Incidence of De Novo Post-Transplant Malignancies in Thai Adult Kidney Transplant Recipients: A Single-Center, Population-Controlled, Retrospective Cohort Study at the Highest Volume Kidney Transplant Center in Thailand

Kidney transplant recipients (KTRs) are at increased risk of developing de novo post-transplant malignancies (PTMs), with regional differences in types with excess risk compared to the general population. A single-center, population-controlled, retrospective cohort study was conducted at a tertiary care center in Thailand among all adults who underwent their first kidney transplant from 1986 to 2018. Standardized incidence ratios (SIRs) of malignancy by age, sex, and place of residence were obtained using data from the National Cancer Registry of Thailand as population control. There were 2,024 KTRs [mean age, 42.4 years (SD 11.4); female patients, 38.6%] during 16,495 person-years at risk. Of these, 125 patients (6.2%) developed 133 de novo PTMs. The SIR for all PTMs was 3.85 (95% CI 3.22, 4.56), and for pooled solid and hematologic PTMs, it was 3.32 (95% CI 2.73, 3.99). Urothelial malignancies had the largest excess risk, especially in women [female SIR 114.7 (95% CI 66.8, 183.6); male SIR 17.5 (95% CI 8.72, 31.2)]. The next two most common cancers were non-Hodgkin’s lymphoma and skin cancer [SIR 20.3 (95% CI 13.6, 29.1) and 24.7 (95% CI 15.3-37.8), respectively]. Future studies are needed to identify the risk factors and assess the need for systematic screening among PTMs with excess risk in KTRs

Transient Induction of ANG II-Dependent Malignant Hypertension Causes Sustained Elevation of Blood Pressure and Augmentation of the Pressor Response to ANG II in CYP1A1-REN2 Transgenic Rats

BACKGROUND: Transgenic rats with inducible expression of the mouse Ren2 renin gene [strain name: TGR(Cyp1a1Ren2)] allow induction of various degrees of ANG II-dependent hypertension. Dietary administration of the aryl hydrocarbon indole-3-carbinol (I3C) at a dose of 0.15% induces a slowly developing form of ANG II-dependent hypertension whereas dietary administration of a higher dose (0.3%) of I3C results in the development of ANG II-dependent malignant hypertension. Cessation of administration of 0.15% I3C results in the normalization of blood pressure, indicating the reversibility of hypertension induced by this dose of I3C. The present study was performed to determine if ANG II-dependent malignant hypertension is similarly reversible following cessation of dietary administration of 0.3% I3C. METHODS: Cyp1a1-Ren2 rats (n=6) were fed a normal diet containing 0.3% I3C for 11 days to induce malignant hypertension. RESULTS: Cyp1a1-Ren2 rats induced with I3C exhibited pronounced increases in systolic blood pressure (SBP) (132±3 to 229±11 mmHg, P<0.001) and marked decreases in body weight (303±4 to 222±2 g, P<0.001). When I3C administration was terminated, SBP decreased to 167±4 mmHg (P<0.01) and body weight increased to normal levels (309±2 g, P<0.01) within 12 days. However, SBP remained significantly elevated (172±1 mmHg, P<0.01) for up to 3 weeks following termination of dietary administration of 0.3% I3C. In addition, the magnitude of the blood pressure response to intravenous bolus administration of 50 ng of ANG II (50 μl in volume) 3 weeks following cessation of dietary I3C administration was substantially higher than that observed in normotensive control rats (134±1 mmHg, n=6) not previously induced with 0.3% I3C (53±2 vs. 38±3 mmHg, P<0.05). CONCLUSIONS: The present findings demonstrate that transient induction of ANG II-dependent malignant hypertension results in prolonged elevations of arterial blood pressure and marked augmentation of the magnitude of the pressor response to ANG II in Cyp1a1-Ren2 transgenic rats

Characteristics and outcomes of hospitalised patients with vertebral fragility fractures: a systematic review

Background: The complex management for patients presenting to hospital with vertebral fragility fractures provides justification for the development of specific services for them. A systematic review was undertaken to determine the incidence of hospital admission, patient characteristics, and health outcomes of vertebral fragility fracture patients to inform the development of such a service. Methods: Non-randomised studies of vertebral fragility fracture in hospital were included. Searches were conducted using electronic databases and citation searching of the included papers. Results: 19 studies were included. The incidence of hospital admission varied from 2.8-19.3 per 10,000/year. The average patient age was 81 years, the majority having presented with a fall. A diagnosis of osteoporosis or previous fragility fracture was reported in around one third of patients. Most patients (75% men and 78% women) had five or more co-pathologies. Most patients were managed non-operatively with a median hospital length of stay of 10 days. One third of patients were started on osteoporosis treatment. Inpatient and one year mortality was between 0.9-3.5%, and 20–25% respectively: between 34-50% were discharged from hospital to a care facility. Many patients were more dependent with activities of daily living on discharge compared to their pre-admission level. Older age and increasing comorbidities was associated with longer hospital stay and higher mortality. Conclusion: These findings indicate that specific hospital services for patients with vertebral fragility fractures should take into consideration local hospitalisation rates for the condition, and should be multifaceted - providing access to diagnostic, therapeutic, surgical and rehabilitation interventions

Direct Renin Inhibition With Aliskiren Normalizes Blood Pressure in Cyp1a1-Ren2 Transgenic Rats With Inducible Angiotensin II-Dependent Malignant Hypertension

BACKGROUND: Cyp1a1-Ren2 transgenic rats [strain name: TGR(Cyp1a1Ren2)], administered indole-3-carbinol (I3C) develop angiotensin (ANG) II-dependent hypertension due to hepatic expression of the Ren2 renin gene. Although AT(1) receptor blockade prevents the development of hypertension and normalizes the elevated arterial blood pressure of Cyp1-Ren2 rats, little information is available regarding the blood pressure and renal functional responses to direct inhibition of renin in this high circulating renin model of ANG II-dependent hypertension. The present study was performed to determine the effects of acute direct renin inhibition with aliskiren on blood pressure and renal hemodynamics in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension. METHODS: Mean arterial pressure (MAP) and renal hemodynamics were measured in pentobarbital-anesthetized male Cyp1a1-Ren2 rats during control conditions and following administration of the renin inhibitor, aliskiren (10 mg/kg, iv). RESULTS: Rats induced with I3C had higher MAP (194±7 vs. 141±2 mmHg, P<0.001), lower renal plasma flow (RPF; 2.47±0.23 vs. 4.17±0.35 ml/min.g, P<0.001), and lower glomerular filtration rate (GFR; 1.01±0.07 vs. 1.34±0.06 ml/min.g, P=0.01) than noninduced Cyp1a1-Ren2 rats (n=5). Aliskiren administration decreased MAP (194±7 to 136±2 mmHg, P<0.001) and increased RPF (2.47±0.23 vs. 4.31±0.20 ml/min.g, P<0.001) in hypertensive but not in normotensive rats, without altering GFR. CONCLUSIONS: Acute renin inhibition with aliskiren normalizes MAP and RPF in Cyp1a1-Ren2 rats with malignant hypertension. The normalization of MAP and RPF following acute renin inhibition indicates that renin generated by expression of the Ren2 gene is responsible for the maintenance of malignant hypertension and the associated reduction in renal hemodynamic function in Cyp1a1-Ren2 rats

Enhanced Urinary Angiotensinogen Excretion in Cyp1a1-Ren2 Transgenic Rats With Inducible ANG II-Dependent Malignant Hypertension

BACKGROUND: Previous studies have demonstrated that the urinary excretion of angiotensinogen is significantly increased in ANG II-infused hypertensive rats, which is associated with an augmentation of intrarenal ANG II levels. These findings suggest that urinary angiotensinogen excretion rates provide an index of intrarenal ANG II levels in ANG II-dependent hypertensive states. However, little information is available regarding the urinary excretion of angiotensinogen in ANG II-dependent malignant hypertension. METHODS: The present study was performed to determine if urinary angiotensinogen excretion is increased in Cyp1a1-Ren2 transgenic rats [strain name: TGR(Cyp1aRen2)] with inducible ANG II-dependent malignant hypertension. Adult male Cyp1a1-Ren2 rats (n=6) were fed a normal diet containing 0.3% indole-3-carbinol (I3C) for 10 days to induce ANG II-dependent malignant hypertension. RESULTS: Rats induced with I3C exhibited pronounced increases in systolic blood pressure (SBP) (208±7 vs. 127±3 mmHg, P<0.001), marked proteinuria (29.4±3.6 vs. 5.9±0.3 mg/day, P<0.001), and augmented urinary angiotensinogen excretion (996±186 vs. 241±31 ng/day, P<0.01). Chronic administration of the AT(1) receptor antagonist, candesartan (25 mg/L in drinking water, n=6), prevented the I3C-induced increases in SBP (125±5, P<0.001), proteinuria (7.3±1.0 mg/day, p<0.001) and urinary angiotensinogen excretion (488±51 ng/day, P<0.01). CONCLUSIONS: These data demonstrate that the urinary excretion of angiotensinogen is markedly augmented in ANG II-dependent malignant hypertension. Such increased urinary angiotensinogen excretion may contribute to augmented intrarenal ANG II levels and, thereby, to the increased blood pressure in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension

Irreversible renal damage after transient renin-angiotensin system stimulation:involvement of an AT1-receptor mediated immune response

Transient activation of the renin-angiotensin system (RAS) induces irreversible renal damage causing sustained elevation in blood pressure (BP) in Cyp1a1-Ren2 transgenic rats. In our current study we hypothesized that activation of the AT1-receptor (AT1R) leads to a T-cell response causing irreversible impairment of renal function and hypertension. Cyp1a1-Ren2 rats harbor a construct for activation of the RAS by indole-3-carbinol (I3C). Rats were fed a I3C diet between 4-8 weeks of age to induce hypertension. Next, I3C was withdrawn and rats were followed-up for another 12 weeks. Additional groups received losartan (20 mg/kg/day) or hydralazine (100 mg/kg/day) treatment between 4-8 weeks. Rats were placed for 24h in metabolic cages before determining BP at week 8, 12 and 20. At these ages, subsets of animals were sacrificed and the presence of kidney T-cell subpopulations was investigated by immunohistochemistry and molecular marker analysis. The development of sustained hypertension was completely prevented by losartan, whereas hydralazine only caused a partial decrease in BP. Markers of renal damage: KIM-1 and osteopontin were highly expressed in urine and kidney samples of I3C-treated rats, even until 20 weeks of age. Additionally, renal expression of regulatory-T cells (Tregs) was highly increased in I3C-treated rats, whereas the expression of T-helper 1 (Th1) cells demonstrated a strong decrease. Losartan prevented these effects completely, whereas hydralazine was unable to affect these changes. In young Cyp1a1-Ren2 rats AT1R activation leads to induction of an immune response, causing a shift from Th1-cells to Tregs, contributing to the development of irreversible renal damage and hypertension

Activation of Thiazide-Sensitive Co-Transport by Angiotensin II in the cyp1a1-Ren2 Hypertensive Rat

Transgenic rats with inducible expression of the mouse Ren2 gene were used to elucidate mechanisms leading to the development of hypertension and renal injury. Ren2 transgene activation was induced by administration of a naturally occurring aryl hydrocarbon, indole-3-carbinol (100 mg/kg/day by gastric gavage). Blood pressure and renal parameters were recorded in both conscious and anesthetized (butabarbital sodium; 120 mg/kg IP) rats at selected time-points during the development of hypertension. Hypertension was evident by the second day of treatment, being preceded by reduced renal sodium excretion due to activation of the thiazide-sensitive sodium-chloride co-transporter. Renal injury was evident after the first day of transgene induction, being initially limited to the pre-glomerular vasculature. Mircoalbuminuria and tubuloinsterstitial injury developed once hypertension was established. Chronic treatment with either hydrochlorothiazide or an AT1 receptor antagonist normalized sodium reabsorption, significantly blunted hypertension and prevented renal injury. Urinary aldosterone excretion was increased ∼20 fold, but chronic mineralocorticoid receptor antagonism with spironolactone neither restored natriuretic capacity nor prevented hypertension. Spironolactone nevertheless ameliorated vascular damage and prevented albuminuria. This study finds activation of sodium-chloride co-transport to be a key mechanism in angiotensin II-dependent hypertension. Furthermore, renal vascular injury in this setting reflects both barotrauma and pressure-independent pathways associated with direct detrimental effects of angiotensin II and aldosterone

AT1 Receptor Blockade Prevents the Increase in Blood Pressure and the Augmentation of Intrarenal ANG II Levels in Hypertensive Cyp1a1-Ren2 Transgenic Rats Fed With a High-Salt Diet

BACKGROUND: The present study was performed to determine the effects of high-salt diet on the magnitude of the increases in systolic blood pressure (SBP) and kidney tissue ANG II levels that occur following induction of ANG II-dependent malignant hypertension in Cyp1a1-Ren2 transgenic rats with inducible expression of the mouse Ren2 renin gene [strain name: TGR (Cyp1a1Ren2)]. METHODS: Cyp1a1-Ren2 rats (n=6) were fed a normal diet containing 0.3% indole-3-carbinol (I3C) for 10 days to induce ANG II-dependent malignant hypertension. RESULTS: Rats induced with I3C exhibited increases in (SBP) and elevations of ANG II levels in kidney cortex and medulla. In a second group of rats (n=6), high salt intake alone did not alter basal SBP; however, subsequent dietary administration of 0.3% I3C during continued high salt intake elicited a substantially greater increase in SBP than observed in rats fed a normal salt diet. ANG II levels in kidney cortex and medulla of rats induced with I3C and fed a high salt diet were elevated similarly to those in rats induced with I3C alone. Chronic administration of the AT(1) receptor antagonist, losartan (100 mg/L in drinking water, n=6), markedly attenuated the I3C-induced increase in SBP and prevented the augmentation of ANG II levels in kidney cortex and medulla in rats induced with I3C and maintained on a high salt diet. CONCLUSIONS: Activation of AT(1) receptors contributes to the augmented blood pressure and elevated kidney tissue ANG II levels that occur in Cyp1a1-Ren2 transgenic rats with malignant hypertension maintained on a high salt diet