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Introduction: There is evidence that SARS-CoV2 has a particular affinity for kidney tissue and is often associated with kidney failure., Methods: We assessed whether proteinuria can be predictive of kidney failure, the development of chronic kidney disease, and mortality in 37 critically ill COVID-19 patients. We used machine learning (ML) methods as decision trees and cut-off points created by the OneR package to add new aspects, even in smaller cohorts., Results: Among a total of 37 patients, 24 suffered higher-grade renal failure, 20 of whom required kidney replacement therapy. More than 40% of patients remained on hemodialysis after intensive care unit discharge or died (27%). Due to frequent anuria proteinuria measured in two-thirds of the patients, it was not predictive for the investigated endpoints; albuminuria was higher in patients with AKI 3, but the difference was not significant. ML found cut-off points of >31.4 kg/m2 for BMI and >69 years for age, constructed decision trees with great accuracy, and identified highly predictive variables for outcome and remaining chronic kidney disease., Conclusions: Different ML methods and their clinical application, especially decision trees, can provide valuable support for clinical decisions. Presence of proteinuria was not predictive of CKD or AKI and should be confirmed in a larger cohort., Competing Interests: Christoph Wanner received honoraria for steering committee membership and lecturing outside the present work from AstraZeneca, Bayer, Boehringer-Ingelheim, Eli Lilly, Mundipharma, and MSD. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have nothing to declare.

Recently, changes in urinary albumin and in GFR have been recognized as risk factors for the development of end-stage kidney disease and mortality. Though most clinical epidemiology studies of chronic kidney disease (CKD) used renal function and proteinuria at baseline alone, definitive diagnosis of CKD with multiple measurements intensifies the differences in the risk for mortality between the CKD and non-CKD populations. We hypothesized that a transient diagnosis of proteinuria and reduced renal function each indicate a significantly higher mortality compared to definitive non-CKD as the negative control and lower mortality compared with definitive CKD as the positive control. The present longitudinal study evaluated a general-population cohort of 338,094 persons who received annual health checkups, with a median 4.3-year study period. There were 2,481 deaths, including 510 CVD deaths (20.6%) and 1,328 cancer deaths (53.5%), and mortality risk was evaluated for transient proteinuria and for transiently reduced renal function. The hazard ratios (HRs) for all-cause mortality and cancer mortality were not significant, but that for cardiovascular mortality was significantly higher for transient proteinuria (HR, 1.94 [95% confidence interval, 1.27-2.96] in men and 2.78 [1.50-5.16] in women). On the other hand, transiently reduced renal function was not significant for either cardiovascular mortality risk or cancer mortality risk. We surmise that this is the first study of the mortality risk of transient dipstick proteinuria in a large general-population cohort with cause-specific death registration. Transiently positive proteinuria appears to be a significant risk specifically for cardiovascular mortality compared with definitely negative for proteinuria., Competing Interests: The authors have declared that no competing interests exist.

Objective: A quantitative basis for the use of dipstick urinalysis for risk assessment of all-cause mortality is scarce. Therefore, we investigated the association between dipstick proteinuria and all-cause mortality in a general population and evaluated the effect of confounders on this association., Methods: The study population included 17,342,956 adults who underwent health examinations between 2005 and 2008 under the National Health Insurance System. Proteinuria was determined using a single dipstick urinalysis, and the primary outcome of this study was all-cause mortality. The prognostic impact of proteinuria was assessed by constructing a multivariable Cox model., Results: The mean age of the study population (53.24% male) was 46.06 years; 724,681 deaths from all causes occurred over a median follow-up period of 9.34 years (interquartile range 8.17-10.16), and the maximum follow-up was 12.12 years. After full adjustment for covariates, a higher level of dipstick proteinuria indicated a higher risk of all-cause death [Hazard ratios (95% confidence intervals); 1.22 (1.20-1.24), 1.47 (1.45-1.49), 1.81 (1.77-1.84), 2.32 (2.24-2.41), 2.74 (2.54-2.96); trace to 4+, respectively], and various subgroup analyses did not affect the main outcome for the total population. ≥1+ proteinuria in the group without metabolic diseases (hypertension, diabetes, dyslipidemia, or obesity) resulted in higher hazard ratios than those in the group with metabolic diseases and negative or trace proteinuria., Conclusions: Our study showed a strong association between dipstick proteinuria and all-cause mortality in this nationwide population-based cohort in South Korea., Competing Interests: The authors have declared that no competing interests exist.

Objectives: The treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is based on remission-induction and remission-maintenance. Methotrexate is a widely used immunosuppressant but only a few studies explored its role for maintenance in AAV. This trial investigated the efficacy and safety of methotrexate as maintenance therapy for AAV., Methods: In this single-centre, open-label, randomised trial we compared methotrexate and cyclophosphamide for maintenance in AAV. We enrolled patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), the latter with poor-prognosis factors and/or peripheral neuropathy. Remission was induced with cyclophosphamide. At remission, the patients were randomised to receive methotrexate or to continue with cyclophosphamide for 12 months; after treatment, they were followed for another 12 months. The primary end-point was relapse; secondary end-points included renal outcomes and treatment-related toxicity., Results: Of the 94 enrolled patients, 23 were excluded during remission-induction or did not achieve remission; the remaining 71 were randomised to cyclophosphamide (n = 33) or methotrexate (n = 38). Relapse frequencies at months 12 and 24 after randomisation were not different between the two groups (p = 1.00 and 1.00). Relapse-free survival was also comparable (log-rank test p = 0.99). No differences in relapses were detected between the two treatments when GPA+MPA and EGPA were analysed separately. There were no differences in eGFR at months 12 and 24; proteinuria declined significantly (from diagnosis to month 24) only in the cyclophosphamide group (p = 0.0007). No significant differences in adverse event frequencies were observed., Conclusions: MTX may be effective and safe for remission-maintenance in AAV., Trial Registration: clinicaltrials.gov NCT00751517.

Background: The link of low estimated glomerular filtration rate (eGFR) and high proteinuria to cardiovascular disease (CVD) mortality is well known. However, its link to mortality due to other causes is less clear., Methods: We studied 367,932 adults (20-93 years old) in the Korean Heart Study (baseline between 1996-2004 and follow-up until 2011) and assessed the associations of creatinine-based eGFR and dipstick proteinuria with mortality due to CVD (1,608 cases), cancer (4,035 cases), and other (non-CVD/non-cancer) causes (3,152 cases) after adjusting for potential confounders., Results: Although cancer was overall the most common cause of mortality, in participants with chronic kidney disease (CKD), non-CVD/non-cancer mortality accounted for approximately half of cause of death (47.0%for eGFR <60 ml/min/1.73 m2 and 54.3% for proteinuria ≥1+). Lower eGFR (<60 vs. ≥60 ml/min/1.73 m2) was significantly associated with mortality due to CVD (adjusted hazard ratio 1.49 [95% CI, 1.24-1.78]) and non-CVD/non-cancer causes (1.78 [1.54-2.05]). The risk of cancer mortality only reached significance at eGFR <45 ml/min/1.73 m2 when eGFR 45-59 ml/min/1.73 m2 was set as a reference (1.62 [1.10-2.39]). High proteinuria (dipstick ≥1+ vs. negative/trace) was consistently associated with mortality due to CVD (1.93 [1.66-2.25]), cancer (1.49 [1.32-1.68]), and other causes (2.19 [1.96-2.45]). Examining finer mortality causes, low eGFR and high proteinuria were commonly associated with mortality due to coronary heart disease, any infectious disease, diabetes, and renal failure. In addition, proteinuria was also related to death from stroke, cancers of stomach, liver, pancreas, and lung, myeloma, pneumonia, and viral hepatitis., Conclusion: Low eGFR was associated with CVD and non-CVD/non-cancer mortality, whereas higher proteinuria was consistently related to mortality due to CVD, cancer, and other causes. These findings suggest the need for multidisciplinary prevention and management strategies in individuals with CKD, particularly when proteinuria is present.

Patients with primary membranous nephropathy (MN) who experience spontaneous remission of proteinuria generally have an excellent outcome without need of immunosuppressive therapy. It is, however, unclear whether non-nephrotic proteinuria at the time of diagnosis is also associated with good prognosis since a reasonable number of these patients develop nephrotic syndrome despite blockade of the renin-angiotensin system. No clinical or laboratory parameters are available, which allow the assessment of risk for development of nephrotic proteinuria. Phospholipase A2 Receptor antibodies (PLA2R-Ab) play a prominent role in the pathogenesis of primary MN and are associated with persistence of nephrotic proteinuria. In this study we analysed whether PLA2R-Ab levels might predict development of nephrotic syndrome and the clinical outcome in 33 patients with biopsy-proven primary MN and non-nephrotic proteinuria under treatment with blockers of the renin-angiotensin system. PLA2R-Ab levels, proteinuria and serum creatinine were measured every three months. Nephrotic-range proteinuria developed in 18 (55%) patients. At study start (1.2±1.5 months after renal biopsy and time of diagnosis), 16 (48%) patients were positive for PLA2R-Ab. A multivariate analysis showed that PLA2R-Ab levels were associated with an increased risk for development of nephrotic proteinuria (HR = 3.66; 95%CI: 1.39-9.64; p = 0.009). Immunosuppressive therapy was initiated more frequently in PLA2R-Ab positive patients (13 of 16 patients, 81%) compared to PLA2R-Ab negative patients (2 of 17 patients, 12%). PLA2R-Ab levels are associated with higher risk for development of nephrotic-range proteinuria in this cohort of non-nephrotic patients at the time of diagnosis and should be closely monitored in the clinical management.

Background: Proteinuria is a target for renoprotection in kidney diseases. However, optimal level of proteinuria reduction in IgA nephropathy (IgAN) is unknown., Methods: We conducted a retrospective observational study in 500 patients with biopsy-proven IgAN. Time-averaged proteinuria (TA-P) was calculated as the mean of every 6 month period of measurements of spot urine protein-to-creatinine ratio. The study endpoints were a 50% decline in estimated glomerular filtration rate (eGFR), onset of end-stage renal disease (ESRD), and slope of eGFR., Results: During a median follow-up duration of 65 (12-154) months, a 50% decline in eGFR occurred in 1 (0.8%) patient with TA-P of <0.3 g/g compared to 6 (2.7%) patients with TA-P of 0.3-0.99 g/g (hazard ratio, 2.82; P = 0.35). Risk of reaching a 50% decline in eGFR markedly increased in patients with TA-P of 1.0-2.99 g/g (P = 0.002) and those with TA-P≥3.0 g/g (P<0.001). ESRD did not occur in patients with TA-P<1.0 g/g compared to 26 (20.0%) and 8 (57.1%) patients with TA-P of 1.0-2.99 and ≥3.0 g/g, respectively. Kidney function of these two groups deteriorated faster than those with TA-P<1.0 g/g (P<0.001). However, patients with TA-P of 0.3-0.99 g/g had a greater decline of eGFR than patients with TA-P<0.3 g/g (-0.41±1.68 vs. -0.73±2.82 ml/min/1.73 m2/year, P = 0.03)., Conclusion: In this study, patients with TA-P<1.0 g/g show favorable outcomes. However, given the faster eGFR decline in patients with TA-P of 0.3-0.99 g/g than in patients with TA-P<0.3 g/g, the ultimate optimal goal of proteinuria reduction can be lowered in the management of IgAN.

Limited prospective data are available on the importance of estimated glomerular filtration rate (GFR) and proteinuria in the prediction of all-cause mortality (ACM) in community-based elderly populations. We examined the relationship between GFR or proteinuria and ACM in 949 randomly selected community-dwelling elderly subjects (aged ≥65 years) over a 5-year period. A spot urine sample was used to measure proteinuria by the dipstick test, and GFR was estimated using the chronic kidney disease-epidemiology collaboration (CKD-EPI) equation. Information about mortality and causes of death was collected by direct enquiry with the subjects and from the national mortality data. Compared to subjects without proteinuria, those with proteinuria of grade ≥1+ had a 1.725-fold (1.134-2.625) higher risk of ACM. Compared to subjects with GFR ≥90 ml/min/1.73 m2, those with GFR<45 ml/min/1.73 m2 had a 2.357 -fold (1.170-4.750) higher risk for ACM. Among the 403 subjects included in the analysis of renal progression, the annual rate of GFR change during follow-up period was -0.52±2.35 ml/min/1.73 m2/year. The renal progression rate was 7.315-fold (1.841-29.071) higher in subjects with GFR<60 ml/min/1.73 m2 than in those with GFR ≥60 ml/min/1.73 m2. Among a community-dwelling elderly Korean population, decreased GFR of <45 ml/min/1.73 m2 and proteinuria were independent risk factors for ACM.

Systemic lupus erythematosus is a polymorphic and multigenic inflammatory autoimmune disease. Cyclic AMP (cAMP) modulates inflammation and the inhibition of cyclic nucleotide phosphodiesterase type 4 (PDE4), which specifically hydrolyzes cAMP, inhibits TNFα secretion. This study was aimed at investigating the evolution of PDE activity and expression levels during the course of the disease in MRL/lpr lupus-prone mice, and to evaluate in these mice the biological and clinical effects of treatments with pentoxifylline, denbufylline and NCS 613 PDE inhibitors. This study reveals that compared to CBA/J control mice, kidney PDE4 activity of MRL/lpr mice increases with the disease progression. Furthermore, it showed that the most potent and selective PDE4 inhibitor NCS 613 is also the most effective molecule in decreasing proteinuria and increasing survival rate of MRL/lpr mice. NCS 613 is a potent inhibitor, which is more selective for the PDE4C subtype (IC₅₀= 1.4 nM) than the other subtypes (PDE4A, IC₅₀= 44 nM; PDE4B, IC₅₀= 48 nM; and PDE4D, IC₅₀= 14 nM). Interestingly, its affinity for the High Affinity Rolipram Binding Site is relatively low (K(i) = 148 nM) in comparison to rolipram (K(i) = 3 nM). Finally, as also observed using MRL/lpr peripheral blood lymphocytes (PBLs), NCS 613 inhibits basal and LPS-induced TNFα secretion from PBLs of lupus patients, suggesting a therapeutic potential of NCS 613 in systemic lupus. This study reveals that PDE4 represent a potential therapeutic target in lupus disease.