Kidney disease in adults with Prader-Willi syndrome: international cohort study and systematic literature review

Abstract

Background: Prader-Willi syndrome (PWS) is a rare, complex, genetic disorder characterized by hyperphagia, hypotonia, delayed psychomotor development, low muscle mass and hypothalamic dysfunction. Adults with PWS often have obesity, hypertension and type 2 diabetes mellitus (DM2), known risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD). Early symptoms of CVD and CKD may be masked by intellectual disability and inability to express physical complaints. Furthermore, kidney diseases are often asymptomatic. Therefore, renal and cardiovascular disease might be missed in patients with PWS. Microalbuminuria is an early sign of microvascular damage in the kidneys and other vascular beds. Therefore, we screened our adult PWS cohort for the presence of elevated urinary albumin and (micro)albuminuria.

Methods: We retrospectively collected anthropometric measurements, blood pressure, medical history, medication use, urine dipstick and biochemical measurements form electronic patient files. In addition, we performed a systematic literature review on kidney disease in PWS.

Results: We included 162 adults with genetically confirmed PWS (56% male, median age 28 years), of whom 44 (27%) had DM2. None had known CVD. All subjects had normal estimated glomerular filtration rate (eGFR) according to non-PWS reference intervals. Elevated urinary albumin or (micro)albuminuria was present in 28 (18%); 19 out of 75 (25%) had an increased urinary albumin-to-creatinine ratio (UACR) and 10 out of 57 (18%) had an increased urinary protein-to-creatinine ratio. Elevated urinary albumin was present at a young age (median age 26 (IQR 24-32) years) and was associated with an significantly higher BMI and LDL-cholesterol levels and higher prevalence of DM2, hypertension and dyslipidemia than those with normal UACR (p=0.027, p=0.019, p<0.001, p<0.001, p=0.011 and respectively).

Conclusion: Upon screening, one in every five adults with PWS had increased urinary albumin or (micro)albuminuria, early signs of microvascular disease. All had normal eGFR, according to non-PWS reference intervals, and none had a formal diagnosis of CVD. As muscle mass is low in PWS, creatinine levels and eGFR may be spuriously normal. Urinalysis in this patient group can be used as a screening tool for microvascular (kidney) disease. We propose an algorithm for the detection and management of microvascular disease in adults with PWS.

Keywords: Prader-Willi Syndrome; cardiovascular disease; kidney disease; kidney function tests; proteinuria; urine tract infections.

Figure 1

Systematic literature review (63).

Figure 2

Recommendations for screening and the management for (micro)albuminuria and its risk factors in adults with PWS. angiotensin-converting enzyme inhibitor (ACE-I), angiotensin-II receptor antagonist (ATII) electrocardiogram (ECG), estimated glomerular filtration rate (eGFR), Left ventricular hypertrophy (LVH), minutes (min), urinary tract infection (UTI), urinary albumin-to-creatinine ratio (UACR), urinary protein-to-creatinine ratio (UPCR). a. Diagnosed by repeated measurements or 30-minute measurement. b. preferably in a first morning urine sample. c. Consider using adjusted reference values for adults with PWS (e.g. >98 ml/min/1.73m2 in males and >93 ml/min/1.73m2 in females) (20). d. Obesity in adults with PWS should be aggressively management with for example a hypocaloric diet, structured regular exercise and restriction of access to food. e. For example the 2018 ESC/ESH guidelines for the management of arterial hypertension (116). f. For example the 2019 ESC guidelines on diabetes (117). g. For example the ESC 2021 guideline (118) on cardiovascular disease prevention.