Urinary urea excretion, a marker for protein intake, was inversely related to graft failure in RTR with BMI less than 25 kg/m and in RTR with an eGFR of 45 mL per min per 1.73 m or higher. In addition, urinary urea excretion was inversely related to mortality.

The effect of a low protein intake on survival in renal transplant recipients (RTR) is unknown. A low protein intake may increase risks of malnutrition, low muscle mass, and death. We aimed to study associations of protein intake with mortality and graft failure and to identify potential intermediate factors. Protein intake was estimated from 24‐h urinary urea excretion (24‐h UUE). Graft failure was defined as return to dialysis or retransplantation. We used Cox regression analyses to analyze associations with outcome and potential intermediate factors in the causal path. In 604 RTR, mean ± SD 24‐h UUE was 380 ± 114 mmol/24‐h. During median follow‐up for 7.0 yr (interquartile range: 6.2–7.5 yr), 133 RTR died and 53 developed graft failure. In univariate analyses, 24‐h UUE was associated with lower risk of mortality (HR [95% CI] = 0.80 [0.69–0.94]) and graft failure (HR [95% CI] = 0.72 [0.56–0.92]). These associations were independent of potential confounders. In causal path analyses, the association of 24‐h UUE with mortality disappeared after adjustment for muscle mass. Low protein intake is associated with increased risk of mortality and graft failure in RTR. Causal path analyses reveal that the association with mortality is explained by low muscle mass. These findings suggest that protein intake restriction should not be advised to RTR.

Cardiovascular disease (CVD) is the leading cause of death in renal transplant recipients (RTR). Elevated plasma asymmetric dimethylarginine (pADMA), an endogenous nitric oxide synthase inhibitor produced from the turnover of methylated arginine moieties in proteins, is a risk factor for CVD and mortality. It is unknown how urinary ADMA excretion (uADMA), one of the main ADMA elimination routes, is associated with long-term survival. Furthermore, the association of pADMA and uADMA with markers for turnover of arginine-methylated proteins is unknown. We analyzed ADMA using a validated GC-MS/MS method in plasma and 24-h urine samples of 685 RTR, included ≥ 1 year after transplantation. We also analyzed urine symmetric dimethylarginine (uSDMA) using the same method. Urinary creatinine and urea excretions were used as markers for turnover of muscle protein and amino acids, respectively. We applied Cox regression analyses to study associations of pADMA, uADMA, and uSDMA with all-cause and CVD mortality. Mean pADMA was 0.61 ± 0.12 µM, uADMA was 31 ± 13 µmol/24 h, and uSDMA was 52 ± 19 µmol/24 h. Over median follow-up of 5.4 [4.9-6.1] years, 147 RTR died, of which 58 (39%) from CVD. High pADMA was associated with high all-cause mortality (HR per SD [95% CI]: 1.45 [1.26-1.67], P < 0.001), while high uADMA was associated with low all-cause and CVD mortality (HR per SD [95% CI]: 0.57 [0.47-0.69], P < 0.001, and 0.55 [0.40-0.74], P < 0.001, respectively). The associations were independent of adjustment for potential confounders. Creatinine excretion was associated with both pADMA (st. β:− 0.21, P = 0.003) and uADMA (st. β: 0.49, P < 0.001), and urea excretion was associated with uADMA (st. β: 0.56, P < 0.001). Associations of uSDMA with outcomes and with creatinine excretion and urea excretion were comparable to those of uADMA. The associations of pADMA, uADMA and uSDMA with mortality were strongly affected by adjustment for creatinine excretion and urea excretion. We found for the first time that high uADMA and high uSDMA are associated with less risk of all-cause and CVD mortality. The links of uADMA and uSDMA with markers of muscle protein and amino acid turnover may serve to further understand ADMA and SDMA homeostasis and their clinical implications. Keywords Kidney transplantation • ADMA • SDMA • Muscle mass • Protein turnover • Long-term survival Abbreviations ADMA Asymmetric dimethylarginine AGXT2 Alanine-glyoxylate aminotransferase 2 BMI Body mass index BSA Body surface area CI Confidence interval CKD-EPI Chronic kidney disease epidemiology collaboration CVD Cardiovascular disease DDAH Dimethylarginine dimethylaminohydrolase D-NAME N G-Nitro-d-arginine methyl ester eGFR Estimated glomerular filtration rate GFR Glomerular filtration rate Handling Editor: P. Beltran-Alvarez. M. Yusof Said and A. Bollenbach shared first authorship.