Effect of renin-angiotensin-aldosterone system inhibition, dietary sodium restriction, and/or diuretics on urinary kidney injury molecule 1 excretion in nondiabetic proteinuric kidney disease: a post hoc analysis of a randomized controlled trial

BACKGROUND: Tubulointerstitial damage plays an important role in chronic kidney disease (CKD) with proteinuria. Urinary kidney injury molecule 1 (KIM-1) reflects tubular KIM-1 and is considered a sensitive biomarker for early tubular damage. We hypothesized that a decrease in proteinuria by using therapeutic interventions is associated with decreased urinary KIM-1 levels. STUDY DESIGN: Post hoc analysis of a randomized, double-blind, placebo-controlled, crossover trial. SETTING & PARTICIPANTS: 34 proteinuric patients without diabetes from our outpatient renal clinic. INTERVENTION: Stepwise 6-week interventions of losartan, sodium restriction (low-sodium [LS] diet), their combination, losartan plus hydrochlorothiazide (HCT), and the latter plus an LS diet. OUTCOMES & MEASUREMENTS: Urinary excretion of KIM-1, total protein, and N-acetyl-beta-d-glucosaminidase (NAG) as a positive control for tubular injury. RESULTS: Mean baseline urine protein level was 3.8 +/- 0.4 (SE) g/d, and KIM-1 level was 1,706 +/- 498 ng/d (increased compared with healthy controls; 74 ng/d). KIM-1 level was decreased by using placebo/LS (1,201 +/- 388 ng/d; P = 0.04), losartan/high sodium (1,184 +/- 296 ng/d; P = 0.09), losartan/LS (921 +/- 176 ng/d; P = 0.008), losartan/high sodium plus HCT (862 +/- 151 ng/d; P = 0.008) and losartan/LS plus HCT (743 +/- 170 ng/d; P = 0.001). The decrease in urinary KIM-1 levels paralleled the decrease in proteinuria (R = 0.523; P < 0.001), but not blood pressure or creatinine clearance. 16 patients reached target proteinuria with protein less than 1 g/d, whereas KIM-1 levels normalized in only 2 patients. Urinary NAG level was increased at baseline and significantly decreased during the treatment periods of combined losartan plus HCT only. The decrease in urinary NAG levels was not closely related to proteinuria. LIMITATIONS: Post hoc analysis. CONCLUSIONS: Urinary KIM-1 level was increased in patients with nondiabetic CKD with proteinuria and decreased in parallel with proteinuria by using losartan, sodium restriction, their combination, losartan plus HCT, and the latter plus sodium restriction. These results are consistent with the hypothesis of amelioration of proteinuria-induced tubular damage. Long-term studies are warranted to evaluate whether targeting treatment on KIM-1 can improve outcomes in patients with CKD with proteinuria.     

A case of longitudinally extensive transverse myelitis (LETM): neuromyelitis optica

Neuromyelitis optica (NMO), characterised by longitudinally extensive transverse myelitis (LETM), was previously thought to be a variant of multiple sclerosis. Transverse myelitis may be a manifestation of autoimmune connective tissue diseases and NMO is now recognised to be a humorally mediated autoimmune disease. We present a case of NMO associated with non-organ-specific autoantibodies and the absence of the characteristic NMO-IgG antibody. Our case provides an opportunity to review the diagnostic criteria of NMO and its distinction from other autoimmune and demyelinating conditions. We report successful treatment with plasmapheresis and rituximab in NMO-IgG-negative relapsing disease.     

Successful use of subcutaneous anakinra in hemophagocytic lymphohistiocytosis precipitated by candidiasis in a patient with systemic lupus erythematosus: A case report and description of a novel therapeutic regimen

Hemophagocytic lymphohistiocytosis (HLH) is a rare and often fatal condition characterized by inappropriate immune system activation leading to a “cytokine storm”, and ultimately resulting in end-organ damage. Causes include primary defects in genes involved in immune-mediated cytolytic pathways, or secondary triggers such as infection or malignancy. We describe a case of HLH precipitated by fungal infection which occurred as a consequence of immunosuppression for management of systemic lupus erythematosus (SLE) and necrotizing myopathy. The patient presented with immune-mediated disease of the muscles and lung which was treated with high-dose corticosteroids and aggressive immunosuppression. HLH emerged in the context of confirmed candidiasis and features of severe sepsis. The patient responded rapidly to antifungal therapy and high-dose anakinra, which was administered subcutaneously and progressively weaned over 4 weeks. She completed HLH treatment as an outpatient and remains well at 12 months with controlled SLE and no recurrence of HLH.     

CMV in critically ill patients: pathogen or bystander?

Despite broad variability in study populations, methodologies for CMV detection, and analytic methods used, multiple studies have documented frequent CMV infection in non-immunocompromised adults with critical illness due to a variety of causes. Higher rates of CMV infection in studies of seropositive patients suggest that reactivation of latent infection rather than primary infection is the main mechanism in this setting. Risk factors for CMV reactivation (other than seropositivity) have not been clearly defined and there does not appear to be a consistent association with severity of illness. Furthermore, CMV reactivation in this setting has been associated with important adverse clinical outcomes, including increased duration of mechanical ventilation, longer length of stay and all-cause mortality. There are several biologically plausible mechanisms that could link CMV reactivation with adverse outcomes, including: direct lung injury (CMV pneumonia), amplification of inflammation systemically and within the lung, or predisposition to other nosocomial infections, but clinical data in the ICU setting are limited. Further observational studies are unlikely to significantly advance our understanding of the role of CMV in critically ill patients. Given the significant impact of critical illness, limited current therapeutic options, the availability of generally well-tolerated antiviral options for CMV, and the clinical data supporting a possible pathogenic role for CMV, there is a strong rationale for a randomised controlled trial of CMV prevention as a novel means of improving the outcomes of critically ill patients.     

Identification of medically important yeasts using PCR-based detection of DNA sequence polymorphisms in the internal transcribed spacer 2 region of the rRNA genes

Identification of medically relevant yeasts can be time-consuming and inaccurate with current methods. We evaluated PCR-based detection of sequence polymorphisms in the internal transcribed spacer 2 (ITS2) region of the rRNA genes as a means of fungal identification. Clinical isolates (401), reference strains (6), and type strains (27), representing 34 species of yeasts were examined. The length of PCR-amplified ITS2 region DNA was determined with single-base precision in less than 30 min by using automated capillary electrophoresis. Unique, species-specific PCR products ranging from 237 to 429 bp were obtained from 92% of the clinical isolates. The remaining 8%, divided into groups with ITS2 regions which differed by /=99%. Seven clinical isolates contained ITS2 sequences that did not agree with their phenotypic identification, and ITS2-based phylogenetic analyses indicate the possibility of new or clinically unusual species in the Rhodotorula and Candida genera. This work establishes an initial database, validated with over 400 clinical isolates, of ITS2 length and sequence polymorphisms for 34 species of yeasts. We conclude that size and restriction analysis of PCR-amplified ITS2 region DNA is a rapid and reliable method to identify clinically significant yeasts, including potentially new or emerging pathogenic species.