Introduction 

The Bardet-Biedl syndrome (BBS) is a rare, inherited disorder caused by genetic mutations. Some of its key clinical features include learning disabilities, retinal degeneration, polydactyly, and renal defects. Genito-urinary anomalies observed during prenatal ultrasound, polydactyly, and obesity are the early signs associated with BBS.¹ Numerous renal anomalies have been linked to BBS, with renal failure being the most common cause of death in patients suffering from this disorder.⁴ This article further explores the BBS-associated renal impairment in more detail.

What is bardet-biedl syndrome?

BBS – dysfunction of the primary cilium 

BBS is considered a model of non-motile ciliopathy – it involves a dysfunction of the primary cilia (PC).¹ PC is are organelles that receive signals from the external surrounding environment and transfer them into the cell. The signals are then integrated into various processes such as differentiation, migration, proliferation, and polarisation, which are important in maintaining organ development and homeostasis.²

Defects in cilia function are known as ciliopathies and include various developmental and degenerative diseases.² BBS patients share numerous clinical features with patients who suffer from other ciliopathies.¹ In the kidney, PC are found on polarised epithelial cells that line the renal tubules and project into the lumen of the tubule. This is where they have a sensory role. Cilia have been suggested to be implicated in key features associated with renal ciliopathies, such as cyst initiation, development, and progression to kidney failure.³

Symptoms and causes

Polydactyly, as well as genito-urinary anomalies exhibited during prenatal ultrasound, are considered to be early signs of BBS. Features such as cysts, pelvic dilation, and hyperechoic kidneys have been reported in infants, however, these findings are not specific to BBS. Another early disease sign is obesity, which can often develop during the first year of a patient’s life.¹

Other symptoms typically appear during the first decade of life, with the average age upon BBS diagnosis reported to be 9 years of age, whereas the median age is 5.8 years of age ¹. Below are some of the major features associated with BBS:⁵

• Retinal cone-rod dystrophy 
• Central obesity (with birth weight commonly being normal)
• Postaxial polydactyly 
• Cognitive impairment 
• Hypogonadism & genitourinary abnormalities
• Kidney disease (being a significant morbidity and mortality)
• Neurological abnormalities (including developmental delay, epilepsy, and behavioural or psychiatric abnormalities)
• Olfactory dysfunction (including hyposmia and insomnia)
• Dental or oral abnormalities 
• Cardiovascular abnormalities, as well as other thoraco-abdominal abnormalities⁵

BBS is an autosomal recessive genetic disorder that is caused by pathogenic variants. There are at least 26 genes associated with BBS, with the BBS10 gene dysfunction reported to be causing the most severe renal impairment alongside significant adiposity. It is important to determine the specific genetic cause, as it can be helpful when discussing the disease prognosis, as well as for genetic counselling purposes.⁵

BBS-associated renal anomalies 

Various renal abnormalities have been associated with BBS in the literature, while renal failure is the most common cause of death in patients with this disease.⁴

The renal phenotype observed in BBS patients shows high variability. While early disease reports did not discuss renal involvement, the first descriptions of renal dysfunction started emerging during the 1980s. Since then, kidney defects, renal impairment, and urinary tract malformations have been associated with BBS.⁸

BSS and chronic kidney disease (CKD)

CKD is an important feature of BSS, however, it is not obligatory for the disease.⁷ One study, involving 350 patients with BBS-related renal disease, investigated CKD prevalence and severity. It reported that CKD occurred in 42% of adults and 31% of children, while 8% of adults and 6% of children had stage 4-5 CKD. Renal disease in children was commonly found during their first year of life. Furthermore, 51% of patients who had available ultrasounds showed structural renal abnormalities, and 35% of adults exhibited hypertension.⁶

Patients who have underlying severe urinary tract and kidney development abnormalities are thought to be at risk for CKD. Comorbidities, including obesity, urinary tract infections, diabetes, and hypertension, can relate to adult-onset severe CKD.⁷

Structural and functional impairment 

Structural kidney anomalies observed in BBS patients include:⁸

• Calyceal cysts and clubbing 
• Renal agenesia 
• Foetal lobulations 
• Parenchymal cysts⁸

Regarding the frequency of the occurring structural impairments, one study reported that foetal lobulation as well as diverticula/calyceal cysts/clubbing were present in 96% of the 38 selected BBS patients ⁹. Another study concluded that only four out of 41 patients exhibited no renal anomalies.¹⁰

In terms of functional kidney-related impairment observed in BBS patients, it can include:

• Reduced glomerular filtration rate^{8 10}
• Hyposthenuria in the absence of renal insufficiency¹⁰
• Hydronephrosis⁵
• Vesicoureteral reflux⁵
• Progressive renal parenchymal disease, oftentimes linked with polyuria and polydipsia symptoms⁵

Correlation with specific genetic mutations 

The type of the BBS-linked genetic mutation a patient carries is important when predicting the disease-associated kidney anomalies. For instance:⁷

• BBS1 mutations are more likely to result in no or mild to moderate CKD, while BBS10 mutations are more likely to lead to severe CKD. Furthermore, BBS10, BBS12, and BBS6 variants have a higher probability of leading to severe CKD development compared to BBS1
• Patients carrying BBS1, BBS4, or BBS8 mutations have been suggested to exhibit a low frequency of kidney anomalies, whereas patients carrying BBS2, BBS7, and BBS9 a high frequency⁷

Treatment and management

Kidney-related treatment options

For children and adults with BBS and CKD, blood pressure should be evaluated and treated, if necessary. Furthermore, BBS patients exhibiting hypertension, CKD, or obesity should undergo ambulatory blood pressure measurement.⁷ Patients with chronic renal dysfunction typically receive peritoneal dialysis as well as haemodialysis, which can be followed by kidney transplantation.¹²

In cases of kidney failure, no evidence suggests that BBS patients should not be kidney transplant candidates, given that the outcomes are comparable to the general population. Severe obesity, however, has been suggested to be a potential relative contraindication to kidney transplantation – there have been reports of inappropriate median body mass index (BMI) increases following the procedure. Given that the risk of New-Onset Diabetes after Renal Transplantation is elevated in BBS patients due to obesity, this should inform the choice of the immunosuppressive regimen. Finally, cardiovascular abnormalities should be evaluated prior to transplantation.⁷

Some additional global recommendations concerning uro-nephrology in BBS are below:⁷

• Nephrotoxic drugs should be avoided in general
• In cases of high blood pressure, regular cardiac ultrasound and electrocardiogram are recommended
• In cases of high blood pressure and diabetes, and CKD, a cardiac ischemia test should be performed
• If dysfunctional voiding is present, the risk for urinary tract infection should be prevented and managed⁷

Multidisciplinary treatment approach

Overall, BBS is treated symptomatically, with a focus on diabetes, metabolic syndrome, and hypertension management to reduce the negative secondary effects of these conditions on the eyes and the kidneys, which are already impaired in BBS patients.¹¹

The management of BBS asks for a multidisciplinary approach, involving a range of medical professionals – nephrologists, cardiologists, ophthalmologists, paediatricians, orthopaedic surgeons, dental professionals, audiologists, and speech pathologists.⁴

Various management options are available for different types of BBS-related impairments. For instance, with cone-rod dystrophy present, educational plans should be adopted to accommodate blindness. In cases with learning disabilities, specialised schools and educational programmes can be considered. Regarding obesity control, exercise as well as a healthy carbohydrate-reduced diet are recommended. Furthermore, surgery to remove accessory digits can be an option for cosmetic purposes. Alternative ways of sensing dangerous materials should be present for patients with a loss of smell/reduced sense of smell.⁴

Setmelanotide was the first drug approved to manage obesity in BBS patients.¹³ Furthermore, there are various therapies that show future potential and benefit for BBS patients:¹¹

• Genetic therapeutics
  • Gene therapy 
  • Exon skipping therapy
  • Read-through therapy
  • Gene editing¹¹
• Other interventions
  • Pharmacogenomic profiling 
  • Drug repurposing (rapamycin with potential to rectify the renal cystic phenotype)¹¹

Summary 

• BBS is an inherited autosomal recessive genetic disorder caused by a variety of genetic mutations. It involves a dysfunction of the primary cilia, which are key in organ homeostasis and development^{1 2 5}
• Some of the key features of BBS involve retinal cone-rod dystrophy, obesity, polydactyly, kidney impairment, cognitive impairment, and more⁵ 
• Various renal abnormalities have been linked to BBS in the literature, with a high phenotypic variability^{4 8}
  • Chronic kidney disease (CKD), as well as structural and functional renal impairment, have been reported in BBS patients^{7 8}
• Certain BBS-associated genetic mutations are more likely to result in renal anomalies; for instance, BBS10, BBS12, and BBS6 variants are more likely to lead to severe CKD compared to the BBS1 variant⁷
  • Furthermore, patients with BBS2, BBS7 and BBS9 variants have higher frequency of kidney anomalies⁷
• Based on the type of kidney impairment, different management options are available, including dialysis, renal transplantation¹²
• High blood pressure and diabetes are important factors to pay attention to when dealing with uro-nephrology issues in BBS patients⁷
• BBS management requires a multidisciplinary approach, involving a variety of medical professionals⁴