Non-immune interventions to protect kidney allografts in the long term

Chronic rejection, the primary cause of late renal allograft loss, results from a complex interplay between immunological and non-immunological factors. During the past few decades, transplant research has focused almost exclusively on identifying more powerful and minimally toxic immunosuppressive strategies to prevent acute rejection and alloimmune response toward the graft, whereas poor attention has been paid to non-immunological factors. However, the discrepancy between remarkable improvements in the prevention of acute rejection and failure to ameliorate long-term graft outcomes suggests that non-immunological injuries may have an important role in the progressive loss of graft function. As kidney graft resembles the remnant kidney, in which a low nephron mass initiates a self-perpetuating process of progressive renal function loss, the same therapeutic tools able to retard progression of chronic renal disease are expected to be effective in kidney transplant patients as well. Indeed, high blood pressure (BP) levels, along with increased urinary protein excretion and hyperlipidemia, have been associated with reduced graft survival. Hence, strict BP control, renin-angiotensin system blockade to reduce proteinuria, and statins for hyperlipidemia control should probably represent the standard of care for kidney transplant patients. Furthermore, a multimodal nephroprotective strategy that includes smoking cessation, and tight glucose control for diabetes, might eventually be crucial to improve long-term graft outcomes.     

Efficacy of cyclosporine A treatment in relapsing febrile lobular panniculitis associated with small vessel vasculitis

Weber-Christian Disease (WCD), also known as relapsing febrile lobular non-suppurative panniculitis, is a rare condition characterized by recurrent subcutaneous inflammatory nodules in the adipose tissue in addition to fever, malaise and other systemic manifestations such as polyarthralgia and polymyalgia. The association with small vessel vasculitis has been rarely reported. We report here an unusual case of WCD associated with small vessels vasculitis also describing the efficacy of Cyclosporin A treatment.     

Liver diseases in Mexico and their associated mortality trends from 2000 to 2007: A retrospective study of the nation and the federal states

Introduction. Liver disease is a major health issue in Mexico. Although several studies have been performed to analyze the impact of liver diseases on the Mexican population, none has compared the prevalence and impact of liver disease between states within Mexico. AIM: To analyze trends in mortality associated with liver diseases from 2000 to 2007 at the national and state levels.Methods. Data was obtained from the Ministry of Health (number of deaths) and the National Population Council (CONAPO) (population at risk) and mortality rates were analyzed using statistical software.Results. Mortality due to viral hepatitis, liver tumors, and cirrhosis increased over the study period. Alcohol-related mortality decreased but was still the main cause of liver-related deaths. Viral hepatitis infection occurred predominantly in the northern states and liver tumors occurred predominantly in the central region. Alcohol-related deaths were elevated along the Pacific shoreline and deaths associated with cirrhosis occurred mainly in the central and southern states.Conclusion. Incidence of liver-related mortality has increased and will continue to do so in the future.     

ABCB1 Genotypes Predict Cyclosporine-Related Adverse Events and Kidney Allograft Outcome

Cyclosporine A (CsA) is a substrate of P-glycoprotein, an efflux transporter encoded by the ABCB1 gene. Compared with carriers of the wild-type gene, carriers of T allelic variants in exons 21 or 26 have reduced P-glycoprotein activity and, secondarily, increased intracellular concentration of CsA; therefore, carriers of T variants might be at increased risk for CsA-related adverse events. We evaluated the associations between ABCB1 genotypes (in exons 12, 21, and 26) and CsA-related outcomes in 147 renal transplant recipients who were receiving CsA-based immunosuppression and were included in the Mycophenolate Steroids Sparing study. During a median of 65.5 mo follow-up, carriers of T allelic variants in exons 21 or 26 had a three-fold risk for delayed graft function (DGF), a trend to slower recovery of renal function and lower GFR at study end, and significantly higher incidences of new-onset diabetes and cytomegalovirus reactivation compared with carriers of the wild-type genotype. T variants in both exons 21 and 26 were independently associated with 3.8- and 3.5-fold higher risk for DGF, respectively (P = 0.022 and P = 0.034). The incidence of acute rejection and the mean CsA dose and blood levels were comparable in genotype groups. In conclusion, renal transplant recipients with T allelic variants in ABCB1 exons 21 or 26 are at increased risk for CsA-related adverse events. Genetic evaluation may help to identify patients at risk and to modulate CsA therapy to optimize graft and patient outcomes.The introduction of cyclosporine A (CsA) therapy in the early 1980s opened a new era in organ transplantation. Compared with steroid- and azathioprine-based regimens, immunosuppressive protocols including this inhibitor of calcineurin—a key enzyme involved in T cell activation¹—decreased the incidence of acute rejections from 40% to 50% to 20% to 30% and increased one-year survival rates of the grafts from 60% to between 80% and 90%.² Thirty years later, CsA remains a cornerstone of immunosuppressive therapy for recipients of both renal and nonrenal transplants worldwide. However, standard recommended doses are associated with nephrotoxicity, resulting in delayed graft function (DGF) and progressive renal function deterioration in the long term.^3,4 Moreover, CsA worsens glucose tolerance and lipid profile; increases systemic BP; and, similarly to other immunosuppressants, enhances the risk of opportunistic infections, lymphoproliferative disorders, and cancer.^1,5To minimize side effects without increasing the risk of rejection, treatment is titrated to target CsA blood levels according to well established guidelines.⁶ However, the therapeutic index remains narrow, whereas the frequency and severity of CsA-related adverse effects are considerably variable among patients, even at comparable CsA levels.^1,6 This suggests the possibility that a heterogeneous individual susceptibility may result in increased risk in some patients despite exposure to CsA levels that in the majority of cases are devoid of significant toxicity.⁶ Thus, identifying markers or predictors of individual response to CsA therapy might help to tailor CsA therapy and optimize the risk/benefit profile of CsA-based immunosuppression.Drug efficacy and tolerability are influenced by several factors, including the activity of proteins and enzymes involved in drug transport and metabolism.⁷ CsA is a substrate of an efflux transporter—the P-glycoprotein (P-gp) encoded by the multidrug resistance-1 gene (now referred as ABCB1)—which actively transports lipophilic drugs and other xenobiotics from the intracellular to the extracellular domain.⁸ This transporter is expressed in lymphocytes,⁹ and in other leukocytes,¹⁰ as well as in hepatocytes and on the brush border of enterocytes and proximal tubular cells.⁸ Reduced expression or functional inhibition of this efflux-pump invariably results in increased intracellular and tissue drug concentrations,^8,9 but may have unpredictable effects on CsA blood levels. Indeed, CsA blood levels increased, decreased, or did not change in different settings, likely because of different balances between enhanced distribution into the tissue compartment and decreased excretion into the gastrointestinal lumen or urinary tract.⁷ Increased CsA concentrations in lymphocytes,¹¹ polymorphonuclear cells,¹² and other circulating leukocytes¹³ have been associated with increased production and release of reactive oxygen species (ROS). ROS production by leukocytes is the primary defense against invading micro-organisms, but has also been involved in the pathogenesis of ischemia-reperfusion damage of engrafted tissues or organs.^3,14 Thus, increased intracellular CsA disposition with enhanced ROS production might amplify oxidative stress and tissue damage to the graft after reperfusion.¹⁵ Increased intralymphocyte drug concentration is also associated with more effective inhibition of lymphocyte proliferation by CsA in vitro,¹⁶ an effect that, in vivo, might translate into more effective protection against graft rejection,¹⁷ but also into excess risk of opportunistic infections, lymphoproliferative disorders, or cancer.P-glycoprotein expression and activity are reduced in carriers of one or two T allelic variants in exons 12, 21, and 26 as compared with carriers of the wild-type ABCB1 gene.^8,18,19 Thus, at comparable CsA exposure, carriers of the allelic variants are expected to have higher intracellular and tissue CsA levels than wild-type carriers and, conceivably, should be exposed to more, and more severe, CsA-related events. We formally tested this hypothesis in a large cohort of renal transplant recipients prospectively monitored in the setting of a randomized, controlled, clinical trial, the Mycophenolate Steroids Sparing (MYSS) study, which aimed to compare the risk/benefit profile of mycophenolate mofetil and azathioprine therapy in immunosuppressive regimens including the CsA microemulsion Neoral.²⁰     

Bortezomib-induced peripheral neurotoxicity: a neurophysiological and pathological study in the rat

Bortezomib is a new proteasome inhibitor with a high antitumor activity, but also with a potentially severe peripheral neurotoxicity. To establish a preclinical model and to characterize the changes induced on the peripheral nerves, dorsal root ganglia (DRG) and spinal cord, bortezomib was administered to Wistar rats (0.08, 0.15, 0.20, 0.30 mg/kg/day twice [2q7d] or three times [3q7d] weekly for a total of 4 weeks). At baseline, on days 14, 21 and 28 after the beginning the treatment period and during a 4-week follow-up period sensory nerve conduction velocity (SNCV) was determined in the tail of each animal. Sciatic nerve, DRG and spinal cord specimens were processed for light and electron microscope observations and morphometry. At the maximum tolerated dose bortezomib induced a significant reduction in SNCV, with a complete recovery at the end of the follow-up period. Sciatic nerve examination and morphometric determinations demonstrated mild to moderate pathological changes, involving predominantly the Schwann cells and myelin, although axonal degeneration was also observed. Bortezomib-induced changes were also observed in DRG and they were represented by satellite cell intracytoplasmatic vacuolization due to mitochondrial and endoplasmic reticulum damage, closely resembling the changes observed in sciatic nerve Schwann cells. Only rarely did the cytoplasm of DRG neurons has a dark appearance and clear vacuoles occurring in the cytoplasm. Spinal cord was morphologically normal. This model is relevant to the neuropathy induced by bortezomib in the treatment of human malignancies and it could be useful in increasing our knowledge regarding the mechanisms underlying bortezomib neurotoxicity.     

Cellular prion protein regulates the motor behaviour performance and anxiety-induced responses in genetically modified mice

The cellular prion protein (PrP(C)) is a sialoglycoprotein involved in neuroplasticity processes and synaptic transmission. This study investigated behavioural responses (balance in the rota-rod test at 24 rpm, motility in the open-field test, anxiety in the elevated plus-maze test) in Zurich developed wild-type adult mice (WT, controls of normal PrP(C) expression), in knockout (KO) mice (Prnp(0/0), with no PrP(C) expression), and in PrP(C) overexpressing Tg-20 mice. After 8 min in the rota-rod test, Tg-20 animals presented significantly fewer falls (1.08+/-1.56 falls) than both WT (7.27+/-4.36) and KO (7.6+/-6.15) mice (p<0.01). In the open field test, Tg-20 animals showed significantly increased motility [rearing=23.4+/-7.85, crossing=97.30+/-32.11) when compared with KO mice (rearing=5.45+/-3.69 and crossing=59.73+/-15.43) or WT mice (rearing=6.5+/-20.23 and crossing=45.18+/-20.33) (p<0.01). In the elevated plus-maze test, Tg-20 mice showed less anxiety (head projections=7.3+/-1.62) when compared with WT animals (3.38+/-0.67) (p<0.05). Moreover, KO mice spent more time in the centre of the plus maze (37.80+/-5.57 s) than did WT mice (22.57+/-3.82) (p<0.05). PrP(C) overexpressing mice evoked increased motility, less anxiety, and increased equilibrium when compared with WT control animals in the behavioural protocols used. KO animals also tended to evoke fewer anxiety-related responses in the elevated plus-maze test. These findings indicate that the levels of PrP(C) in adult life are associated with possible changes in motility, anxiety, and equilibrium.