What is the management approach for CKM (Craniofacial-Kinetic-Muscular) syndrome?

Management of CKM (Cardiovascular-Kidney-Metabolic) Syndrome

The management of CKM syndrome requires a comprehensive approach targeting the interconnected cardiovascular, kidney, and metabolic conditions through lifestyle modifications, pharmacological interventions, and regular monitoring to reduce morbidity and mortality.

Definition and Epidemiology

• CKM syndrome is a recently defined framework by the American Heart Association (AHA) that describes the interconnection between cardiovascular disease, type 2 diabetes, and chronic kidney disease 1.
• Approximately 25% of the population has at least one CKM condition according to National Health and Nutrition Examination Survey data from 1999-2020 1.
• In China, a nationwide population-based study showed that 18.8% of adults were at stage 0,15.5% at stage 1,42.1% at stage 2,14.7% at stage 3, and 8.9% at stage 4 of CKM syndrome 2.

Pathophysiology

• CKM syndrome originates from excess and/or dysfunctional adipose tissue, which secretes proinflammatory and prooxidative products 1.
• These inflammatory mediators lead to tissue damage in arteries, heart, and kidneys, while also reducing insulin sensitivity 1.
• The molecular mechanisms include hyperglycemia, insulin resistance, heightened renin-angiotensin-aldosterone system activity, oxidative stress, lipotoxicity, endoplasmic reticulum stress, mitochondrial dysfunction, and chronic inflammation 3.

Risk Stratification and Staging

CKM syndrome is classified into 4 stages based on risk factors and clinical manifestations:

• Stage 0: No risk factors or clinical disease
• Stage 1: Presence of risk factors without clinical disease
• Stage 2: Presence of risk factors with early signs of disease
• Stage 3: Established disease in one organ system
• Stage 4: Established disease in multiple organ systems 1, 2

Management Approach

Diagnostic Evaluation

• Obtain a comprehensive 3-generation family history focusing on symptoms of cardiovascular disease, diabetes, kidney disease, and other neurological complications 4.
• Brain imaging (MRI preferred over CT) should be performed when clinical symptoms suggest involvement of the central nervous system 4.
• Screening should include both biological factors and social determinants of health 1.

Cardiovascular Management

• Perform baseline echocardiogram and electrocardiogram to assess for structural heart disease and arrhythmias 4.
• Monitor blood pressure at each visit and treat hypertension according to current guidelines 4.
• For patients with established cardiovascular disease, follow-up with a cardiologist is essential to determine the need for interventional procedures 4.

Renal Management

• Regular assessment of kidney function through serum creatinine, estimated glomerular filtration rate, and urinary albumin-to-creatinine ratio 5, 1.
• For patients with advanced kidney disease, consider conservative kidney management (CKM) as an alternative to dialysis in appropriate cases 4.
• Implement symptom management algorithms for kidney-related complications 4.

Metabolic Management

• Address excess adiposity primarily through diet and exercise in early stages 1.
• Implement pharmacological treatment of metabolic syndrome components in later stages 1.
• Monitor for diabetes and initiate appropriate therapy when indicated 1, 3.

Neurological Management

• Antiepileptic therapy is reasonable for first seizure thought to be due to a cerebral cavernous malformation (CCM), which may be associated with some forms of CKM syndrome 4.
• Genetic counseling should be considered for patients with familial or multifocal manifestations 4.
• MRI should be performed in patients who develop new neurological symptoms 4.

Genetic Testing and Counseling

• Consider genetic testing when multiple manifestations are present without other explanatory factors 4.
• In cases with positive mutations, counsel the individual and family about inheritance patterns and identify at-risk individuals 4.
• Genetic screening of asymptomatic individuals raises ethical issues that should be addressed before testing 4.

Special Considerations

Pregnancy Management

• Patients with genetic components of CKM syndrome should consider genetic counseling prior to pregnancy 4.
• The risk of neurological symptoms during pregnancy is likely not different than in the non-pregnant state 4.
• MRI without contrast should be considered for new neurological symptoms during pregnancy 4.

Addressing Health Disparities

• Substantial racial and ethnic differences exist in CKM syndrome prevalence and outcomes, likely due to social determinants of health 1.
• A multifaceted, multi-level approach including interdisciplinary care and clinical decision support tools may help combat these inequities 6.
• Barriers to pharmacoequity in CKM syndrome include multimorbidity, polypharmacy, low awareness, clinical inertia, cost, and fragmented care 6.

Monitoring and Follow-up

• Regular follow-up with specialists based on the affected organ systems 4.
• For patients with cardiovascular involvement: echocardiogram every 2-3 years in childhood/adolescence and every 3-5 years in adulthood if no previous heart disease 4.
• Annual evaluation of any dermatologic manifestations 4.
• Neurological follow-up for seizure management if present 4.

Prognosis

• Mortality risk increases progressively with advancing CKM stages 2.
• Compared to stage 0, adjusted hazard ratios for all-cause death are: stage 1 (0.77), stage 2 (1.36), stage 3 (2.47), and stage 4 (4.00) 2.
• Population attributable fractions for all-cause death caused by stages 2,3, and 4 are 13.4%, 18.6%, and 22.0%, respectively 2.