The paradox of bardoxolone methyl: a call for every witness on the stand?

People with type 2 diabetes and chronic kidney disease (CKD) remain an extremely vulnerable population with increased cardiovascular morbidity, mortality and mounting societal costs. As such, any effort to improve their dismal outcome is heavily supported. Yet, most drugs fail to replicate the promising signals of early experiments in humans in large and methodologically sound trials. As a recent example, an independent data and safety committee advised the termination of a phase 3 trial due to excessive cardiovascular disease and especially heart failure in patients allocated to the antioxidant synthetic triterpenoid bardoxolone methyl versus placebo. We evaluate the reasons why this outcome in hindsight was possibly not totally unexpected and develop a mechanistic model that shows that the consistent drop in serum magnesium concentration in patients exposed to bardoxolone methyl might have contributed to the development of heart failure. As such, this trial, despite its negative outcome, might provide additional pieces of the puzzle enabling us to get a better grip on diseases that share increased inflammation and oxidative stress, such as type 2 diabetes, metabolic syndrome, heart failure and CKD.

Immediate posttransplantation cotrimoxazole-induced immune thrombocytopenia.

Drug-induced immune thrombocytopenia (DITP) can be caused by numerous drugs. When this condition develops, platelet destruction results from binding of antibodies to normal platelets only in the presence of a sensitizing drug. A recently proposed model suggests that these drug-dependent antibodies are derived from a pool of naturally occurring antibodies with weak affinity for specific epitopes on certain platelet membrane glycoproteins. We describe here a case of DITP secondary to cotrimoxazole exposure in the immediate posttransplantation phase in a renal transplant recipient. Apart from heparin-induced thrombocytopenia, DITP posttransplantation has to the best of our knowledge never been described, perhaps because of its immune-mediated origin. Our case demonstrates that DITP can occur posttransplantation, that cotrimoxazole due to its intensive use in the transplanted population is one of the most likely causative agents and that a timely recognition and treatment might have important consequences for both graft and patient.

Posttransplantation hypomagnesemia and its relation with immunosuppression as predictors of new-onset diabetes after transplantation.

New-onset diabetes after transplantation (NODAT) is a frequent complication and has an impact on patient and graft survival. Hypomagnesemia is common in both renal transplant recipients and in diabetics. This study examines the relationship between hypomagnesemia, NODAT and the type of immunosuppression in renal transplant recipients. We conducted a retrospective single-center analysis (2002-2008) in order to assess NODAT the first year posttransplantation as defined by American Diabetes Association criteria. Serum magnesium (Mg) levels were defined as the median of all Mg levels registered during the first month posttransplantation. Patients with NODAT (N = 75; 29.5%) versus non-NODAT had lower Mg levels (p < 0.001). Patients with an Mg level < versus > or = 1.9 mg/dL showed a faster development of NODAT (log-rank p < 0.001). Mg levels were lower in patients on calcineurin inhibitors (CNI) versus no CNI patients (p < 0.001). Mg levels, albumin, BMI, triglycerides, posttransplantation hyperglycemia, tacrolimus levels and the use of sirolimus were predictors of NODAT in the multivariate analysis. Hypomagnesemia was an independent predictor of NODAT in renal transplant recipients. We confirm that the use of CNI is associated with NODAT, but, to a large extent, this effect seems attributable to the induction of hypomagnesemia. After adjustment for Mg, sirolimus was also associated with NODAT.

Acute kidney injury in solid organ transplant recipients.

Delayed and slow graft function (DGF/SGF) in de novo kidney transplantation endanger outcomes of graft and patient, while predisposing the patient to acute rejection and lesser graft function. Causes and work-up of DGF/SGF are described in the present paper. Also, the epidemiology and pathophysiology of chronic renal failure both in kidney graft recipients and in recipients of other solid organs is discussed, especially in relation to calcineurin inhibitor (CNI) immunosuppression. An acute kidney injury event will have a greater and faster impact on impaired renal reserve in case of chronic renal failure. Major causes of acute kidney injury (AKI) of the native kidneys of solid organ recipients and of the transplanted kidney are: severe infections, acute toxic kidney injury caused by CNI treatment concomitant CYP450 3A4 inhibiting medication, toxic and infectious events inducing haemolytic uraemic syndrome, toxic rhabdomyolysis, acute interstitial nephritis, rapid IV immunoglobulin infusion and exposure to other well-known nephrotoxins, such as NSAIDs, amphotericin and aminoglycosides.

Right atrial thrombus in an asymptomatic hemodialysis patient with malfunctioning catheter and patent foramen ovale.

The creation of an accurate functioning arteriovenous fistula has been a long-lasting problem in the hemodialysis setting. In spite of recent guidelines and largely because of the old age of the current dialysis population and a high incidence of diabetes mellitus, atherosclerosis, and related vascular problems, it is not always possible to create an adequate fistula. In that case, long-term tunneled indwelling central vein catheters are a frequently used alternative. Of the many possible complications related to venous access in hemodialysis patients, catheter dysfunction is the most prevalent. We report a 23-year-old female hemodialysis patient in whom such malfunctioning was followed by echocardiography that revealed a large right atrial thrombus (RAT) in close contact to the tip of a long-term indwelling catheter in the presence of a patent foramen ovale. Although RAT is a rare complication in hemodialysis patients, it has very specific therapeutic implications. The present patient underwent a successful surgical atrial thrombectomy. Our experience underscores that in cases of malfunctioning catheter, echocardiographic screening is mandatory.

Delayed gastric emptying in dyspeptic chronic hemodialysis patients.

Hemodialysis patients frequently experience such dyspeptic symptoms as nausea, vomiting, abdominal distension, early satiety, and anorexia. Gastroparesis might be a cause of malnutrition, and parameters of gastric emptying are inversely correlated with serum albumin levels. The aim of the present study is to determine whether delayed gastric emptying is related to dyspeptic symptoms. In 54 hemodialysis patients, a standardized history for dyspeptic symptoms was taken. In addition, gastric emptying for solids was measured in 26 patients, using the (13)C-octanoic acid breath test. There was a high prevalence of dysmotility-like dyspepsia in the hemodialyzed population. A significant difference in gastric emptying between dyspeptic hemodialysis patients and healthy volunteers and between dyspeptic and nondyspeptic hemodialysis patients was shown. There was a significant correlation between gastric emptying and dysmotility-like dyspepsia. Serum albumin level inversely correlated with gastric emptying. In conclusion, there is a high prevalence of dysmotility-like dyspepsia in hemodialysis patients. Dyspeptic patients have significantly delayed gastric emptying compared with both healthy volunteers and nondyspeptic patients.