Does the PKU diet contribute to impaired renal function?

Abstract

The recent report by Hennermann et al provides novel evidence of impaired renal function, proteinuria and arterial hypertension in adolescent and adult PKU patients (median age 24 years) treated lifelong with the low-phe, amino acid (AA)-based diet (Hennermann et al 2012). I wish to call attention to our recent research publications (not cited by the authors) that support their findings and highlight the need for additional research to elucidate the contribution of the PKU diet to impaired renal function.Briefly, impaired renal function was observed in 19 % of subjects (11 out of 59) based on a glomerular filtration rate (GFR, measured by 51 Cr-EDTA) that was below the normal range and associated with longer lifelong years of diet time and greater proteinuria compared to subjects with a normal GFR (Supplementary Table 2, Hennermann et al 2012). Lifelong plasma phe concentration did not correlate with GFR and total dietary protein intake was within the range of a typical Western diet (0.75-1.14 g pro/kg/day). Given that the majority of nitrogen is provided by a mixture of AAs rather than intact dietary protein in the PKU diet, evidence presented by Hennermann et al suggests that the low-phe AA diet may contribute to alterations in renal function that warrant prospective, controlled investigation to identify the underlying pathophysiology.Our recent studies comparing low-phe diets comprised of AAs versus primarily intact protein from glycomacropeptide (GMP) in murine and human PKU are consistent with the potential for the AA-based PKU diet to impair renal function. Specifically, chronic ingestion of the AA diet significantly increased renal mass, water intake and urine output and wild type littermates compared with the GMP diet. PKU subjects fed the AA diet in an inpatient metabolic study showed significantly lower plasma AA concentrations, higher blood urea nitrogen concentrations, and lower carbon dioxide at 2.5 h after a meal compared with the GMP diet (van Calcar et al 2009). These changes suggest that the AA diet provides a high dietary acid load and invokes greater renal workload, due to rapid absorption of AAs followed by subsequent degradation to urea, compared with the low-phe GMP diet.The low-phe, AA-based diet implemented in infancy has shown tremendous success in preventing severe cognitive impairment due to PKU. Unfortunately, there is evidence of suboptimal health outcomes in PKU subjects treated with the AA diet including neurocognitive/psychosocial issues, oxidative stress, skeletal fragility (Enns et al 2010), and now, the potential for impaired renal function. In order to develop improved treatments that minimize these chronic complications associated with PKU, additional research with controlled dietary treatments is needed.

The BMI Z-Score and Protein Energy Ratio in Early- and Late-Diagnosed PKU Patients from a Single Reference Center in Mexico

“…Recommending an unnecessarily high P:E ratio may contradict PKU recommendation guidelines and require excessive and expensive protein substitutes, including metabolic formula [ 57 ]. Moreover, renal dysfunction has been observed in HPA/PKU patients treated with relatively high protein intake from synthetic amino acid formula [ 58 , 59 ].…”

Phenylketonuria, co‐morbidity, and ageing: A review

“…Kidney function may be impaired in those with PKU treated with a low‐Phe diet due to a relatively high protein intake from synthetic AA . Burton et al reported an increased prevalence ratio of renal insufficiency with hypertension in PKU compared to controls .…”

“…Kidney function may be impaired in those with PKU treated with a low-Phe diet due to a relatively high protein intake from synthetic AA. [14][15][16] Burton et al reported an increased prevalence ratio of renal insufficiency with hypertension in PKU compared to controls. 5 A single study on chronic kidney disease (CKD) looked at 80 on-diet PKU patients (aged 15-43 years) with variable dietary adherence recruited from a metabolic centre in Berlin.…”

Advances in the nutritional and pharmacological management of phenylketonuria

“…Reduced renal function in PKU could decrease renal 1,25 (OH) 2 D synthesis and reduce fractional calcium absorption, leading to a decline in BMD. Taken together, the AA diet provides a high dietary acid load and might also impair renal function (32) resulting in multiple negative effects on bone health. The pathophysiology of skeletal fragility in PKU is an important topic for future investigation.…”