EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: In kidney transplant recipients, reduced muscle mass and hand-grip strength are associated with impaired nutritional status. Serum testosterone is highly associated with muscle strength in the general population. Here, we aimed to determine the associations among serum testosterone, hand-grip strength, and nutritional and inflammatory parameters, as well as graft function.

Materials and Methods: Our study included 144 stable male kidney transplant recipients from our renal transplant outpatient clinic. All patients were evaluated for clinical parameters (age, duration of hemodialysis, and posttransplant time), biochemical parameters (calcium, phosphorus, parathyroid hormone, C-reactive protein, albumin, creatinine), and serum testosterone levels. Body composition was analyzed with the bioimpedance spectroscopy analysis technique using a body composition monitor that estimates body mass index and percent fat. Hand-grip strength was analyzed by using a dynamometer (ProHealthcareProducts.com, Park City, UT, USA). We calculated estimated glomerular filtration rate using the Modification of Diet in Renal Disease-4 equation.

Results: Demographic characteristics, duration of dialysis before transplant, biochemical parameters, and estimated glomerular filtration rates were similar among study patients. Mean (standard deviation) serum testosterone was 588.0 (55.5) ng/dL, mean body mass index was 26.8 (0.6) kg/m², and mean hand-grip strength was 42.2 (1.7) mm². Serum testosterone levels were positively correlated with hand-grip strength (r = 0.445; P = .033) and serum albumin (r = 0.399; P = .05) and negatively correlated with serum C-reactive protein (r = -0.454; P = .05) and age. In linear multiple regression analysis, serum albumin (P = .033) and testosterone levels (P = .038) were shown to be predictors of hand-grip strength. However, we could not show a significant correlation between graft function and testosterone.

Conclusions: Serum testosterone level is correlated with hand-grip strength and C-reactive protein and albumin levels, which may indicate that testosterone affects nutritional status and inflammation in male renal transplant recipients.

Key words : C-reactive protein, Muscle weakness, Renal transplantation

Muscle weakness is a common problem in patients who are on maintenance hemodialysis. Although kidney transplantation is the criterion standard for patients with end-stage kidney disease, muscle weakness may continue, especially in the early posttransplant period. Muscle weakness is associated with several factors, including increased catabolism driven by inﬂammation, lack of physical activity, depression, prolonged hospitalization, secondary hyperparathyroidism, anemia, and steroid myopathy.¹

Serum testosterone, which decreases in patients with end-stage renal disease, is highly associated with muscle strength. It is well known that hypothalamopituitary and testicular dysfunction may recover after successful renal transplant; however, the extent of recovery is controversial.² The use of hand-grip strength to assess muscle strength has been reported to be reliable in dialysis patients and is correlated with lean body mass. In kidney transplant recipients, reduced muscle mass and hand-grip strength are associated with impaired nutritional status.

Reports on muscle weakness and hormonal dysfunction are scarce in kidney transplant recipients. In this study, we aimed to determine the associations among serum testosterone, hand-grip strength, and nutritional and inflammatory parameters as well as graft function in stable kidney transplant recipients.

Materials and Methods

This study included renal transplant recipients
who were regularly followed in the Nephrology Department of Baskent University Medical Faculty Ankara Hospital. Exclusion criteria included patients with gynecomastia, galactorrhea, testicular atrophy, acute graft rejection, graft failure (glomerular filtration rate of < 30 mL/min), posttransplant diabetes mellitus, and congestive heart failure. Patients who were using drugs that affected sex hormones (H2 receptor blockers, spironolactone, ketoconazole, benzodiazepines, tricyclic antidepressants, and opiates) were also excluded. Patients without regular follow-up data and those who had malignant disease, had rheumatologic or chronic inflammatory diseases of unknown origin, or had systemic vasculitis history and presence of active infection were also excluded. Our study included 144 stable male renal transplant recipients from our renal transplant outpatient clinic. The study was approved by the Ethical Review Committee of the Baskent University Faculty of Medicine. All of the protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration. Written informed consent was obtained from all participants.

We evaluated clinical parameters (age, duration of hemodialysis, posttransplant time), biochemical parameters (calcium, phosphorus, parathyroid hormone, C-reactive protein [CRP], albumin, creatinine), and serum testosterone levels of all study patients. Patient body composition was analyzed with the bioimpedance spectroscopy analysis technique using a body composition monitor (Fresenius Medical Care Deutschland GmbH, Germany), which estimates body mass index (BMI) and percent fat. Hand-grip strength was analyzed with a dynamometer (ProHealthcareProducts.com, Park City, UT, USA). We calculated the estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease-4 equation.³

Anthropometric measurements
For bioimpedance spectroscopy analysis, 4 electrodes were placed on the right hand and foot on the side contralateral to the arteriovenous fistula (if present) of supine patients. Two electrodes were dorsally placed on the hand in the metacarpophalangeal articulations and in the corpus, respectively, 5 cm apart. The electrode pair on the foot was located in the metatarsophalangeal and in the articulation, 6 cm apart. Dry weight, fat mass, fat-free mass, BMI, and muscle mass were analyzed.

Hand-grip strength
Hand-grip strength was evaluated using a Takei TKK 5401 digital hand-grip dynamometer (Takei Scientific Instruments Co., Ltd, Niigata, Japan). Maximum strength of the dominant hand was measured 3 times, and the highest recorded value was considered maximal grip strength.

Statistical analyses
Statistical analyses were performed with SPSS software (Statistical Package for the Social Sciences, version 11.0, SSPS Inc., Chicago, IL, USA). Normality of data was analyzed by using the Kolmogorov-Smirnov test. All numerical variables with normal distribution are expressed as means and standard deviation, whereas variables with skew distribution are expressed as medians and interquartile range. Categorical variables are expressed as percentages and compared by chi-square test. Normally distributed numeric variables were analyzed by independent sample t tests or one-way analysis of variance (post hoc Tukey test). Skew-distributed numeric variables were compared using the Mann-Whitney U test and the Kruskal-Wallis tests. Spearman and Pearson correlation tests were used for correlation analyses. A P value < .05 was considered statistically significant.

Demographic characteristics, duration of dialysis before transplant, biochemical parameters (serum calcium, phosphorus, lipid profile), and eGFR levels are shown in Table 1. Mean (SD) serum testosterone level was 588.0 (55.5) ng/mL, mean (SD) BMI was 26.8 (0.6) kg/m², and mean (SD) hand-grip strength was 42.2 (1.7) mm².

Serum testosterone levels were positively correlated with hand-grip strength (r = 0.445; P = .033) (Figure 1) and serum albumin (r = 0.399; P = .05) (Figure 2) and negatively correlated with serum CRP levels (r = -0.454; P = .05) and age (Table 2 and Figure 3).

In linear multiple regression analysis, serum albumin (P = .033) and testosterone levels (P = .038) were shown to be predictors of hand-grip strength. However, we could not demonstrate a significant correlation between graft function and testosterone.

Our present study is the first to reveal the associations among serum testosterone, hand-grip strength, and inflammation, which may indicate that testosterone can affect nutritional status and inflammation in male renal transplant recipients.

The high prevalence of hypogonadism and inflammation in patients who are on maintenance hemodialysis has been reported in previous studies.^4,5 Although successful renal transplant leads to improved testosterone levels, immunosuppression and underlying comorbidities may contribute to impaired gonadal function compared with healthy individuals.^6,7 On the other hand, similar to the chicken or the egg phenomenon, nutritional status and inflammation also result in impaired testosterone in male renal transplant recipients. In our study, we only included patients who were receiving the same immunosuppressive protocol (prednisolone, mycophenolate mofetil, and calcineurin inhibitors), which have negligible effects on the hypothalamic-pituitary-gonadal axis. We excluded patients who were receiving sirolimus because of its possible negative effect on serum testosterone.

It is well-known that restoration of kidney function by renal transplant improves CRP, a common finding with chronic inflammation.⁸ In the present study, serum testosterone levels were all within normal ranges and positively correlated with CRP in male renal transplant recipients. A previous study that compared renal replacement therapies reported improved gonadal function and CRP levels in recipients,⁹ similar to our present study. In addition, a previous study showed a negative association between testosterone concentration and serum inflammation that was independent of age in patients with end-stage renal disease.¹⁰ Also in support, Malkin and associates demonstrated that testosterone replacement in hypogonadal men with diabetes or coronary disease shifts the cytokine balance to a state of reduced inflammation.¹¹ Moreover, previous trials have also shown improved testosterone levels after resolution of inflammation.¹²

Another finding of our study was the significant positive association between serum testosterone and albumin, which may be both related to inflammation and nutrition. Our results supported a previous study that showed reduced inflammatory cytokines and increased albumin levels after normalization of testosterone levels.¹³

It is well documented that testosterone actively induces muscle protein synthesis and has anabolic effects.¹⁴ Although measurements of the muscle compartment are difﬁcult by traditional methods, hand-grip strength has been shown to be useful for assessment of the functional status of general muscles. Previous studies detected a positive correlation between testosterone and hand-grip strength in healthy elderly men^15,16 and male nonrenal patients.^17,18 Gungor and associates demonstrated that the association between endogenous testosterone and mortality was the result of aging in patients who were on hemodialysis.¹⁹ However, a recent study found that serum total testosterone was an independent determinant of muscle mass in men undergoing hemodialysis.²⁰ To our knowledge, our present study is the first to show the associations among testosterone, muscle strength, and inflammation in male renal transplant recipients. We believe that the underlying disease of end-stage renal disease, social isolation, immunosuppression with steroid treatment, and inadequate physical activity may result in decreased muscle mass or muscle atrophy in male renal transplant recipients compared with healthy men.

Reports showing an association between serum testosterone and graft function are scarce. A heart transplant study detected the relation between low testosterone and allograft vasculopathy.²¹ A retrospective study identified a cohort of men with low testosterone levels at the time of transplant who had significantly reduced graft survival in the early posttransplant period.²² In our present study, we could not demonstrate an association between testosterone and graft function. This may due to the untimed collection of blood samples, as most serum testosterone levels improve early after transplant.

There are several limitations of the study. First is its cross-sectional design, with inherent lack of pretransplant data and small sample size. Second, samples were not collected on the same day after transplant; therefore, results may be affected by the diurnal variations of testosterone. In addition, we did not evaluate proteinuria, which can affect graft function and survival.

In conclusion, we showed that the serum testosterone level is positively correlated with hand-grip strength and with albumin and negatively correlated with CRP, indicating that testosterone may affect nutritional status and inflammation in male kidney transplant recipients. Larger studies starting from the pretransplant period should be designed to obtain more information on inflammation, skeletal muscle strength, and gonadal function.

Volume: 16 Issue: 1 March 2018 - Supplement - 1

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