Phase II prefusion non-stabilised Covid-19 mRNA vaccine randomised study.

ChulaCov19 mRNA vaccine demonstrated promising phase 1 results. Healthy adults aged 18-59 years were double-blind randomised 4:1 to receive two intramuscular doses of ChulaCov19 50 µg or placebo. Primary endpoints were safety and microneutralization antibody against-wild-type (Micro-VNT50) at day 50. One hundred fifty adults with median (IQR) age 37 (30-46) years were randomised. ChulaCov19 was well tolerated, and most adverse events were mild to moderate and temporary. Geometric mean titres (GMT) of neutralizing titre against wild-type for ChulaCov19 on day 50 were 1367 IU/mL. T-cell IFN-γ-ELISpot showed the highest responses at one week (Day29) after dose 2 then gradually declined. ChulaCov19 50 µg is well tolerated and elicited high neutralizing antibodies and strong T-cell responses in healthy adults.Trial registration number: ClinicalTrials.gov Identifier NCT04566276, 28/09/2020.

Therapeutic drug monitoring of mycophenolic acid and clinical outcomes of lupus nephritis: a systematic review and meta-analysis.

INTRODUCTION: Mycophenolic acid (MPA) is a primary immunosuppressive agent used in the treatment of lupus nephritis (LN). While therapeutic drug monitoring (TDM) of MPA is well established in organ transplantation, its role in LN treatment remains uncertain. Our objective was to review and summarise current knowledge on TDM of MPA in the LN treatment. METHODS: A systematic search was conducted in the online databases, specifically targeted patients diagnosed with LN receiving MPA treatment. The included studies had to report both MPA pharmacokinetic parameters and renal outcomes. A random-effects model meta-analysis was conducted to assess the relationship between clinical responses and MPA pharmacokinetics. RESULTS: A total of 1507 studies were initially screened, resulting in the inclusion of 16 studies for meta-analysis, encompassing 433 patients. The response group exhibited significantly higher MPA area under the concentration-time curve (AUC) compared with the non-response group (51.44±21.73 mg·h/L vs 30.30±16.24 mg·h/L). The weighted mean difference (WMD) of MPA-AUC between responders and non-responders was 16.83 mg·h/L (95% CI 10.59 to 23.06; p<0.001). Similarly, trough concentration (C0) of MPA showed a strong association with renal response, evidenced by C0 values of 2.50±1.73 mg/L in the response group vs 1.51±1.33 mg/L in the non-response group (WMD 1.37 mg/L; 95% CI 0.77 to 1.97; p<0.001). There was no significant relationship identified between MPA-AUC and adverse events. CONCLUSION: This meta-analysis emphasised the meaningful correlation between MPA AUC and C0 with renal response in LN treatment. Randomised controlled trials are necessary to validate this approach and determine its superiority over fixed dosing in the context of LN treatment.

Effect of canagliflozin in non-diabetic obese patients with albuminuria: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Sodium-glucose co-transporter 2 inhibitor (SGLT2i) has been shown to improve renal outcomes in both diabetic and non-diabetic kidney disease. However, the effect of SGLT2i on renal outcomes in patients with non-diabetic obesity is still not established. MATERIALS AND METHODS: In this double-blind, randomized controlled trial, we assigned non-diabetic patients with body mass index (BMI) ≥ 25 kg/m2, persistent 24-hour urine albumin-creatinine ratio (UACR) ≥ 10 mg/gCr, and estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m2, who had been treated with renin-angiotensin system blockade, to canagliflozin 100 mg daily or placebo for 24 weeks. The reduction in UACR and eGFR at 12 and 24 weeks were explored. (Thai Clinical Trials Registry 20190203003). RESULTS: Of 247 non-diabetic obese patients screened, 32 patients met inclusion criteria and underwent randomization. The median baseline of UACR was 69.1 mg/gCr. There were no statistically significant differences in albuminuria reduction between the groups at 12 weeks and 24 weeks. The estimated GFR in the canagliflozin group decreased significantly from baseline at 12 weeks (-5.39 mL/min/1.73m2; 95% CI -9.81 to -0.97; p = 0.017) but not at 24 weeks (-1.16 mL/min/1.73m2; 95% CI -5.58 to 3.26; p = 0.66), and there was no significant change from baseline in the placebo group at both 12 and 24 weeks. CONCLUSION: Canagliflozin 100 mg daily was well tolerated but did not significantly reduce UACR in non-diabetic obese patients with microalbuminuria. However, a significant temporary decline in eGFR might reflect a subtle reduction in glomerular hyperfiltration.

Complement Factor I Gene Variant in an Atypical Hemolytic Uremic Syndrome Triggered by Hypereosinophilia Syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a condition characterized by acute kidney injury (AKI), thrombocytopenia, and microangiopathic hemolytic anemia secondary to complement pathway dysregulation. Several triggers have been identified as causing aHUS in genetically susceptible patients; however, hypereosinophilia syndrome (HES)-triggered aHUS has not been reported. In this article, we present a case of aHUS presented with generalized urticarial rashes and angioedema. The initial investigations revealed hypereosinophilia (maximal absolute eosinophil count of 6,840 cells/µL) with normal bone-marrow analyses; hence, idiopathic HES was diagnosed. During hospitalization, the patient developed convulsion, stuporous, and full-blown thrombotic microangiopathy (TMA), with AKI requiring temporary hemodialysis. A kidney biopsy confirmed the existence of renal TMA. Next-generation sequencing of the coding regions of aHUS-related genes was performed, revealing an underlying complement factor I (CFI) deficiency, a heterozygous variant p.P64L of CFI gene. The patient was successfully treated with high-dose steroids and extended duration of plasmapheresis.

Safety and immunogenicity of a prefusion non-stabilized spike protein mRNA COVID-19 vaccine: a phase I trial.

Effective mRNA SARS-CoV-2 vaccines are available but need to be stored in freezers, limiting their use to countries that have appropriate storage capacity. ChulaCov19 is a prefusion non-stabilized SARS-CoV-2 spike-protein-encoding, nucleoside-modified mRNA, lipid nanoparticle encapsulated vaccine that we report to be stable when stored at 2-8 °C for up to 3 months. Here we report safety and immunogenicity data from a phase I open-label, dose escalation, first-in-human trial of the ChulaCov19 vaccine (NCT04566276). Seventy-two eligible volunteers, 36 of whom were aged 18-55 (adults) and 36 aged 56-75 (elderly), were enroled. Two doses of vaccine were administered 21 d apart at 10, 25 or 50 µg per dose (12 per group). The primary outcome was safety and the secondary outcome was immunogenicity. All three dosages of ChulaCov19 were well tolerated and elicited robust dose-dependent and age-dependent B- and T-cell responses. Transient mild/moderate injection site pain, fever, chills, fatigue and headache were more common after the second dose. Four weeks after the second dose, in the adult cohort, MicroVNT-50 geometric mean titre against wild-type SARS-CoV-2 was 848 (95% CI, 483-1,489), 736 (459-1,183) and 1,140 (854-1,522) IU ml-1 at 10, 25 and 50 µg doses, respectively, versus 285 (196-413) IU ml-1 for human convalescent sera. All dose levels elicited 100% seroconversion, with geometric mean titre ratios 4-8-fold higher than for human convalescent sera (P < 0.01), and high IFNγ spot-forming cells per million peripheral blood mononuclear cells. The 50 µg dose induced better cross-neutralization against Alpha, Beta, Gamma and Delta variants than lower doses. ChulaCov19 at 50 µg is well tolerated and elicited higher neutralizing antibodies than human convalescent sera, with strong T-cell responses. These antibodies cross-neutralized four variants of concern. ChulaCov19 has proceeded to phase 2 clinical trials. We conclude that the mRNA vaccine expressing a prefusion non-stabilized spike protein is safe and highly immunogenic.

Benefits of Switching Mycophenolic Acid to Sirolimus on Serological Response after a SARS-CoV-2 Booster Dose among Kidney Transplant Recipients: A Pilot Study.

Kidney transplant recipients (KTRs) have a suboptimal immune response to COVID-19 vaccination due to the effects of immunosuppression, mostly mycophenolic acid (MPA). This study investigated the benefits of switching from the standard immunosuppressive regimen (tacrolimus (TAC), MPA, and prednisolone) to a regimen of mammalian target of rapamycin inhibitor (mTORi), TAC and prednisolone two weeks pre- and two weeks post-BNT162b2 booster vaccination. A single-center, opened-label pilot study was conducted in KTRs, who received two doses of ChAdOx-1 and a single dose of BNT162b2. The participants were randomly assigned to continue the standard regimen (control group, n = 14) or switched to a sirolimus (an mTORi), TAC, and prednisolone (switching group, n = 14) regimen two weeks before and two weeks after receiving a booster dose of BNT162b2. The anti-SARS-CoV-2 S antibody level after vaccination in the switching group was significantly greater than the control group (4051.0 [IQR 3142.0-6466.0] BAU/mL vs. 2081.0 [IQR 1077.0-3960.0] BAU/mL, respectively; p = 0.01). One participant who was initially seronegative in the control group remained seronegative after the booster dose. These findings suggest humoral immune response benefits of switching the standard immunosuppressive regimen to the regimen of mTORi, TAC, and prednisolone in KTRs during vaccination.

Immunogenicity of the third and fourth BNT162b2 mRNA COVID-19 boosters and factors associated with immune response in patients with SLE and rheumatoid arthritis.

OBJECTIVES: To evaluate the safety and immunogenicity of third and fourth BNT162b2 boosters in patients with SLE and rheumatoid arthritis (RA). METHODS: Patients with SLE and RA aged 18-65 years who completed a series of inactivated, adenoviral vector, or heterogenous adenoviral vector/mRNA vaccines for at least 28 days were enrolled. Immunogenicity assessment was done before and day 15 after each booster vaccination. The third BNT162b2 booster was administered on day 1. Patients with suboptimal humoral response to the third booster dose (antireceptor-binding domain (RBD) IgG on day 15 <2360 BAU/mL) were given a fourth BNT162b2 booster on day 22. RESULTS: Seventy-one patients with SLE and 29 patients with RA were enrolled. The third booster raised anti-RBD IgG by 15-fold, and patients with positive neutralising activity against the Omicron variant increased from 0% to 42%. Patients with positive cellular immune response also increased from 55% to 94%. High immunosuppressive load and initial inactivated vaccine were associated with lower anti-RBD IgG titre. Fifty-four patients had suboptimal humoral responses to the third booster and 28 received a fourth booster dose. Although anti-RBD IgG increased further by sevenfold, no significant change in neutralising activity against the Omicron variant was observed. There were two severe SLE flares that occurred shortly after the fourth booster dose. CONCLUSIONS: The third BNT162b2 booster significantly improved humoral and cellular immunogenicity in patients with SLE and RA. The benefit of a short-interval fourth booster in patients with suboptimal humoral response was unclear. TRIAL REGISTRATION NUMBER: TCTR20211220004.

Comparison of Immunogenicity and Safety of Inactivated, Adenovirus-Vectored, and Heterologous Adenovirus-Vectored/mRNA Vaccines in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis: A Prospective Cohort Study.

Background: Impaired immune responses to COVID-19 vaccines have been observed in autoimmune rheumatic disease patients. Determining the most effective and safe vaccine regimen is critically needed in such a population. We aim to compare the immunogenicity and safety of three COVID-19 vaccine regimens in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Methods: SLE and RA patients aged 18−65 years who received inactivated (CoronaVac or COVILO), adenovirus-vectored (AZD1222), or heterogeneous (AZD1222/BNT162b2) vaccines were enrolled. Humoral and cellular immune responses were assessed at day 28 after the second vaccination. This was performed using the serum binding antibody level against the receptor-binding domain of the SARS-CoV-2 spike protein (anti-RBD Ig) and IFNy-ELISpot assay (ELISpot), respectively. Reactogenicity was reviewed on day 7 following each vaccination. Disease activity was assessed before and on day 28 after the second vaccination. Results: The cohort consisted of 94 patients (64 SLE and 30 RA). Inactivated, AZD1222, and AZD1222/BNT162b2 vaccines were administered to 23, 43, and 28 patients, respectively. Anti-RBD titers were lowest in the inactivated vaccine group (2.84 AU/mL; 95% CI 0.96−8.44), followed by AZD1222 (233.7 AU/mL; 95% CI 99.0−505.5), and AZD1222/BNT162b2 (688.6 AU/mL; 95% CI 271−1745), p < 0.0001. After adjusting for relevant factors, the inactivated vaccine was associated with the lowest humoral response, while adenovirus-vectored/mRNA vaccine was the highest. The proportion of positive ELISpot test was also lowest in the inactivated vaccine group (27%), followed by the adenovirus-vectored vaccine (67%), and the adenovirus-vectored/mRNA vaccine (73%) (p = 0.03). All types of vaccine were well-tolerated. There was no flare of autoimmune disease post-vaccination. Conclusion: Adenovirus-vectored and adenovirus-vectored/mRNA vaccines elicited a stronger humoral and cellular immune response than inactivated vaccines, suggesting that they may be more suitable in SLE and RA patients receiving immunosuppressive therapy.

Pharmacokinetics and pharmacodynamics profiles of enteric-coated mycophenolate sodium in female patients with difficult-to-treat lupus nephritis.

Relapsed or resistant lupus nephritis (LN) is considered a difficult-to-treat type of LN, and enteric-coated mycophenolate sodium (EC-MPS) has been used in this condition. Therapeutic drug monitoring using the area under the plasma mycophenolic acid concentration from 0 to 12 h postdose (MPA-AUC0-12h ) ≥45 µg.h/ml is a useful approach to achieve the highest efficiency. This study assessed EC-MPS's pharmacokinetic (PK) and pharmacodynamic (PD) profiles and investigated an optimal level of the single time point of plasma MPA concentration. Nineteen biopsy-proven patients with class III/IV LN received 1440 mg/day of EC-MPS for 24 weeks. PK (maximum plasma MPA concentration [Cmax ], time to Cmax , and MPA-AUC0-12h ) and PD (activity of inosine-5'-monophosphate dehydrogenase [IMPDH]) parameters were measured at weeks 2, 8, 16, and 24. We found that IMPDH activity decreased from baseline by 31-42% within 2-4 h after dosing, coinciding with the increased plasma MPA concentration. MPA-AUC0-12h ≥45 µg.h/ml was best predicted by a single time point MPA concentration at C0.5, C2, C3, C4, and C8 (r2  = 0.516, 0.514, 0.540, 0.611, and 0.719, respectively), independent of dose, albumin, urine protein/creatinine ratio, and urinalysis. The MPA-C0.5 cutoff of 2.03 g/ml yielded the highest overall sensitivity of 85% and specificity of 88.2% in predicting MPA-AUC0-12h ≥45 µg.h/ml. A single timepoint of plasma MPA-C0.5 ≥2.03 µg/ml may help guide EC-MPS adjustment to achieve adequate drug exposure. Further study of EC-MPS used to validate this cutoff is warranted.

Immunogenicity, safety and reactogenicity of a heterogeneous booster following the CoronaVac inactivated SARS-CoV-2 vaccine in patients with SLE: a case series.

Since the COVID-19 pandemic, CoronaVac, an inactivated SARS-CoV-2 vaccine, has been widely deployed in several countries for emergency use. However, the immunogenicity of the inactivated vaccine was relatively lower when compared to other vaccine types and was even more attenuated in autoimmune patients with rheumatic disease. A third-dose SARS-CoV-2 vaccination in immunosuppressed population is recommended in order to improve immune response. However, the data were limited to those initially received mRNA or viral vector SARS-CoV-2 vaccine. Thus, we aimed to describe the safety, reactogenicity and immunogenicity of patients with systemic lupus erythematosus (SLE) who received a heterogenous booster SARS-CoV-2 vaccine following the initial CoronaVac inactivated vaccine series. Our findings support that the third booster dose of mRNA or viral vector vaccine following the inactivated vaccine is well tolerated and elicited a substantial humoral and cellular immune response in inactive patients with SLE having maintenance immunosuppressive therapy without interruption of immunosuppressive medications.

Quantification of CYP3A and Drug Transporters Activity in Healthy Young, Healthy Elderly and Chronic Kidney Disease Elderly Patients by a Microdose Cocktail Approach.

Background: Ageing and chronic kidney disease (CKD) affect pharmacokinetic (PK) parameters. Since mechanisms are related and remain unclear, cytochrome P450 (CYP) 3A and drug transporter activities were investigated in the elderly with or without CKD and compared to healthy adults using a microdose cocktail. Methods: Healthy young participants (n = 20), healthy elderly participants (n = 16) and elderly patients with CKD (n = 17) received, in study period 1, a single dose of microdose cocktail probe containing 30 µg midazolam, 750 µg dabigatran etexilate, 100 µg atorvastatin, 10 µg pitavastatin, and 50 µg rosuvastatin. After a 14-day wash-out period, healthy young participants continued to study period 2 with the microdose cocktail plus rifampicin. PK parameters including area under the plasma concentration-time curve (AUC), maximum plasma drug concentration (Cmax), and half-life were estimated before making pairwise comparisons of geometric mean ratios (GMR) between groups. Results: AUC and Cmax GMR (95% confidence interval; CI) of midazolam, a CYP3A probe substrate, were increased 2.30 (1.70-3.09) and 2.90 (2.16-3.88) fold in healthy elderly and elderly patients with CKD, respectively, together with a prolonged half-life. AUC and Cmax GMR (95%CI) of atorvastatin, another CYP3A substrate, was increased 2.14 (1.52-3.02) fold in healthy elderly and 4.15 (2.98-5.79) fold in elderly patients with CKD, indicating decreased CYP3A activity related to ageing. Associated AUC changes in the probe drug whose activity could be modified by intestinal P-glycoprotein (P-gp) activity, dabigatran etexilate, were observed in patients with CKD. However, whether the activity of pitavastatin and rosuvastatin is modified by organic anion transporting polypeptide 1B (OATP1B) and of breast cancer resistance protein (BCRP), respectively, in elderly participants with or without CKD was inconclusive. Conclusions: CYP3A activity is reduced in ageing. Intestinal P-gp function might be affected by CKD, but further confirmation appears warranted. Clinical Trial Registration:http://www.thaiclinicaltrials.org/ (TCTR 20180312002 registered on March 07, 2018).

SLCO1B1 and ABCG2 Gene Polymorphisms in a Thai Population.

INTRODUCTION: Genetic polymorphisms of drug transporters influence drug transporter activity and alter pharmacokinetic profiles of the drugs. Organic anion transporting polypeptide 1B1 (OATP1B1) and breast cancer resistance protein (BCRP) are important transporters encoded by solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene and ATP-binding cassette subfamily G member 2 (ABCG2) gene, respectively. Polymorphisms in these genes are associated with increased plasma statins concentrations, statin-induced myopathy and poor response to allopurinol treatment. PURPOSE: We explored allele and genotype frequencies of SLCO1B1 and ABCG2 genes including their predicted phenotypes in 53 Thai participants. Of these, 17 had chronic kidney disease and were on statins. MATERIALS AND METHODS: Genotyping analysis for SLCO1B1 c.521T>C (rs4149056), c.388A>G (rs2306283), g.-11187G>A (rs4149015), and ABCG2 c.421C>A (rs2231142) was done by using TaqMan® Real time PCR. All were tested for Hardy-Weinberg Equilibrium. RESULTS: Most of the participants (80%) had normal function haplotypes SLCO1B1 (*1A and *1B) while decreased (*5, *15, and *17) and unknown (*21) function haplotypes were less observed. Four phenotypes of SLCO1B1 were observed: 69.81% had normal function (*1A/*1A,*1A/*1B, and *1B/*1B), 13.21% had intermediate function (*1A/*17, *1B/*15 and *1B/*17), 9.43% had indeterminate function (*1A/*21 and *1B/*21) and 7.55% had low function (*5/*15, *15/*15, and *15/*17). ABCG2 c.421A allele frequency was 25%. The frequency of ABCG2 c.421CA and AA phenotypes were 37.7% and 5.7%, respectively. The allele and genotype frequencies observed are consistent with reports in Asians. However, there were differences in major allele distributions between Asians and Caucasians for SLCO1B1 c.388A>G; SLCO1B1 c.388G were highly found in Asians, but c.388A were more observed in Caucasians. CONCLUSION: This study showed that in the Thai population, there were 4 SNPs of SLCO1B1 and ABCG2 genes. This finding may be clinically applied to minimize inter-individual variability of drugs such as statins and allopurinol. Further study with a larger sample size is needed to assess the drug profiles and responses to treatment.

Interferon-Inducible Protein 10 and Disease Activity in Systemic Lupus Erythematosus and Lupus Nephritis: A Systematic Review and Meta-Analysis.

There is increasing evidence of a correlation between interferon-inducible protein 10 (IP-10) and disease activity of systemic lupus erythematosus (SLE) and lupus nephritis (LN). We conducted a comprehensive search on IP-10 using MEDLINE, Scopus, and Cochrane electronic databases from the beginning to the end of December 2017. All studies that compared serum and/or urine IP-10 between active SLE/LN patients and any control groups were identified and included in this systematic review and meta-analysis. The mean difference (MD) of IP-10 level among active SLE and LN patients, as well as the correlation of IP-10 with disease activity, were meta-analyzed using a random-effects model. From 23 eligible studies, 15 provided adequate data for meta-analysis. Serum IP-10 was significantly elevated in patients with active SLE compared to non-active SLE patients (MD 356.5 pg/mL, 95% CI 59.6 to 653.4, p = 0.019). On the other hand, the levels of serum IP-10 was not different between active LN and non-active LN. However, serum IP-10 was positively correlated with disease activity like SLE disease activity index (SLEDAI) (pooled r = 0.29, 95% CI 0.22 to 0.35, p < 0.001). Furthermore, urine IP-10 tended to be higher in patients with active LN compared to non-active LN patients but this did not reach statistical significance (MD 3.47 pg/mgCr × 100, 95% CI -0.18 to 7.12, p = 0.06). Nevertheless, urine IP-10 was positively correlated with renal SLEDAI (pooled r = 0.29, 95% CI 0.05 to 0.50, p = 0.019). In conclusion, serum and urine IP-10 levels may be useful in monitoring the disease activity of SLE and LN. Serum IP-10 was correlated with systemic disease whereas urine IP-10 was a useful biomarker for detecting active LN.

The sensitivity and specificity of the routine kidney biopsy immunofluorescence panel are inferior to diagnosing renal immunoglobulin-derived amyloidosis by mass spectrometry.

Immunoglobulin light chain amyloidosis is the most frequent type of renal amyloidosis in the United States, accounting for 81% of cases. Accurate typing is crucial for early diagnosis and treatment of immunoglobulin-derived amyloidosis and to avoid treating other amyloidoses with potentially toxic chemotherapy. Immunofluorescence is the first step to type renal immunoglobulin-derived amyloidosis but the performance characteristics of this method are largely unknown. Here, we establish the sensitivity and specificity of immunofluorescence for diagnosing immunoglobulin-derived amyloidosis in patients whose amyloid typing was performed by the current gold standard of laser microdissection/mass spectrometry. Renal biopsy pathology reports originating from several institutions with a diagnosis of amyloidosis and which had amyloid typing by laser microdissection/mass spectrometry performed at our center were reviewed. Reported immunofluorescence staining for kappa or lambda of 2+ or more, with weak or no staining for the other light chain was considered positive for light chain amyloidosis by immunofluorescence. Based on microdissection/mass spectrometry results, of the 170 cases reviewed, 104 cases were typed as immunoglobulin-derived amyloidosis and 66 were typed as non-immunoglobulin-derived amyloidosis. Immunofluorescence sensitivity for diagnosing immunoglobulin-derived amyloidosis was 84.6%. The remaining 16 cases could not be diagnosed by immunofluorescence due to reported weak staining for all antigens or reported lack of preferential staining for one antigen. Immunofluorescence specificity was 92.4%. Five cases, all amyloid A amyloidosis, were misdiagnosed as immunoglobulin-derived amyloidosis by immunofluorescence. Immunofluorescence failed to accurately differentiate immunoglobulin-derived from non-immunoglobulin-derived amyloidosis in 12.3% of cases of renal amyloidosis. Relying on immunofluorescence alone for determining immunoglobulin-derived vs. non-immunoglobulin-derived amyloidosis may lead to misdiagnosis. Thus, immunofluorescence has inferior sensitivity and specificity compared with laser microdissection/mass spectrometry in the typing of immunoglobulin-derived amyloidosis.

Urine TWEAK level as a biomarker for early response to treatment in active lupus nephritis: a prospective multicentre study.

BACKGROUND: TNF-like weak inducer of apoptosis (TWEAK) is a proinflammatory molecule that plays a key role in active inflammation of lupus nephritis (LN). Urine TWEAK (uTWEAK) levels were found to be associated with renal disease activity among patients with LN. Here, we determined whether serial measurements of uTWEAK during induction therapy could predict treatment response or not. METHODS: Spot urine samples were collected from patients with biopsy-proven active LN at time of flare, and 3 and 6 months after flare to assess the uTWEAK levels. All patients received standard immunosuppressive therapy and treatment response was evaluated at 6 months. The performance of uTWEAK as a predictor for treatment response was compared with clinically used biomarkers for patients with LN. RESULTS: Among 110 patients with LN, there were 29% complete responders (CR), 34% partial responders (PR) and 37% non-responders (NR). On average, uTWEAK level was consistently low in CR, trended down by 3 months in PR and persistently elevated in NR. uTWEAK levels at month 3 were able to predict complete response at month 6 (OR adjusted for age, sex and creatinine=0.34 [95% CI 0.15 to 0.80], the area under the receiver operating characteristic curve [ROC-AUC]=0.68, p=0.02). The optimal threshold for uTWEAK level at month 3 was 0.46 pg/mgCr, discriminating complete response with 70% sensitivity and 63% specificity. Combining uTWEAK and urine protein at month 3 improved predictive performance for complete response at 6 months (ROC-AUC 0.83, p<0.001). CONCLUSIONS: In addition to urine protein, uTWEAK level at 3 months after flare can improve the accuracy in predicting complete response at 6 months of induction therapy.

Risk of ESRD and Mortality in Kidney and Bladder Stone Formers.

RATIONALE & OBJECTIVES: Kidney stones have been associated with increased risk for end-stage renal disease (ESRD). However, it is unclear whether there is also an increased risk for mortality and if these risks are uniform across clinically distinct categories of stone formers. STUDY DESIGN: Historical matched-cohort study. SETTING & PARTICIPANTS: Stone formers in Olmsted County, MN, between 1984 and 2012 identified using International Classification of Diseases, Ninth Revision codes. Age- and sex-matched individuals who had no codes for stones were the comparison group. PREDICTOR: Stone formers were placed into 5 mutually exclusive categories after review of medical charts: incident symptomatic kidney, recurrent symptomatic kidney, asymptomatic kidney, bladder only, and miscoded (no stone). OUTCOMES: ESRD, mortality, cardiovascular mortality, and cancer mortality. ANALYTICAL APPROACH: Cox proportional hazards models with adjustment for baseline comorbid conditions. RESULTS: Overall, 65 of 6,984 (0.93%) stone formers and 102 of 28,044 (0.36%) non-stone formers developed ESRD over a mean follow-up of 12.0 years. After adjusting for baseline hypertension, diabetes mellitus, dyslipidemia, gout, obesity, and chronic kidney disease, risk for ESRD was higher in recurrent symptomatic kidney (HR, 2.34; 95% CI, 1.08-5.07), asymptomatic kidney (HR, 3.94; 95% CI, 1.65-9.43), and miscoded (HR, 6.18; 95% CI, 2.25-16.93) stone formers, but not in incident symptomatic kidney or bladder stone formers. The adjusted risk for all-cause mortality was higher in asymptomatic kidney (HR, 1.40; 95% CI, 1.18-1.67) and bladder (HR, 1.37; 95% CI, 1.12-1.69) stone formers. Chart review of asymptomatic and miscoded stone formers suggested increased risk for adverse outcomes related to diagnoses including urinary tract infection, cancer, and musculoskeletal or gastrointestinal pain. CONCLUSIONS: The higher risk for ESRD in recurrent symptomatic compared with incident symptomatic kidney stone formers suggests that stone events are associated with kidney injury. The clinical indication for imaging in asymptomatic stone formers, the correct diagnosis in miscoded stone formers, and the cause of a bladder outlet obstruction in bladder stone formers may explain the higher risk for ESRD or death in these groups.

Admission serum phosphate levels predict hospital mortality.

BACKGROUND: The aim of this study was to assess the relationship between admission serum phosphate levels and in-hospital mortality in all hospitalized patients. METHODS: All adult hospitalized patients who had admission serum phosphate available between years 2009 and 2013 were enrolled. Admission serum phosphate was categorized based on its distribution into six groups (<2.5, 2.5-3.0, 3.1-3.6, 3.7-4.2, 4.3-4.8 and ≥4.9 mg/dL). The odds ratio (OR) of in-hospital mortality by admission serum phosphate, using the phosphate category of 3.1-3.6 mg/dL as the reference group, was obtained by logistic regression analysis. RESULTS: 42,336 patients were studied. The lowest incidence of in-hospital mortality was associated with a serum phosphate within 3.1-4.2 mg/dL. A U-shaped curve emerged demonstrating higher in-hospital mortality associated with both serum phosphate <3.1 and >4.2 mg/dL. After adjusting for potential confounders, both serum phosphate <2.5 and >4.2 mg/dL were associated with in-hospital mortality with ORs of 1.60 (95%CI 1.25-2.05), 1.60 (95%CI 1.29-1.97), and 3.89 (95%CI 3.20-4.74) when serum phosphate were <2.5, 4.3-4.8 and ≥4.9 mg/dL, respectively. Among subgroups of patients with chronic kidney disease (CKD) and cardiovascular disease (CVD), the highest mortality was associated with a serum phosphate ≥4.9 mg/dL with ORs of 4.11 (95%CI 3.16-5.39) in CKD patients and 5.11 (95%CI 3.33-7.95) in CVD patients. CONCLUSION: Hospitalized patients with admission serum phosphate <2.5 and >4.2 mg/dL are associated with an increased risk of in-hospital mortality. The highest mortality risk is associated with CKD and CVD patients with admission hyperphosphatemia.

The Changing Incidence and Presentation of Urinary Stones Over 3 Decades.

OBJECTIVE: To evaluate trends in the incidence of kidney stones and characteristics associated with changes in the incidence rate over 3 decades. PATIENTS AND METHODS: Adult stone formers in Olmsted County, Minnesota, from January 1, 1984, to December 31, 2012, were validated and characterized by age, sex, stone composition, and imaging modality. The incidence of kidney stones per 100,000 person-years was estimated. Characteristics associated with changes in the incidence rate over time were assessed using Poisson regression models. RESULTS: There were 3224 confirmed symptomatic (stone seen), 606 suspected symptomatic (no stone seen), and 617 incidental asymptomatic kidney stone formers. The incidence of confirmed symptomatic kidney stones increased from the year 1984 to 2012 in both men (145 to 299/100,000 person-years; incidence rate ratio per 5 years, 1.14, P<.001) and women (51 to 217/100,000 person-years; incidence rate ratio per 5 years, 1.29, P<.001). Overall, the incidence of suspected symptomatic kidney stones did not change, but that of asymptomatic kidney stones increased. Utilization of computed tomography for confirmed symptomatic stones increased from 1.8% in 1984 to 77% in 2012; there was a corresponding higher increased incidence of symptomatic small stones (≤3 mm) than of larger stones (>3 mm). Confirmed symptomatic kidney stones with documented spontaneous passage also increased. The incidence of kidney stones with unknown composition increased more than that of stones with known composition. CONCLUSION: The incidence of both symptomatic and asymptomatic kidney stones has increased dramatically. The increased utilization of computed tomography during this period may have improved stone detection and contributed to the increased kidney stone incidence.

Impact of admission serum calcium levels on mortality in hospitalized patients.

OBJECTIVES: To assess the relationship between admission serum calcium levels and in-hospital mortality in all hospitalized patients. METHODS: All adult hospitalized patients who had admission serum calcium levels available between years 2009 and 2013 were enrolled. Admission serum calcium was categorized based on its distribution into six groups (<7.9, 7.9 to <8.4, 8.4 to <9.0, 9.0 to <9.6, 9.6 to <10.1, and ≥10.1 mg/dL). The odds ratio (OR) of in-hospital mortality by admission serum calcium, using the calcium category of 9.6-10.1 mg/dL as the reference group, was obtained by logistic regression analysis. RESULTS: 18,437 patients were studied. The lowest incidence of in-hospital mortality was associated with admission serum calcium within 9.6 to <10.1 mg/dL. A higher in-hospital mortality rate was observed in patients with serum calcium <9.6 and ≥10.1 mg/dL. Also, 38% and 33% of patients with admission serum calcium <7.9 and ≥10.1 mg/dL were on calcium supplements before admission, respectively. After adjusting for potential confounders, both serum calcium <8.4 and ≥10.1 mg/dL were associated with an increased risk of in-hospital mortality with ORs of 2.86 [95% confidence interval (CI) 1.98-4.17], 1.74 (95% CI 1.21-2.53), and 1.69 (95% CI 1.10-2.59) when serum calcium were within <7.9, 7.9 to <8.4, and ≥10.1 mg/dL, respectively. CONCLUSION: Hypocalcemia and hypercalcemia on admission were associated with in-hospital mortality. Highest mortality risk is observed in patients with admission hypocalcemia (<7.9 mg/dL). One-third of patients with hypercalcemia on admission were on calcium supplements.

The effect of aspirin on kidney allograft outcomes; a short review to current studies.

CONTEXT: The use of aspirin in chronic kidney disease (CKD) patients has been shown to reduce myocardial infarction but may increase major bleeding. However, its effects in kidney transplant recipients are unclear. EVIDENCE ACQUISITIONS: A literature search was performed using MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews from inception through September 2016. We included studies that reported odd ratios, relative risks or hazard ratios comparing outcomes of aspirin use in kidney transplant recipients. Pooled risk ratios (RR) and 95% confidence interval (CI) were assessed using a random-effect, generic inverse variance method. RESULTS: We included 9 studies; enrolling 19759 kidney transplant recipients that compared aspirin with no treatment. Compared to no treatment, aspirin reduced the risk of allograft failure (4 studies; RR: 0.57, 95% CI: 0.33 to 0.99), allograft thrombosis (2 studies; RR: 0.11, 95% CI: 0.02 to 0.53), and major adverse cardiac events (MACEs) or mortality (2 studies; RR: 0.72, 95% CI: 0.59 to 0.88), but not allograft rejection (3 studies; RR: 0.86, 95% CI: 0.45 to 1.65) or delayed graft function (DGF) (2 studies; RR: 1.00, 95% CI: 0.58 to 1.72) in kidney transplant recipients. The data on risk of major or minor bleeding were limited. CONCLUSIONS: Our meta-analysis demonstrates that administration of aspirin in kidney transplant recipients is associated with reduced risks of allograft failure, allograft thrombosis, and MACEs or mortality, but not allograft rejection or DGF. Future studies are needed to assess the risk of bleeding, and ultimately weigh the overall risks and benefits of aspirin use in specific kidney transplant patient populations.