Urinary thrombin as a marker of local disseminated intravascular coagulation in patients with chronic kidney disease

The aim of this research was to study the diagnostic markers of nonovert local disseminated intravascular coagulation (DIC) syndrome in the urine of patients with chronic kidney disease (CKD). We conducted a prospective study involving 140 patients with CKD, of these patients, 100 patients (71.4%; 95% CI 53.4-76.7) had glomerulonephritis (GN) and 40 patients (28.6%; 95% CI 21.3-36.8) had diabetic nephropathy (DN). We diagnosed overt DIC syndrome on the International Society of Thrombosis and Haemostasis (ISTH) scale (>5 points) in 18.6 % of patients. We determined the level of thrombin in the urine of patients who had <5 points on ISTH scale for the diagnosis of local nonovert DIC syndrome in the kidneys. In the urine of healthy individuals, the level of thrombin did not exceed 1 ng/ml, so we found no thrombinuria at a thrombin level <1 ng/ml. In 56.1% of patients, we found urinary thrombin levels >1 ng/ml. The average level of thrombin in the urine of these patients was 6.5 (4.8; 10.6) ng/ml. In our opinion, the presence of thrombinuria indicates the intensity of monocytic-macrophage inflammation in the glomeruli and may be a criterion for nonovert, local DIC syndrome in the kidneys. The association of overt DIC syndrome with decreased blood albumin, reduced glomerular filtration rate (GFR), increased daily protein excretion (DPE) indicates its occurrence in severe underlying disease, in the presence of nephrotic syndrome and in the severe stages of CKD. Early diagnosis of nonovert local DIC syndrome would be more useful, since the process is still reversible and controlled, and timely use of antiplatelet and anticoagulant therapy would affect the course and the progression of CKD.

Spot Urine Protein Excretion in the First Year Following Kidney Transplantation Associates With Allograft Rejection Phenotype at 1-Year Surveillance Biopsies: An Observational National-Cohort Study

Introduction: Urine protein excretion is routinely measured to assess kidney allograft injury, but the diagnostic value of this measurement for kidney transplant pathology remains unclear. Here we investigated whether spot urine protein excretion in the first year following transplantation associates with allograft rejection phenotype at 1-year surveillance biopsies and de-novo occurrence of donor-specific antibodies (DSA).Patients and Methods: This prospective, observational national-cohort study included 139 non-sensitized patients who received a deceased donor kidney transplant between December 2014 and 2018. All patients received basiliximab induction and tacrolimus-based immunosuppression. Estimated protein excretion rate (ePER) was calculated monthly from spot urine protein-to-creatinine ratios. At 1-year, all recipients underwent surveillance graft biopsy and were screened for de-novo DSA. Screening-positive sera were subjected to single antigen bead (SAB) testing. The occurrence of de-novo DSA was determined based on SAB reactivity patterns using a mean fluorescence intensity threshold &gt;1,000.Results: Among the 139 study patients, 27 patients (19%) had histologic evidence of T cell-mediated rejection (TCMR), and 9 patients (7%) had histologic evidence of antibody-mediated rejection (AMR) at 1-year surveillance biopsy. One year after transplant, 19 patients (14%) developed de-novo DSA. Compared with patients without rejection and no de-novo DSA, mixed-effects linear regression analysis showed a significant difference in slope of ePER during the first year in patients with AMR and de-novo DSA at 1-year (46, 95% CI 25–68 mg/day/1.73 m2 per month and 34, 95% CI 20–49 mg/day/1.73 m2 per month, respectively). Patients with vascular TCMR also showed a significant difference in ePER slope over time compared with patients with non-rejection findings (31, 95% CI 9–52 mg/day/1.73 m2 per month). The discriminatory power of ePER for intragraft rejection processes was better in patients with AMR (AUC 0.95, 95% CI 0.90–0.99; P &lt; 0.001) than in those with TCMR (AUC 0.68, 95% CI 0.59–0.79; P = 0.002), with 89% sensitivity and 93% specificity for proteinuria &gt;550 mg/day/1.73m2.Conclusions: An increase in ePER in the first year following kidney transplantation associates with AMR, vascular TCMR and de-novo DSA at 1-year and may be used as a non-invasive clinical marker of intragraft endothelial cell injury.

Clinical efficacy and safety of full-dose versus half-dose corticosteroids plus leflunomide for IgA nephropathy

Background The results of leflunomide (LEF) in patients with IgA nephropathy (IgAN) were inconsistent. Methods A total of 149 kidney biopsy-confirmed IgAN patients with an estimated glomerular filtration rate (eGFR) ≥ 50 ml/min/1.73 m2 and protein excretion levels ≥0.75 g/d were enrolled, with 65 subjects receiving half-dose CS plus LEF (LEF group), and the 84 counterpart patients accepting full-dose corticosteroid (Full CS group). The primary outcomes included the complete remission (CR) rates and incidence of adverse events (AEs). The secondary outcomes were the overall remission (OR) rates and a combined event (eGFR reduced ≥30%, end-stage renal disease [ESRD], hemodialysis, peritoneal dialysis or kidney transplantation). Results During the 18 months of follow-up, the CR rates were 72 and 64% in the LEF and Full CS groups (P = 0.299), respectively. The proportion of patients with OR rates in the LEF group and Full CS group was 89% versus 75%, respectively (P = 0.027). Serious AEs were observed only in the Full CS group (P = 0.017). The incidences of total AEs (P = 0.036) and infections (P = 0.024) were lower in the LEF group than in the Full CS group. Conclusions LEF combined with half-dose CS is superior to full-dose CS in the treatment of IgAN.

Excreted Trypanosoma brucei proteins inhibit Plasmodium hepatic infection

Malaria, a disease caused by Plasmodium parasites, remains a major threat to public health globally. It is the most common disease in patients with sleeping sickness, another parasitic illness, caused by Trypanosoma brucei. We have previously shown that a T. brucei infection impairs a secondary P. berghei liver infection and decreases malaria severity in mice. However, whether this effect requires an active trypanosome infection remained unknown. Here, we show that Plasmodium liver infection can also be inhibited by the serum of a mouse previously infected by T. brucei and by total protein lysates of this kinetoplastid. Biochemical characterisation showed that the anti-Plasmodium activity of the total T. brucei lysates depends on its protein fraction, but is independent of the abundant variant surface glycoprotein. Finally, we found that the protein(s) responsible for the inhibition of Plasmodium infection is/are present within a fraction of ~350 proteins that are excreted to the bloodstream of the host. We conclude that the defence mechanism developed by trypanosomes against Plasmodium relies on protein excretion. This study opens the door to the identification of novel antiplasmodial intervention strategies.

Regulatory role and mechanisms of myeloid TLR4 in anti-GBM glomerulonephritis

Myeloid cells and TLR4 play a critical role in acute kidney injury. This study investigated the regulatory role and mechanisms of myeloid TLR4 in experimental anti-glomerular basement membrane (GBM) glomerulonephritis (GN). Anti-GBM GN was induced in tlr4flox/flox and tlr4flox/flox−lysM−cre mice by intravenous injection of the sheep anti-mouse GBM antibody. Compared to control mice, conditional disruption of tlr4 from myeloid cells, largely macrophages (> 85%), suppressed glomerular crescent formation and attenuated progressive renal injury by lowering serum creatinine and 24-h urine protein excretion while improving creatinine clearance. Mechanistically, deletion of myeloid tlr4 markedly inhibited renal infiltration of macrophages and T cells and resulted in a shift of infiltrating macrophages from F4/80+iNOS+ M1 to F4/80+CD206+ M2 phenotype and inhibited the upregulation of renal proinflammatory cytokines IL-1β and MCP-1. Importantly, deletion of myeloid tlr4 suppressed T cell-mediated immune injury by shifting Th1 (CD4+IFNγ+) and Th17 (CD4+IL-17a+) to Treg (CD4+CD25+FoxP3+) immune responses. Transcriptome analysis also revealed that disrupted myeloid TLR4 largely downregulated genes involving immune and cytokine-related pathways. Thus, myeloid TLR4 plays a pivotal role in anti-GBM GN by immunological switching from M1 to M2 and from Th1/Th17 to Treg and targeting myeloid TLR4 may be a novel therapeutic strategy for immune-mediated kidney diseases.

Postnatal assessment for renal dysfunction in women with hypertensive disorders of pregnancy

Background Hypertensive disorders of pregnancy are associated with chronic kidney disease. Early detection of renal dysfunction enables implementation of strategies to prevent progression. International guidelines recommend review at 6–8 weeks postpartum to identify persistent hypertension and abnormal renal function, but evidence for the efficacy of this review is limited. Methods All women attending a specialist fetal-maternal medicine clinic for hypertensive disorders of pregnancy (pre-eclampsia, chronic hypertension, gestational hypertension) were invited for a 6–8 weeks postpartum review of their blood pressure and renal function in order to establish the prevalence and independent predictors of renal dysfunction. Renal dysfunction was defined as low estimated Glomerular Filtration Rate (eGFR < 60 ml/min/1.73 m2) or proteinuria (24-h protein excretion > 150 mg or urinary albumin-to-creatinine ratio > 3 mg/mmol). All women attending a specialist clinic for hypertensive disorders were invited for a 6–8 weeks postpartum review of their blood pressure and renal function. Demographics, pregnancy and renal outcomes were prospectively collected. Results Between 2013 and 2019, 740 of 1050 (70.4%) women who had a pregnancy complicated by a hypertensive disorder attended their 6–8 weeks postpartum visit. Renal dysfunction was present in 32% of the total cohort and in 46% and 22% of women with and without pre-eclampsia, respectively. Multivariate logistic regression demonstrated that independent predictors were pre-eclampsia, chronic hypertension, highest measured antenatal serum creatinine, highest measured antenatal 24-h urinary protein, and blood pressure ≥ 140/90 mmHg at the postnatal visit. Conclusions Renal dysfunction was present in one in three women with hypertensive disorders of pregnancy at 6–8 weeks postpartum. This includes women with gestational hypertension and chronic hypertension without superimposed pre-eclampsia, and thus these women should also be offered postnatal review. Graphic abstract

Renal Involvement in Hereditary Transthyretin Amyloidosis: An Italian Single-Centre Experience

Objective: Hereditary transthyretin amyloidosis (ATTRv) represents a diagnostic challenge considering the great variability of clinical presentation and multiorgan involvement. In the present study, we report the prevalence of kidney involvement and kidney function over time in a cohort of ATTRv patients with different transthyretin gene mutations. Patients and Methods: For this study, we systematically collected data from all patients with a diagnosis of ATTRv followed at the Neurology Unit of Fondazione Policlinico Universitario A. Gemelli IRCCS. Kidney involvement was defined as presence of estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 obtained with CKD-EPI equation, abnormal urinary protein excretion (UPE) (>150 mg/24 h) and/or albuminuria >30 mg/24 h (or mg/g creatinine). The analysis included data from 46 patients with 122 measurements of serum creatinine. Results: Among the 46 patients included in the analysis, kidney involvement was present in 37%, with 15% showing reduced eGFR and 22% abnormal UPE (63% of patients with available UPE data). No single predictor was associated with either eGFR values or its slope over time. Conclusions: Kidney involvement is quite common in patients with ATTRv regardless of the underlying genetic variant. In particular, abnormal UPE appears to be a common feature of the disease.

MATERNAL PROTEINURIA IN TWIN COMPARED WITH SINGLETON PREGNANCIES

INTRODUCTION: The exact amount of albumin ltered each day by kidneys is controversial. Normal rate of albumin excretion is less than 20 mg/day. The upper limit of the urinary protein excretion is 150 mg/d in normal non–pregnant women. Total protein excretion, however, increases to 150-250 mg daily in normal pregnancy due to increase in blood volume and, therefore, the glomerular ltration rate. This study was conducted to compare 24 hour urinary protein excretion in twin and singleton pregnancies, not complicated by hypertension. MATERIALS AND METHODS: This is a prospective study done in the department of Obstetrics and Gynaecology in R.G.Kar Medical College and Hospital, Kolkata from June, 2015 to May, 2016. A total of 86 women (43 twin and 43 singleton pregnancies) participated in this study. Six collections were inadequate based on creatinine excretion and were excluded. So, 80 women (40 twin and 40 singleton pregnancies) comprised the nal cohort. RESULT: In our study four twin pregnancies (ten percent) were found to have proteinuria ≥ 300 mg/day at the time of the specimen collection but no singleton pregnancy had this level of proteinuria. And only one of these twin pregnancies (who had proteinuria ≥ 300 mg/day ) subsequently developed hypertensive disorder in pregnancy. Rest three twin pregnancies were normotensive, yet they showed proteinuria ≥ 300 mg/day. Though statistical analysis of 24 hour urine protein ≥ 300 mg in singleton and twin pregnancies did not show signicans (P0.1238) in our study. CONCLUSION: Twin pregnancy had signicantly more proteinuria as measured by 24 hour urine protein, than singleton pregnancy. And they are more likely to have proteinuria without hypertension and this value can exceed 300 mg/day. So, a reevaluation of the diagnostic criteria for preeclampsia in twin pregnancies is needed.

Comparative study of 24-hour urinary protein and spot urine protein creatinine ratio in pre-eclamptic women

Background: The aim of the study was to evaluate the ability of the random urine P/C ratio to predict significant proteinuria, as well as to introduce a diagnostic test for pre-eclampsia which will avoid the inconvenience and time consumption of 24-hour urine protein collection. The objective of this study was to compare spot urine protein- creatinine ratio with 24-hour urine protein for estimation of proteinuria in pre-eclampsia.Methods: A total of 50 pregnant women with pre-eclampsia were prospectively studied for proteinuria in Rajarajeswari medical college and Hospital Bangalore for a period of 9 months from September 2018 to May 2019. Spot urine specimens for measuring P/C ratio were obtained immediately before 24-hour urine collection. The correlation between the spot urine P/C ratio and urinary protein excretion in the 24-hour collections was examined using the Spearman correlation test.Results: PCR at a cut off value 0.15 g/mmol had sensitivity and specificity of 96.6% and 55% respectively. In prediction of proteinuria of 300 mg/24 hr positive predictive value and negative predictive value 76.3% and 91.6% respectively.Conclusions: We found that there was a strong correlation between 24-hour urine protein excretion and spot urine protein creatinine ratio in pre-eclamptic women. Spot PCR can be used as a reasonable alternative to 24-hour urine protein test which is a cumbersome.