Histological reappraisal of IgA nephropathy: the role of glomerular pattern of injury and mesangial complement deposition.

BACKGROUND: There is a clear need to refine the histological assessment in IgA Nephropathy (IgAN). We sought to investigate the clinical significance of the light microscopy (LM) pattern of glomerular injury and of the intensity of mesangial C3 staining in IgAN. METHODS: We conducted a retrospective, observational study that included all patients with biopsy-proven primary IgAN that had at least 12 months of follow-up. The LM pattern of glomerular injury was reevaluated based on a modified HAAS classification. Mesangial C3 deposition by immunofluorescence (IF) staining was scored semi-quantitatively. The study primary composite endpoint was defined as doubling of serum creatinine or ESRD (dialysis, renal transplant or eGFR < 15 ml/min). The secondary study endpoint was eGFR decline per year. RESULTS: This cohort included 214 patients with IgAN (mean age, 41.4 ± 12.6 years), with a mean eGFR and median 24-h proteinuria of 55.2 ± 31.5 ml/min/1.73m2 and 1.5 g/day (IQR:0.8-3.25), respectively. The most frequent LM pattern was the mesangioproliferative (37.4%), followed by the sclerotic (22.5%) and proliferative/necrotizing patterns (21.4%). Regarding the IF findings, mild-moderate and intense mesangial C3 staining was present in 30.6% and 61.1% of patients, respectively. Those with sclerosing and crescentic patterns had the worst renal survival (5-year renal survival of 48.8% and 42.9%) and the highest rate of eGFR change/year (-2.32 ml/min/y and - 2.16 ml/min/y, respectively) compared to those with other glomerular patterns of injury. In addition, those with intense C3 staining reached the composite endpoint more frequently compared to those without intense C3 staining (35.5% vs. 21.4%, p = 0.04). After multivariate adjustment, patients with crescentic and sclerosing patterns had a 3.6-fold and 2.1-fold higher risk for the composite endpoint compared to those with mesangioproliferative pattern, while an intense mesangial C3 deposition being also associated with a worse renal outcome (HR, 3.33; 95%CI, 1.21-9.2). CONCLUSIONS: We have shown that the LM pattern of glomerular injury and the intensity of mesangial C3 deposition might stratify more accurately the renal outcome in patients with IgAN.

Sodium citrate versus sodium bicarbonate for metabolic acidosis in patients with chronic kidney disease: A randomized controlled trial.

BACKGROUND: Metabolic acidosis (MA) is frequently associated with chronic kidney disease (CKD) progression. Our aim was to compare the effect of oral sodium citrate (SC) with that of oral sodium bicarbonate (SB) on renal function and serum bicarbonate correction, as well as to evaluate their safety profile in patients with MA of CKD. METHODS: We conducted a prospective, single-center, randomized 1:1, parallel, controlled, unblinded clinical trial of 124 patients with MA and CKD stages 3b and 4. The primary outcome was the mean change in estimated glomerular filtration rate (eGFR). The secondary outcomes were mean change in serum bicarbonate level, eGFR decrease by 30%, eGFR decrease by 50%, dialysis, death or prolonged hospitalization, and a combined endpoint. RESULTS: No significant difference was found between the groups in terms of mean eGFR change [adjusted mean difference = -0.99 mL/min/1.73 m2 (95% CI: -2.51 to 0.93, P = .20)]. We observed a mean serum bicarbonate change of 6.15 mmol/L [(95% CI: 5.55-6.74), P < .001] in the SC group and of 6.19 mmol/L [(95% CI: 5.54-6.83), P < .001] in the SB group, but no significant difference between the 2 groups [adjusted mean difference = 0.31 mmol/L (-0.22 to 0.85), P = .25]. Cox proportional hazard analysis showed similar risks regarding eGFR decrease by 30% (P = .77), eGFR decrease by 50% (P = .50), dialysis (P = .85), death or prolonged hospitalization (P = .29), and combined endpoint (P = .57). Study drug discontinuation due to adverse events was significantly more common in the SB group (17.7% vs 4.8%, P = .02). CONCLUSIONS: SC and SB have a similar effect on kidney function decline, both improve serum bicarbonate level, but SB is associated with higher rates of medication discontinuation due to adverse events.

The impact of SARS-CoV-2 infection on renal function in patients with biopsy-proven kidney diseases.

BACKGROUND: We sought to evaluate the long-term effects of COVID-19 on renal function in patients with biopsy-proven kidney diseases. METHODS: A total of 451 patients with biopsy-proven kidney disease and at least 12 months of follow-up subsequent to COVID-19 pandemic onset were included in the study. The primary study endpoint was a composite of a persistent decline of more than 30% in eGFR or ESRD. RESULTS: 23.1% of patients had COVID-19 during a follow-up period of 2.5 y (0.8-2.6), while 17.6% of patients reached the composite endpoint. Those with COVID-19 were more likely to reach the composite endpoint [26.7% vs. 14.8%; OR, 2.1 (95%CI, 1.23-3.58), p = 0.006). There was a significant eGFR change in the first year of follow-up between the two study groups [-2.24 (95%CI,-4.86; 0.37) vs. +2.31 (95%CI, 0.78; 3.85) ml/min, p = 0.004], with an adjusted mean difference of -4.68 ml/min (95%CI,-7.7; -1.59)(p = 0.03). The trend for worse renal outcomes remained consistent in patients with IgAN, MN and FSGS, but not in those with LN. After multivariate adjustment, the independent predictors of the composite endpoint were baseline eGFR (HR, 0.94; 95%CI, 0.92-0.95), COVID-19 (HR, 1.91; 1.16-3.12) and male gender (HR, 1.64; 95%CI, 1.01-2.66). In multivariate linear regression analysis, COVID-19 independently determined a reduction of eGFR at 12 months by 4.62 ml/min/1.73m2 (ß coefficient, -4.62; 95%CI, -7.74 to -1.5, p = 0.004). CONCLUSIONS: There is a significant impact of COVID-19 on long-term renal function in patients with biopsy-proven kidney diseases, leading to a greater decline of eGFR and a worse renal survival.

Oral Furosemide and Hydrochlorothiazide/Amiloride versus Intravenous Furosemide for the Treatment of Resistant Nephrotic Syndrome.

BACKGROUND: Data on diuretic treatment in nephrotic syndrome (NS) are scarce. Our goal was to assess the non-inferiority of the combined oral diuretics (furosemide/hydrochlorothiazide/amiloride) compared to intravenous (i.v.) furosemide in patients with NS and resistant edema. METHODS: We conducted a prospective randomized trial on 22 patients with resistant nephrotic edema (RNE), defined as hypervolemia and a FENa < 0.2%. Based on a computer-generated 1:1 randomization, we assigned patients to receive either intravenous furosemide (40 mg bolus and then continuous administration of 5 mg/h) or oral furosemide (40 mg/day) and hydrochlorothiazide/amiloride (50/5 mg/day) for a period of 5 days. Clinical and laboratory measurements were performed daily. Hydration status was assessed by bioimpedance on day 1 and at the end of day 5 after treatment initiation. The primary endpoint was weight change from baseline to day 5. Secondary endpoints were hydration status change measured by bioimpedance and safety outcomes (low blood pressure, severe electrolyte disturbances, acute kidney injury and worsening hypervolemia). RESULTS: Primary endpoint analysis showed that after 5 days of treatment, there was a significant difference in weight change from baseline between groups [adjusted mean difference: -3.33 kg (95% CI: -6.34 to -0.31), p = 0.03], with a higher mean weight change in the oral diuretic treatment group [-7.10 kg (95% CI: -18.30 to -4.30) vs. -4.55 kg (95%CI: -6.73 to -2.36)]. Secondary endpoint analysis showed that there was no significant difference between groups regarding hydration status change [adjusted mean difference: -0.05 L (95% CI: -2.6 to 2.6), p = 0.96], with a mean hydration status change in the oral diuretic treatment group of -4.71 L (95% CI: -6.87 to -2.54) and -3.91 L (95% CI: -5.69 to -2.13) in the i.v. diuretic treatment group. We observed a significant decrease in adjusted mean serum sodium of -2.15 mmol/L [(95% CI: -4.25 to -0.05), p = 0.04]), favored by the combined oral diuretic treatment [-2.70 mmol/L (95% CI: -4.89 to -0.50) vs. -0.10 mmol/L (95%CI: -1.30 to 1.10)]. No statistically significant difference was observed between the two groups in terms of adverse events. CONCLUSIONS: A combination of oral diuretics based on furosemide, amiloride and hydrochlorothiazide is non-inferior to i.v. furosemide in weight control of patients with RNE and a similar safety profile.

Characteristics of SARS-CoV-2 Infection in an Actively Monitored Cohort of Patients with Lupus Nephritis.

(1) Background: We sought to investigate the impact of the COVID-19 pandemic in patients with lupus nephritis (LN); (2) Methods: A total of 95 patients with LN actively monitored in our department between 26 February 2020, when the first case of COVID-19 was diagnosed in Romania, and 1 May 2021, were included in the study. Multivariate logistic regression analysis was performed to identify the independent risk factors for SARS-CoV-2 infection; (3) Results: A total of 15 patients (15.8%) had a confirmed SARS-CoV-2 infection during a total follow-up time of 105.9 patient-years (unadjusted incidence rate: 14.28 SARS-CoV-2 infections per 100 patient-years). Median time to SARS-CoV-2 infection was 9.3 months (IQR: 7.2-11.3). The majority of patients had a mild form of SARS-CoV-2 infection (73.3%), while the remaining had moderate forms. None of the patients had a severe infection or a SARS-CoV-2-related death. The most frequent symptom was fatigue (73.3%), followed by loss of taste/smell (53.3%) and fever (46.7%). Forty percent of those with SARS-CoV-2 infection were hospitalized for a median 11.5 days (IQR:3.75-14). In the multivariate logistic regression analysis, a current oral corticosteroid dose ≥ 15 mg/day was associated with a 7.69-fold higher risk (OR, 7.69; 95%, 1.3-45.46), while the use of hydroxychloroquine was associated with a 91% lower risk for a SARS-CoV-2 infection (OR, 0.09; 95%CI, 0.01-0.59). (4) Conclusions: Our study confirms that the SARS-CoV-2 infection-associated morbidity might only be moderately increased in patients with LN. The current oral corticosteroid dose was the only independent predictor of infection occurrence, while use of hydroxychloroquine was associated with a protective effect.

Anti-phospholipase A2 receptor antibody screening in nephrotic syndrome may identify a distinct subset of patients with primary membranous nephropathy.

PURPOSE: We sought to investigate the utility of anti-PLA2R antibody as a non-invasive screening method for the diagnosis of primary MN in patients with nephrotic syndrome (NS). METHODS: All consecutive patients with NS admitted in our department, between 01.01.2015 and 31.12.2019 were screened for anti-PLA2R antibodies by an ELISA assay (EUROIMMUN, Lübeck, DE). A positive anti-PLA2R serology was defined as an ELISA value over 2 RU/ml. Subsequently, all patients underwent kidney biopsy to confirm the histological diagnosis. RESULTS: Of the 203 patients with NS, we identified 67 patients with "high" titer of anti-PLA2R antibodies (> 20 RU/ml) and 47 patients with "intermediate" titer (2-20 RU/ml). In the entire cohort, the area under the curve (AUC) was 0.83 (95% CI 0.78-0.89; p < 0.001). With a cutoff of 20 RU/ml, the anti-PLA2R antibodies had a 64% sensitivity (95% CI 53-73%) and 94% specificity (95% CI 88-97%) to discriminate MN from other causes of NS. In addition, the PPV and NPV were 91% (95% CI 82-95%) and 75% (95% CI 69-79%). When analyzing the posttest effect, we identified a LR+ of 11.56 (95% CI 5.2-25.2) and LR- of 0.38 (95% CI 0.29-0.5). The overall accuracy of the test was 80.3% (95% CI 74-85%) and the diagnostic odds ratio was 30.42. When performing subgroup analysis, we identified that in younger patients, in those with preserved renal function or with negative workup for secondary causes, the diagnostic performance of anti-PLA2R antibodies was improved, the sensitivity increasing to 68-71%, the PPV to 93-95% and the LR+ to 12.23-15.4. CONCLUSION: Serum anti-PLA2R antibody screening in patients with NS is a useful method for the diagnosis of primary MN. In younger patients (less than 60 years old) who have a preserved renal function and a negative workup for secondary causes of NS, a positive anti-PLA2R test highly predicts a diagnosis of primary MN.

Serum soluble urokinase plasminogen activator receptor as a potential biomarker of renal impairment severity in diabetic nephropathy.

AIMS: To investigate serum soluble form of urokinase-type plasminogen activator receptor (suPAR) in patients with diabetic kidney disease (DKD) and biopsy-proven diabetic nephropathy (DN), its correlation with histological parameters and its capacity as a biomarker for renal impairment severity. METHODS: We conducted a cross-sectional study on 75 patients with diabetes mellitus (DM) and DKD, among whom 28 had biopsy-proven DN. RESULTS: Among the 75 patients, 9 (12%) had type 1 and 66 (88%) type 2 DM. The median value of the serum suPAR level was 2857.2 pg/mL (1916.4-3700) in the entire cohort and 2472.1 pg/mL (1782.6-3745.8) in the biopsy-proven DN subgroup, respectively. suPAR was significantly correlated with diabetes duration, diabetic retinopathy, anti-proteinuric treatment, albuminuria, kidney function, DN class, interstitial fibrosis and tubular atrophy (IFTA) score and with interstitial inflammation score. suPAR had a good accuracy for the association with chronic kidney disease (CKD) stages G3b-5, macroalbuminuria, DN class IV, IFTA score 3 and interstitial inflammation score 2. CONCLUSIONS: Serum suPAR was increased in DN patients and was associated with DM duration, diabetic retinopathy, renoprotective treatment, kidney function, proteinuria, DN class, IFTA and interstitial inflammation scores. Also, suPAR had a good capacity as a biomarker for advanced renal impairment and severe histological lesions of DN.

Clinical Phenotypes and Predictors of Remission in Primary Membranous Nephropathy.

(1) Background: We sought to investigate the clinical outcome and to identify the independent predictors of clinical remission in a prospectively followed cohort of patients with primary membranous nephropathy (pMN). (2) Methods: We conducted a prospective, observational, non-interventional study that included 65 consecutive patients diagnosed with pMN between January 2015 and December 2019 at our department and followed for at least 24 months. The primary outcomes evaluated during the follow-up period were the occurrence of immunological and clinical remission (either complete or partial remission). Univariate and multivariate Cox proportional hazard regression analyses were performed to identify independent predictors of clinical remission. (3) Results: In the study cohort, 13 patients had a PLA2R-negative pMN, while, of those with PLA2R-associated pMN, 27 patients had a low anti-PLA2R antibody titer (<200 RU/mL), and 25 patients had a high anti-PLA2R antibody titer at baseline (≥200 RU/mL). The clinical outcome was better in patients with PLA2R-negative pMN compared to patients with PLA2R-positive pMN. These patients had a higher percentage of complete remissions (46.2%, compared to 33.3% in those with low anti-PLA2R antibody titer or 24% in those with high anti-PLA2R antibody titer), a faster decline of 24 h proteinuria and lower time to complete remission. In multivariate Cox regression analysis, patients with PLA2R-negative pMN had a 3.1-fold and a 2.87-fold higher chance for achieving a complete or partial remission compared to patients with high anti-PLA2R antibody titer or to all PLA2R-positive patients, respectively. Additionally, patients with a baseline 24 h proteinuria of less than 8 g/day and with an immunological remission at 24 months had a 2.4-fold (HR, 2.4; 95%CI, 1.19-4.8) and a 2.2-fold (HR, 2.26; 95%CI, 1.05-4.87), respectively, higher chance of achieving a clinical response. By contrary, renal function at diagnosis, type of therapeutic intervention or anti-PLA2R antibody titer did not predict the occurrence of clinical remission. (4) Conclusions: We identified a different clinical phenotype between PLA2R-positive and PLA2R-negative pMN. Additionally, we have shown that baseline proteinuria seems to be a more important predictor of clinical outcome than anti-PLA2R-ab titer.

A single-arm pilot study of metformin in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Metformin has shown promising results regarding cystogenesis inhibition in preclinical studies with autosomal dominant polycystic kidney disease (ADPKD) models. We designed a prospective, preliminary, single-arm study to evaluate the tolerability, safety and the effect of Metformin on kidney function and body mass index (BMI) in Romanian patients with ADPKD. METHODS: We enrolled 34 adult patients with ADPKD, chronic kidney disease (CKD) stages 1-5 not on dialysis and without diabetes mellitus. The primary endpoint was to assess the tolerability and safety of Metformin. The secondary endpoints evaluated changes in estimated glomerular filtration rate (eGFR), body mass index (BMI) and renal replacement therapy (RRT) necessity. Patients received an initial dose of Metformin of 500 mg/day within the first month that was increased to 1000 mg/day thereafter according to tolerability. Change in eGFR and BMI was expressed as mean difference with the corresponding 95% confidence intervals and as a percentage. For the primary endpoint, we included all 34 enrolled patients. To assess the secondary endpoint, intention-to-treat (ITT) and per-protocol (PP) analysis was performed. RESULTS: Sixteen patients out of 34 completed the follow-up period at 24 months. Eighteen patients developed adverse events and 63.6% of these events were gastrointestinal related. Nausea was the most common adverse event (17.6%). Two patients (5.8%) permanently discontinued medication due to adverse events. We recorded no case of hypoglycemia, lactic acidosis or death. Mean eGFR changed by - 1.57 ml/min/1.73m2 (95%CI:-22.28 to 19.14, P = 0.87) in ITT and by - 4.57 ml/min/1.73m2 (95%CI:-28.03 to 18.89, P = 0.69) in PP population. Mean BMI change was - 1.10 kg/m2 (95%CI:-3.22 to 1.02, P = 0.30) in ITT population and - 0.80 kg/m2 (95%CI:-3.27 to 1.67, P = 0.51) in PP analysis. Three patients (8.8%) needed RRT. CONCLUSIONS: Metformin was well tolerated, had a good safety profile even in ADPKD patients with advanced CKD and it was not associated with change in eGFR or BMI across the follow-up period. TRIAL REGISTRATION: The study was retrospectively registered on https://www.isrctn.com (number ISRCTN 93749377); date registered: 02/25/2019.

A cross-sectional epidemiological study of HBV, HCV, HDV and HEV prevalence in the SubCarpathian and South-Eastern regions of Romania.

AIM: To evaluate the prevalence of HBV, HCV, HDV and HEV infections in populations with different categories of risk and the seroprevalence of HBV and HCV infections in subjects asking for a medical examination. METHOD: We conducted a cross-sectional, epidemiological study in 2,851 subjects from the SubCarpathian and South-Eastern Romania (including 17 counties, 34% of the country area and 42% of the population). The subjects were divided into four groups: controls (n=2,540, i.e. consecutive subjects asking for a medical examination), subjects with very low risk (students; n=44), with low risk (doctors and nurses; n=93) and with high risk for viral hepatitis (hemodialysis patients; n=174). All subjects were screened for HBsAg, antiHCV and ALT level. In populations at risk, antiHBs, HBeAg, antiHBe, antiHBc (IgG), HBV-DNA, HCV-RNA, antiHDV(IgG) and antiHEV(IgG) were also assessed. RESULTS: In controls, HBV seroprevalence was 5.59% and HCV seroprevalence 4.56%. The risk factors for HBV infection were: age, male gender and South-East region of Romania. The risk factors for HCV infection were: age, female gender, elevated ALT level and the South-East region of Romania. In the very low risk population HBV, HCV, HDV and HEV seroprevalence was: 2.27%, 0%, 0% and 12.5%, respectively. In low risk population the seroprevalence was 2.15%, 1.07%, 0% and 13.98%. In hemodialysis patients, HBV and HCV seroprevalence were 7.91%, respectively 39.26%. HCV-RNA was detectable in 20.69% cases. CONCLUSION: In the South and South-Eastern Romania the seroprevalence of viral hepatitis infections is intermediate, similar to other Romanian regions or the Balkans.