Calcineurin inhibitors (CNIs) are immunosuppressive drugs, which are used widely to prevent rejection of transplanted organs and treat autoimmune disease. Hypertension and renal tubule dysfunction, including hyperkalemia, hypercalciuria, and acidosis often complicate their use1,2. These side effects resemble familial hyperkalemic hypertension (FHHt), a genetic disease characterized by overactivity of the renal sodium chloride co-transporter (NCC), and caused by mutations in WNK kinases. We hypothesized that CNIs induce hypertension by stimulating NCC. In wild-type mice, the CNI tacrolimus caused salt-sensitive hypertension and increased the abundance of phosphorylated NCC, and the NCC regulatory kinases WNK3, WNK4, and SPAK. The functional importance of NCC in this response was demonstrated by showing that tacrolimus did not affect blood pressure in NCC knockout mice, whereas the hypertensive response to tacrolimus was exaggerated in mice over-expressing NCC. Moreover, hydrochlorothiazide reversed tacrolimus-induced hypertension. In kidney transplant recipients treated with tacrolimus, fractional chloride excretion in response to bendroflumethiazide was greater than in controls, and renal NCC abundance was also greater, extending these observations to humans. Together, these findings indicate that tacrolimus-induced hypertension is mediated largely by NCC activation, and suggest that inexpensive and well-tolerated thiazide diuretics may be especially effective in preventing the complications of CNI treatment.

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Introduction: Protein energy wasting is closely related to increased morbidity and mortality in peritoneal dialysis (PD) patients. Simple reliable and easily available methods of determining nutritional status and recognition of short-term changes in body composition are therefore important for clinical practice. Methods: We compared whole-body and segmental composition using multifrequency bioelectrical impedance analysis (MF-BIA) and dual-energy X-ray absorptiometry (DEXA) in 104 stable PD patients. Results: Assessment of whole-body composition showed that lean body mass (LBM) was highly correlated with good method agreement using DEXA as the reference test (r = 0.95, p < 0.0001; bias –0.88 kg, 95% CI –1.53 to 0.23 kg). Similarly, high correlation and good method agreement were found for fat mass (r = 0.93, p < 0.0001; bias 0.69 kg, 95% CI 0.03–1.36 kg). Segmental analysis of LBM revealed strong correlations between LBM for trunk, left and right arms and legs (r = 0.90, 0.84, 0.86, 0.89 and 0.90, respectively, p < 0.0001). Bone mineral content derived by MF-BIA overestimated that measured by DEXA (bias 0.740 kg, 95% CI 0.66–0.82 kg). Conclusion: MF-BIA may potentially be a useful tool for determining nutritional status in PD patients and serial estimations may help recognize short-term changes in body composition.

Cyclooxygenases, particularly COX-2, play an important role in tumor development and progression. We have previously shown that COX-2 expression is an independent prognostic factor in human ovarian carcinoma. In this study, we investigated the effects of the inhibition of COX isoforms by the NSAID NS-398 as well as by COXisoform-specific RNA interference (RNAi) in the human ovarian carcinoma cell lines OVCAR-3 and SKOV-3. OVCAR-3 cells showed a constitutive expression of COX-1 and an induction of high levels of COX-2 and PGE 2 after stimulation with interleukin-1b. In contrast, SKOV-3 cells were negative for both COX isoforms. In OVCAR-3 cells, PGE 2 production was inhibited by NS-398 in concentrations of 1 lm and by a COX-2-specific silencing RNA (siRNA), while a COX-1-specific siRNA did not have an effect. This suggests that COX-2 is the major source of PGE 2 in this cell line. To dissociate COX-2-specific and non-COX-2-specific effects on cell proliferation, a proliferation assay was performed after incubation of cells with NS-398 and COX siRNAs. NS-398 induced an inhibition of cell proliferation at concentrations of 50-500 lm, which are above the concentrations needed for the inhibition of PGE 2 production. This inhibitory effect was present in the COX-positive cell line OVCAR-3 as well as in the COX-negative cell line SKOV-3 and could not be reverted by addition of exogenous PGE 2 . Neither COX-1-nor COX-2-specific siRNAs had an effect on cell proliferation of OVCAR-3 cells. Cell cycle analysis showed an increased accumulation of cells in the G0/G1 phase after treatment with NS-398, but not with COX siRNAs. These experiments suggest that NS-398 reduced cell proliferation in ovarian carcinoma cells by induction of G0/G1 cell cycle arrest independent of COX-2 inhibition. Our study shows that specific inhibition of COX isoforms by RNAi could be used to dissociate effects of NSAIDs. Furthermore, our results suggest that cell cycle arrest is one of the primary mechanisms responsible for the antiproliferative effects of NS-398 on ovarian carcinoma cells.

Background/Aims-By contrast with animal models, in most cases it is not possible to examine the systemic response in patients in the first hours after onset of acute pancreatitis. The aim was to determine whether endoscopic retrograde cholangiopancreaticography (ERP)-induced pancreatitis can be used as a human model for the study ofcytokine release and acute phase response in the first hours of the disease. Patients and methods-Seventy consecutive patients undergoing ERP for different reasons were prospectively evaluated by sampling blood before and 0, 1, 4, 12, 24, and 48 hours after ERP and, in patients who developed an acute post-ERP pancreatitis, daily until C reactive protein (CRP) was within normal range. A post-ERP pancreatitis was defined as a threefold increase of amylase or lipase and at least two of the clinical symptoms: abdominal pain, nausea, vomiting, and peritonism during 24 hours after ERP. Results-Nine out of 70 patients developed an acute pancreatitis. Cytokines and other biochemical variables were measured in those nine and in 34 patients out of the 61 not developing pancreatitis. In the nine patients amylase and lipase increased within the first hour after ERP with maximum values between four and 12 hours. Interleukin-6 increased to maximal concentrations after 24-48 hours and the highest CRP concentrations were found 72 hours after ERP. Tumour necrosis factor did not change. Conclusion-Post-ERP pancreatitis is an ideal model in which to examine the initial cytokine and acute phase response in the first hours after the initiation of the disease.

Background/Aims: Dual energy X-ray absorptiometry (DEXA) scanning is used to assess bone mineral content and diagnose osteoporosis. We had noted anecdotal cases of patients attending for DEXA scanning following recent ingestion of barium-containing radiocontrast media, resulting in spuriously increased bone mineral content. Lanthanum carbonate is prescribed to chronic kidney disease patients as a non-calcium-containing phosphate binder, and as lanthanum is denser than barium, we wondered whether this could affect DEXA scan bone mineral estimations. Methods: DEXA scan records were reviewed from a cohort of 169 chronic dialysis patients, 24 (14%) of whom were prescribed lanthanum carbonate. Results: Estimation of segmental bone mineral content by DEXA was similar between the groups for the arms, legs, ribs, thoracic spine, hips and pelvis, apart from the lumbar spine for which it was greater for the lanthanum group (1.05 ± 0.05 vs. 0.98 ± 0.01 gm/cm², p < 0.05). Similarly, T and Z scores were higher in the lanthanum group for the lumbar spine (T score: –0.2 ± 0.4 vs. –0.92 ± 0.1; Z score: 0.68 ± 0.4 vs. –0.01 ± 0.1; p < 0.05), but not different for the hip (T score: –1.108 ± 0.28 vs. –0.966 ± 0.09; Z: score –0.49 ± 0.25 vs. –0.3 ± 0.01). Conclusion: DEXA scanning in patients prescribed lanthanum can lead to an erroneously high estimation of bone mineral content in areas of the skeleton adjacent to the bowel when the electron beam meets lanthanum.

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