Kidney Dysfunction: A Hidden Torment of Muscular Dystrophy

Written by: Md Abdul Qader 

Infographics by: Salar Bani Hani 

AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.

Introduction: 

Muscles are responsible for a variety of functions, including movement, breathing, and digestion. Muscles are composed of bundles of myofibrils fibers, which contain the proteins actin and myosin that are essential for movement. Muscular dystrophy (MD) is a group of genetic neuromuscular disorders that cause the muscles to weaken and atrophy over time. The manifestations of MD can range from a mild weakness to the inability to walk, talk or breathe. There is currently no cure for muscular dystrophy, but there are treatments that can help slow the progression of the disease and improve the quality of life for people living with MD.

In MD, the extent of muscle wasting can also affect the genitourinary system. While urinary incontinence is more common in older individuals, children with MD may experience lower urinary tract symptoms such as urgency, frequency, hesitancy and feeling of incomplete bladder emptying. In this review, we will delve into the issues related to kidney involvement in patients with MD.

Types of Muscular Dystrophy

The most common types of MD are Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and Emery-Dreifuss muscular dystrophy (EDMD). 

There are many different types of muscular dystrophy, each with its own unique symptoms and progression. 

Figure-1: Dystrophin-glycoprotein complex (DGC). Dystrophin is a rod shape protein that links intracellular cytoskeleton networks to transmembrane components of the DGC, including dystroglycan, sarcoglycans and sarcospan. Dystroglycan is composed of two subunits, α and β. α-Dystroglycan is an extracellular peripheral membrane protein and a receptor for laminin-2, linking the DGC to the ECM. The sarcoglycans form a tight complex with sarcospan, strengthening the connection between α and β-dystroglycan. Besides a structural role, the sarcoglycan-sarcospan subcomplex is also involved in signal transduction and mechano protection. α-Dystroglycan is heavily O-glycosylated (straight lines) in the central mucin domain. β-Dystroglycan and the sarcoglycans contain potential N-glycosylation sites (branch). The syntrophins, dystrobrevin, and nNOS are recruited to the C-terminus of dystrophin and participate in signal transduction pathways.

Duchenne Muscular Dystrophy (DMD) is a rare genetic disorder that primarily affects males. It is caused by a mutation in the dystrophin gene, leading to progressive muscle weakness and wasting. There are 3 types of dystrophin-associated proteins: extracellular (alpha-dystroglycan), transmembrane (ß-dystroglycan, sarcoglycans, sarcospan), cytoplasmic (dystrophin, dystrobrevin, syntrophins etc). These are collectively known as dystrophic-associated protein complex (DAPC) or dystrophin glycoprotein complex (DGC). DAPC maintains important cellular structural integrity and contractility, so dystrophin deficiency leads to contraction damage of the sarcolemma, followed by tear, rupture, and leakage of muscle enzymes and proteins.. There is functional ischemia, free radical injury to the muscle cells causing damage to the skeletal muscle. This damage and degeneration initially follows regeneration but ultimately they are replaced by fatty and fibrotic tissue. Patients with DMD usually presents with delayed motor milestones, muscle weakness, hypertrophy of the calves muscles and gower sign (where they use hands to stand up from the floor and walk to compensate weak upper leg and hip muscles)  

Children with DMD commonly experience lower urinary tract symptoms due to smooth muscle dysfunction in the urinary tract, particularly the urinary bladder. There is a high rate of obesity in young adults of DMD which is related to steroid therapy and contributes to obesity-induced kidney dysfunction. Kidney dysfunction is a significant complication in advanced-stage DMD, with kidney failure being the third leading cause of death in adults. Factors such as chronic heart dysfunction, inadequate water consumption, and the use of diuretics are associated with kidney involvement in DMD patients.

Becker muscular dystrophy (BMD) is a mild form of muscular dystrophy caused by an abnormality in the dystrophin molecule. It is an X-linked recessive disorder, meaning that it primarily affects males. BMD is characterized by elevated creatinine kinase (CK) levels during exertion, fragile muscle fibers, and an increased risk of rhabdomyolysis and acute renal failure. Adults with BMD are more likely to experience urinary incontinence and lower urinary tract dysfunction compared to children with the condition.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscular dystrophy that manifests in two distinct forms: infantile and adult, with adult onset weakness being the most frequent. In an infantile form of FSHD, facial weakness can present as early as age 5, with shoulder and hip girdle weakness by age 10. Sensory neural hearing loss is common, but renal, cardiac, and respiratory complications are rare. Two case reports have been documented: one of infantile FSHD presenting with focal segmental glomerulosclerosis and one of severe glomerular endothelial injury, both with genetic abnormalities on chromosome 4q35. Both children presented with nephrotic syndrome that was unresponsive to corticosteroids, eventually becoming steroid-resistant.

Myotonic dystrophy is an autosomal dominant disorder with a prevalence of 4.5 per 100,000 children. In myotonic dystrophy, the patient has a wide variety of presentations besides muscle weakness and stiffness such as cognitive impairment, endocrine abnormalities, cataracts, cardiac conduction abnormalities and cardiomyopathy. The classic form is also known as myotonic dystrophy type 1 which is associated with a slight decrease in renal function. The risk factors for renal failure include diabetes, hypertension or age. On the other hand bladder function seems to be unaffected in myotonic dystrophy besides they have frequent urinary complaints.  

Limb-girdle muscular dystrophy (LGMD) is a genetic disorder that affects skeletal muscles and is caused by mutations in genes that encode muscle proteins. Symptoms include muscle weakness, wasting, and stiffness. Treatments can slow progression and improve quality of life, but there is no cure. The estimated prevalence of LGMD ranges from 1 in 14,500 to 1 in 123,000. Some subtypes, especially the recessive LGMD (subtype 2), show elevated levels of creatine kinase in blood tests, which indicates muscle damage. High creatine kinase may also indicate a serious kidney disease.

Muscular dystrophy associated with LMNA mutations is caused by mutations in the LMNA gene, which encodes the nuclear envelope proteins lamin A and lamin C. It is an X-linked disorder, meaning males are more likely to be affected than females. Symptoms can vary depending on the mutation but typically include progressive muscle weakness and wasting. There is no cure, but treatments can help slow the disease's progression and improve quality of life. Laminopathies can cause dilated cardiomyopathy, muscular dystrophy, neuropathy, partial lipodystrophy, progeria, and membranous glomerulonephritis. Familial partial lipodystrophy is a rare genetic disorder where a child born with normal adipose tissue followed by a selective loss of adipose tissue from extremities and gluteal region results in apparent abnormal fat distribution at puberty. Partial lipodystrophy associated with glomerulonephritis is thought to have a shared autoimmune cause possibly due to activation of the C3 nephritic factor.

Treatment and outcome: 

Lower urinary tract symptoms are the earliest presentation in common forms of muscular dystrophies. About a half of the children with DMD develop LUTS. Some of them may develop incontinence and enuresis. The treatment of bladder dysfunction and lower urinary tract symptoms remains conservative in cases of MD, especially in DMD and BMD. Other kidney diseases like glomerulonephritis are treated with corticosteroids and other immunosuppressive medications.

For early diagnosis, testing a newborn with creatinine kinase can be a routine screening tool for suspected cases. The findings of raised CK can help to diagnose several other MD. A newborn with raised CK should undergo mutation analysis to confirm the diagnosis. As the involvement of muscle weakness progresses, bladder dysfunction may become more prominent and clinically evident. One of the main causes of low quality of life (QOL) in children with DMD is lower urinary tract diseases (LUTS and LUTD). Thus, urological evaluations ought to be conducted on a regular basis.

AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.