The consequences of treatment for the kidney at the molecular level have not been explored in human lupus nephritis (LN). In this investigation, changes in intra-renal transcript expression were measured and correlated with response in a LN cohort that underwent serial kidney biopsies. The intra-renal transcript expression of 19 patients with proliferative LN (Class III or IV) was measured at diagnostic biopsy (Bx1) and after induction therapy was completed (Bx2) using Nanostring® technology. Patients were segregated by clinical response into complete responders (n=5, CR) or nonresponders (n=4, NR). Transcript expression for each biopsy was compared to normal controls (n=4) and the change in expression was compared in each responder group and between groups. Compared to controls, the CR group had 21 and 28 while NR had 45 and 103 differentially-expressed transcripts at Bx1 and Bx2, respectively. The profiles of these differentially-expressed genes indicated that the type I and II interferon, alternative complement and T cell signaling pathways discriminated CR from NR. Comparing the change in transcript expression from Bx1 to Bx2 revealed a 5-gene signature that differentiated NR from CR and included increased IL1RAP and FCAR in NR and increased NCAM1 in CR. In summary, molecular imaging of serial kidney biopsies from LN patients shows several immune and inflammatory pathways that are dysregulated in the kidneys during active disease that may serve as therapeutic targets to improve clinical response. This approach to LN biomarker development may facilitate personalized medicine in LN and improve long-term kidney outcomes.

IntroductionThe kidney biopsy is used to diagnose and guide initial therapy in patients with lupus nephritis (LN). Kidney histology does not correlate well with clinical measurements of kidney injury or predict how patients will respond to standard-of-care immunosuppression. We postulated that the gene expression profile of kidney tissue at the time of biopsy may differentiate patients who will from those who will not respond to treatment.MethodsThe expression of 511 immune-response genes was measured in kidney biopsies from 19 patients with proliferative LN and 4 normal controls. RNA was extracted from formalin-fixed, paraffin-embedded kidney biopsies done at flare. After induction therapy, 5 patients achieved a complete clinical response (CR), 10 had a partial response (PR) and 4 patients were non-responders (NRs). Transcript expression was compared with normal controls and between renal response groups.ResultsA principal component analysis showed that intrarenal transcript expression from normal kidney, CR biopsies and NR biopsies segregated from each other. The top genes responsible for CR clustering included several interferon pathway genes (STAT1, IRF1, IRF7, MX1, STAT2, JAK2), while complement genes (C1R, C1QB, C6, C9, C5, MASP2) were mainly responsible for NR clustering. Overall, 35 genes were uniquely expressed in NR compared with CR. Pathway analysis revealed that interferon signalling and complement activation pathways were upregulated in both groups, while BAFF, APRIL, nuclear factor-κB and interleukin-6 signalling were increased in CR but suppressed in NR.ConclusionsThese data suggest that molecular profiling of the kidney biopsy at LN flare may be useful in predicting treatment response to induction therapy.

Both warfarin and dabigatran increase systolic BP in rats. The mechanism of this effect is not clear, but our data suggest that it is related to decreased thrombin activity associated with anticoagulant treatment. The superoxide scavenger NAC delayed, but did not prevent, warfarin-induced hypertension.

There are numerous examples of when the media grossly exaggerated the risk of medical treatments to the detriment of public health and health care. What are the causes of such ‘medical hysteria’ and what could prevent it?

PurposeTo identify factors associated with successful sacral nerve stimulator (SNS) trial after SNS implantation for the treatment of medication refractory overactive bladder (OAB).MethodsPatients undergoing treatment for OAB at Lahey Hospital and Medical Center between 2004 and 2016 were identified. Patients undergoing SNS placement were identified; SNS success was defined as permanent implantation of the SNS. Demographic, clinical and treatment data were extracted from patient charts; uni- and multivariate analyses were conducted to identify factors associated with SNS treatment success.ResultsA total of 128 patients were included. On univariate analysis, male sex, prior diagnosis of benign prostatic hyperplasia, and lower volume at first urge on urodynamics (UDS) were associated with unsuccessful SNS trial. On multivariate analysis, male sex (odds ratio [OR], 0.145; 95% confidence interval [CI], 0.036–0.530) and lower volume at first urge on UDS (OR, 0.982; 95% CI, 0.967–0.995) were associated with unsuccessful SNS trial. A threshold value of 100 mL at first urge during preoperative UDS had a specificity of 0.86 in predicting SNS success in men.ConclusionsSNS is frequently successful at relieving OAB symptoms. Male patients and those with lower volumes at first urge on UDS, particularly below 100 mL, are more likely to have an unsuccessful SNS trial. Patients in these groups should be counseled on the lower likelihood of SNS success.