With expanding kidney transplantation programs, remaining hemodialysis patients are more likely to have a high comorbidity burden and may therefore be more prone to lose muscle mass. Our aim was to analyze risk factors for muscle loss in hemodialysis patients with high comorbidity. Fifty-four chronic hemodialysis patients (Charlson Comorbidity Index 9.0 ± 3.4) were followed for 20 weeks using 4-weekly measurements of lean tissue mass, intracellular water, and body cell mass (proxies for muscle mass), handgrip strength (HGS), and biochemical parameters. Mixed models were used to analyze covariate effects on LTM. LTM (−6.4 kg, interquartile range [IQR] −8.1 to −4.8), HGS (−1.9 kg, IQR −3.1 to −0.7), intracellular water (−2.11 L, IQR −2.9 to −1.4) and body cell mass (−4.30 kg, IQR −5.9 to −2.9) decreased in all patients. Conversely, adipose tissue mass increased (4.5 kg, IQR 2.7 to 6.2), resulting in no significant change in body weight (−0.5 kg, IQR −1.0 to 0.1). Independent risk factors for LTM loss over time were male sex (−0.26 kg/week, 95% CI −0.33 to −0.19), C-reactive protein above median (−0.1 kg/week, 95% CI −0.2 to −0.001), and baseline lean tissue index ≥10th percentile (−1.6 kg/week, 95% CI −2.1 to −1.0). Age, dialysis vintage, serum albumin, comorbidity index, and diabetes did not significantly affect LTM loss over time. In this cohort with high comorbidity, we found universal and prominent muscle loss, which was further accelerated by male sex and inflammation. Stable body weight may mask muscle loss because of concurrent fat gain. Our data emphasize the need to assess body composition in all hemodialysis patients and call for studies to analyze whether intervention with nutrition or exercise may curtail muscle loss in the most vulnerable hemodialysis patients.

Background.: In HLA-incompatible kidney transplantation, the efficacy of desensitization in terms of anti-HLA antibody kinetics is not well characterized. We present an overview of the course of anti-HLA antibodies throughout plasma exchange (PE) desensitization in a series of crossmatch-positive patients. Methods.: All consecutive candidates in the Dutch HLA-incompatible kidney transplantation program between November 2012 and January 2022 were included. The eligibility criteria were a positive crossmatch with a living kidney donor and no options for compatible transplantation. Desensitization consisted of 5–10 PE with low-dose IVIg. Results.: A total of 16 patient-donor pairs were included. Patients had median virtual panel-reactive antibody of 99.58%. Cumulative donor-specific anti-HLA antibody (cumDSA) mean fluorescence intensity (MFI) was 31 399 median, and immunodominant DSA (iDSA) MFI was 18 677 for class I and 21 893 for class II. Median anti-HLA antibody MFI response to desensitization was worse in class II as compared with class I (P < 0.001), particularly for HLA-DQ. Class I cumDSA MFI decreased 68% after 4 PE versus 53% in class II. The decrease between the fifth and the 10th PE sessions was modest with 21% in class I versus 9% in class II. Antibody-mediated rejection occurred in 85% of patients, with the iDSA directed to the same mismatched HLA as before desensitization, except for 3 patients, of whom 2 had vigorous rebound of antibodies to repeated mismatches (RMMs). Rebound was highest (86%) in RMM-DSA with prior grafts removed (transplantectomy n = 7), lower (39%) in non-RMM-DSA (n = 30), and lowest (11%) for RMM-DSA with in situ grafts (n = 5; P = 0.018 for RMM-DSA transplantectomy versus RMM-DSA graft in situ). With a median follow-up of 59 mo, 1 patient had died resulting in a death-censored graft survival of 73%. Conclusions.: Patients with class II DSA, and particularly those directed against HLA-DQ locus, were difficult to desensitize.

The early stage of hypertension increases so-called damage-associated molecular patterns (DAMPs). In turn, DAMPs can activate Toll-like receptors (TLRs) and thereby exacerbate hypertension. Although various TLRs have been implicated in the pathogenesis of salt-sensitive hypertension, the role of TLR2 and TLR4 remains unclear. Here, we hypothesize that TLR2 or TLR4 deficiency protects against salt-sensitive hypertension. To address this, we treated wild-type (WT, n=3), TLR2 ^-/- (n=5) and TLR4 ^-/- (n=5) mice with deoxycorticosterone acetate and 0.9% NaCl as drinking water (DOCA-salt) for four weeks. Baseline telemetric mean arterial blood pressure (MAP) was slightly but non-significantly higher in TLR4 ^-/- (108±2 mmHg) and TLR2 ^-/- mice (111±3 mm Hg) compared with WT mice (99±5 mmHg). MAP peaked similarly after two weeks in WT and TLR4 ^-/- mice (111±1 vs. 116±3 mmHg; both P<0.05 vs. baseline), but reduced after four weeks (108±3 vs. 110±2 mmHg). In contrast, TLR2 ^-/- mice displayed a much greater rise in MAP to DOCA-salt and remained hypertensive after two weeks (134±5 mmHg) and after four weeks (128±4 mmHg; P<0.0001 vs. baseline; P<0.05 for delta MAP vs. TLR4 ^-/- ). Kidney sodium transporter analysis showed that the phosphorylated (activated) form of the sodium-chloride cotransporter (NCC) was 2.4-fold higher in TLR2 ^-/- compared with WT mice (P<0.05). In wire myographs of iliac arteries, angiotensin II-induced constriction was non-significantly lower in iliac arteries of TLR4 ^-/- mice (53±9%) than in TLR2 ^-/- (84±9%) and WT mice (84±15%). Addition of the nitric oxide synthase blocker L-NAME increased the contractile response to Ang II in WT mice, but not in TLR2 ^-/- mice, indicating NO deficiency in the latter mice. The Ang II type 2 (AT2) receptor blocker PD123319 blunted the effects of Ang II in both WT and TLR2 ^-/- mice, suggesting that DOCA-salt upregulates constrictor AT2 receptors, but not in TLR4 ^-/- mice. In conclusion, TLR2 deficiency unexpectedly exacerbates experimental salt-sensitive hypertension. This effect appears to involve increased renal sodium reabsorption through NCC, decreased vascular availability of nitric oxide and a constrictive rather than a vasodilatory response to AT2 receptor stimulation.