Effects of mTOR inhibitor–related proteinuria on progression of cardiac allograft vasculopathy and outcomes among heart transplant recipients

We have previously described the use of sirolimus (SRL) as primary immunosuppression following heart transplantation (HT). The advantages of this approach include attenuation of cardiac allograft vasculopathy (CAV), improvement in glomerular filtration rate (GFR), and reduced malignancy. However, in some patients SRL may cause significant proteinuria. We sought to investigate the prognostic value of proteinuria after conversion to SRL. CAV progression and adverse clinical events were studied. CAV progression was assessed by measuring the Δ change in plaque volume (PV) and plaque index (PI) per year using coronary intravascular ultrasound. Proteinuria was defined as Δ urine protein ≥300 mg/24 h at 1 year after conversion to SRL. Overall, 137 patients were analyzed (26% with proteinuria). Patients with proteinuria had significantly lower GFR (P = .005) but similar GFR during follow-up. Delta PV (P < .001) and Δ PI (P = .001) were significantly higher among patients with proteinuria after adjustment for baseline characteristics. Multivariate Cox regression analysis showed higher all-cause mortality (hazard ratio 3.8; P = .01) with proteinuria but similar risk of CAV-related events (P = .61). Our results indicate that proteinuria is a marker of baseline renal dysfunction, and that HT recipients who develop proteinuria after conversion to SRL have less attenuation of CAV progression and higher mortality risk.     

Predictors and Outcomes of Renal Replacement Therapy After Left Ventricular Assist Device Implantation

ObjectiveTo examine the frequency and outcomes of patients requiring renal replacement therapy (RRT) early after left ventricular assist device (LVAD) implantation.Patients and MethodsWe examined use of in-hospital RRT and outcomes in consecutive adults who underwent continuous-flow LVAD implantation from February 15, 2007, through August 8, 2017. Logistic regression was used to examine predictors of RRT. The associations of RRT with outcomes were examined using Cox proportional hazards regression.ResultsOf 354 patients who underwent LVAD implantation, 54 (15%) required in-hospital RRT. Patients receiving RRT had higher preoperative Charlson Comorbidity Index values (median, 5 vs 4; P=.03), Model for End-Stage Liver Disease scores (mean, 19.0 vs 14.5; P<.001), right atrial pressure (mean, 19.1 vs 13.4 mm Hg; P<.001), and estimated 24-hour urine protein levels (median, 357 vs 174 mg; P<.001) and lower preoperative estimated glomerular filtration rate (eGFR) (median, 43 vs 57 mL/min; P<.001) and measured GFR using ¹²⁵I-iothalamate clearance (median, 33 vs 51 mL/min; P=.001) than those who did not require RRT. Approximately 40% of patients with eGFR less than 45 mL/min/1.73 m² and 24-hour urine protein level greater than 400 mg required RRT vs 6% with eGFR greater than45 mL/min/1.73 m² and without significant proteinuria. Lower preoperative eGFR, higher estimated 24-hour urine protein level, higher right atrial pressure, and longer cardiopulmonary bypass time were independent predictors of RRT after LVAD implantation. Of patients requiring in-hospital RRT, 18 (33%) had renal recovery, 18 (33%) required outpatient hemodialysis, and 18 (33%) died before hospital discharge. After median (Q1, Q3) follow-up of 24.3 (8.9, 49.6) months, RRT was associated with increased risk of death (adjusted hazard ratio [HR], 2.86; 95% CI, 1.90-4.33; P<.001) and gastrointestinal bleeding (adjusted HR, 4.47; 95% CI, 2.57-7.75; P<.001).ConclusionIn-hospital RRT is associated with poor prognosis after LVAD. A detailed preoperative assessment of renal function before LVAD may be helpful in risk stratification and patient selection.     

Immune Modulation in Heart Failure: the Promise of Novel Biologics

Purpose of review

Immune system activation plays a central role in heart failure progression. Large-scale immune modulatory clinical trials targeting tumor necrosis factor-α and broad spectrum immune modulation have been negative. The objective of this review is to highlight past, present, and what is in the horizon for the immunomodulation in heart failure with a focus of biologics.

Recent findings

Strategies targeting interleukin-1 pathway are currently undergoing clinical evaluation and data from pilot studies are promising. The potential of cell therapy for immune modulation is increasingly recognized in clinical trials. Strategies targeting anti-cardiac antibodies such as immunoadsorption and intravenous immunoglobulin have been used in clinical practice with positive outcomes but large pragmatic clinical trials are lacking. The use of an aptamer to block anti-cardiac antibodies is undergoing phase 1 clinical evaluation. Promising targets include inflammasomes, toll-like receptors, chemokines, natural killer cells, and macrophages.

Summary

Large-scale immune modulatory clinical trials have been negative. Nevertheless, the experience gained from them along with increasing understanding of molecular mechanisms of immune pathophysiology in heart failure is leading to rapid recognition of new therapeutic targets and approaches.

     

Syndrome of inappropriate antidiuretic hormone secretion due to recurrent oral cancer

Hyponatremia is a common metabolic disorder in clinical practice and is associated with significant morbidity and mortality, especially among the elderly. Hyponatremia resulting from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has been reported in association with neoplasia (including a few reports in patients with head and neck malignancies) and may represent a paraneoplastic condition. Patients with SIADH present with signs and symptoms that cannot be explained by the primary tumour mass effect or its metastases. We describe a 67-year-old male patient with oral squamous-cell carcinoma of recent recurrence admitted because of symptomatic severe hyponatremia resulting from SIADH and discuss the principles of the diagnostic approach and appropriate management.