic kidney disease. A small study of 15 patients with TSC‐associated cystic disease showed a reduction in size and number of cysts following mTOR inhibition [15]. Most patients had a multicystic or microcystic phenotype, with 14 out of 15 patients having an average of 72 cysts. They were treated for almost 3 years, and all 15 patients had an improvement in cyst burden, in terms of total number of cysts (reporting a reduction of 72.1%), sum of cyst diameter and total volume of cysts. Kidney function was preserved throughout. An additional case report from the United States showed a similar effect on three paediatric patients with multicystic or polycystic kidney disease, who were placed on everolimus primarily for subependymal giant cell astrocytomas and seizure control [16]. All three patients had either disappearance of or decreased burden of their cystic kidney disease, along with normalisation of creatinine levels and improvement in kidney function. A recent report of two cases also suggested that mTOR inhibition could slow the progression of CKD in patients with the microcystic phenotype [17]. Further research into the effect of mTOR inhibitors on TSC‐associated cystic disease is warranted.

4. Conclusion

Although it has been shown that TSC1‐related disease is, in general, less severe than TSC2‐related disease [10], there is a wide degree of variation in phenotype for both TSC1 and TSC2 variants. This family manifests a rarely described multicystic phenotype secondary to a TSC1 variant. The father's case demonstrates the risk of progressive kidney disease in TSC, even in the absence of AMLs or TSC2/PKD1 contiguous deletion and highlights the importance of renal monitoring of all adults with TSC. Active surveillance and treatment with mTOR inhibitors may alter the natural history of TSC‐associated cystic kidney disease and are worthy of further investigation.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.