Cachexia is common in many illnesses, including chronic kidney disease (CKD) and cancer, and is characterized by elevated energy expenditure and loss of adipose and muscle mass. New data support an important role for PTH and the PTH/PTHrP receptor (PTHR) in cachexia associated with CKD. “Our findings demonstrate that PTH and PTHrP mediate wasting through their receptor in fat tissue and that fat–muscle crosstalk must promote muscle atrophy,” explain researchers Serkan Kir and Bruce Spiegelman.

Credit: Lara Crow/NPG

loss of PTHR in fat tissue also attenuated atrophy of skeletal muscle

Brown fat is more thermogenic than white fat and contributes to energy homeostasis in rodents and humans. Previous work by Kir et al. on cancer cachexia showed that tumour-derived PTHrP stimulates adipose tissue thermogenesis and that neutralization of PTHrP in tumour-bearing mice inhibits browning and wasting of fat tissue and atrophy of skeletal muscle. “As both PTHrP and PTH share the same receptor, and as PTH is often elevated in patients with CKD who exhibit symptoms of wasting, we suspected that PTH might share some of the cachectic effects of PTHrP,” says Spiegelman. To investigate this hypothesis, the researchers studied the role of PTH in mice with cachexia induced by 5/6 nephrectomy. Nephrectomized mice had hyperparathyroidism and developed uraemia and cachexia associated with browning of white adipose tissue and increased energy expenditure. Kir et al. then used fat cell-specific PTHR-knockout mice to examine the role of the PTHR pathway in adipose browning and wasting. “We found that the knockout mice were resistant to adipose browning and preserved fat mass following nephrectomy,” says Kir. “Surprisingly, loss of PTHR in fat tissue also attenuated atrophy of skeletal muscle, demonstrating the presence of indirect mechanisms through which fat signals to skeletal muscle.”

Nephrologist Kamyar Kalantar-Zadeh, who was not involved in the research, believes these findings are important. “We know that patients with CKD and a high serum PTH level often do poorly and that hyperparathyroidism-associated bone and mineral disorders cannot fully explain the adverse outcomes,” he says. “This study suggests that hyperparathyroidism is also related to muscle wasting, which is among the strongest predictors of death and explains why dialysis patient survival is greatest in countries with the lowest PTH target levels.”

Kir and colleagues are currently developing PTHrP-specific monoclonal antibodies for use in patients with cancer cachexia. They warn, however, that the treatment of CKD-associated cachexia might not be straightforward. “Inhibiting tumour-derived PTHrP is rather simple because PTHrP is an ectopic factor that should not be in the circulation,” says Spiegelman. “However, PTH is an important player in CKD because it regulates plasma calcium and phosphorus and therefore therapeutic targeting of PTH or PTHR in CKD will certainly be limited by the crucial roles of these factors in mineral metabolism.”