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.

Genotype-Phenotype Correlations in Alport Syndrome-A Single-Center Experience.

BACKGROUND: Alport syndrome (AS) is a common and heterogeneous genetic kidney disease, that often leads to end-stage kidney disease (ESKD). METHODS: This is a single-center, retrospective study that included 36 adults with type IV collagen (COL4) mutations. Our main scope was to describe how genetic features influence renal survival. RESULTS: A total of 24 different mutations were identified, of which eight had not been previously described. Mutations affecting each of the type IV collagen α chains were equally prevalent (33.3%). Most of the patients had pathogenic variants (61.1%). Most patients had a family history of kidney disease (71%). The most prevalent clinical picture was nephritic syndrome (64%). One-third of the subjects had extrarenal manifestations, 41.6% of patients had ESKD at referral, and another 8.3% developed ESKD during follow-up. The median renal survival was 42 years (95% CI, 29.98-54.01). The COL4A4 group displayed better renal survival than the COL4A3 group (p = 0.027). Patients with missense variants had higher renal survival (p = 0.023). Hearing loss was associated with lower renal survival (p < 0.001). CONCLUSIONS: Patients with COL4A4 variants and those with missense mutations had significantly better renal survival, whereas those with COL4A3 variants and those with hearing loss had worse prognoses.

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.

Hantavirus infections in the South­Eastern European countries: A study of two cases and literature review.

Hantavirus infection is a rare zoonosis in South-Eastern Europe. Depending on the serotype involved, the virus can cause hemorrhagic fever with renal syndrome which is also known as endemic nephropathy, and cardiopulmonary syndrome. Prompt diagnosis of the disease is essential for reducing the risk of severe manifestations and complications like chronic kidney disease, secondary hypertension or even death because there is no specific treatment or vaccine approved. The present study reported two cases of hemorrhagic fever with renal syndrome diagnosed in the Department of Nephrology of The Fundeni Clinical Institute (Romania). In both patients, kidney needle biopsy played a major role in establishing the diagnosis. The difficulties encountered in diagnosing this disease were also emphasized, taking into consideration the rarity of this infection in South-Eastern Europe. The key literature data on the epidemiology, pathogenesis and management of this infection were further reviewed.

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.

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.

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.

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.

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.

Corticosteroids are the major contributors to the risk for serious infections in autoimmune disorders with severe renal involvement.

INTRODUCTION: We sought to investigate the infection profile and associated risk factors in a compiled cohort of patients with autoimmune disorders with severe renal involvement treated with aggressive immunosuppressive (IS) regimens. METHODS: A total of 162 patients with aggressive glomerulonephritis [101 with lupus nephritis (LN), 24 with cryoglobulinemic vasculitis (CryoVasc), and 37 with ANCA-associated vasculitis (AAV)] were retrospectively reviewed for any infection occurrence. Infection incidence, type, site, and grade (1-5) were recorded. Multivariate Cox proportional hazard regression analysis was performed to identify independent risk factors for infections. RESULTS: A total of 179 infection episodes occurred during a follow-up of 468 patient-years. Eighty-two patients (50.6%) had at least one infection. The incidence rates of infections and severe infections were 38.2 and 14.3 events per 100 patient-years. Patients with AAV had more infections than those with CryoVasc and LN (100.6, 47.5, and 26.6 infections per 100-patient-years, respectively; p = 0.002). Most patients developed infections early during the initial induction therapy (62.1% in the first 6 months of follow-up). In multivariate Cox regression analysis, high-dose oral corticosteroids (≥ 0.5 mg/kg/day in the first month of induction therapy) was an independent predictor of any infection (HR 2.66; 95% CI, 1.5-4.73), severe infections (HR 2.45; 95% CI, 1.03-5.82), and pulmonary infections (HR 2.91; 95% CI, 1.05-8.01). Pulmonary involvement increased the risk for pulmonary infections (HR 3.67; 95% CI, 1.32-10.1) and severe infections (HR 2.45; 95% CI, 1.01-5.92). CONCLUSION: Infections occur frequently with current IS regimens in aggressive glomerulonephritis. Pulmonary involvement and high-dose corticosteroid regimen were the most significant risk factors for infections. Key Points • Infections occur frequently with current immunosuppressive regimens in autoimmune aggressive glomerulonephritis. • High-dose corticosteroids are the major contributors to the risk for serious infections.

Predictive Factors of Abnormal Circadian Blood Pressure Profile in Recipients of Kidney Transplantation.

Arterial hypertension (HT) plays an important role and is a major factor in the occurrence and progression of chronic graft nephropathy. We evaluated 24-hour blood pressure (BP) profile in kidney transplant patients to identify factors predictive of abnormal circadian BP profile. BP was measured over a period of 24 hours using a noninvasive automatic device (EC-3H / ABPM) in 40 renal transplant patients (mean age = 37.2±12.2 years, M = 30, mean serum creatinine = 2.0±1.4 mg/dl). They were under the triple immunosuppressive therapy (CsA / Ts + Aza / MMF + PDN). 35 recipients (87.5%) had a nondipper BP profile, with nocturnal values which fell by less than 10% from the daytime BP values. The other 5 containers (12.5%) had normal dipper BP, with lower nighttime values by more than 10% of the daytime BP values. 17/40 recipients (42.5%) had nocturnal BP values higher than daily rates (extreme non-dipper). In none of the patients there has been excessive dipper profile (low nighttime values over 20% less than the diurnal BP). There were no statistically significant differences between the dipper and non-dipper recipients profile in terms of age, gender, creatinine, mean systolic BP (SBP) and daytime SBP, short-term variability in BP and pulse pressure (p>0.05). Factors predictive of a non-dipper BP profile were elevated median 24h BP, median 24 systolic and diastolic blood pressure (DBP), diurnal, nocturnal and 24h pulse rate (p<0.05). In conclusion, the absence of normal nocturnal BP lower values was relatively frequent (87.5%) in renal allograft recipients. In many studied patients nocturnal BP values were higher than the diurnal ones.

Current therapies in hepatorenal syndrome.

Hepatorenal syndrome (HRS) is a serious complication of liver cirrhosis with critically poor prognosis. The pathophysiologic hallmark is severe renal vasoconstriction, resulting from complex changes in splanchnic and general circulations as well as systemic and renal vasoconstrictors and vasodilators. Rapid diagnosis and management are important, since recent treatment modalities including vasoconstrictor therapy can improve short-term outcome and buy time for liver transplantation, which can result in complete recovery.

Predictive Factors for Coronary Artery Disease among Peritoneal Dialysis Patients without Diabetic Nephropathy.

OBJECTIVES: Scientific literature indicates that the risk of coronary heart disease morbidity and death among peritoneal dialysis patients exceeds risk observed in non-renal patients. The aims of this study were to establish the independent predictors associated with increased risk of coronary heart disease in peritoneal dialysis patients without diabetic nephropathy. MATERIALS AND METHODS: A number of 116 end-stage renal disease patients without diabetic nephropathy undergoing peritoneal dialysis were evaluated for coronary heart disease and predictive risk factors were investigated and identified. Also intima-media thickness measurements, as an early sign of atherosclerosis, were analyzed in a subset of patients in correlation with a number of traditional and non-traditional cardiovascular risk factors. RESULTS: The study sample was found to be characterized by a high prevalence of traditional risk factors: hypertension (95.7%), dyslipidemia (93.1%) and metabolic syndrome (58.6%), but also of dialysis-related risk factors: inflammation (82.8%) and anemia (55.2%). Independent variables found to be associated in regression analysis with coronary heart disease were: age, smoking status, nephroangiosclerosis, albumin, C-reactive protein and iPTH levels. Intima-media thickness was significantly higher in patients with coronary heart disease, values greater than 0.89 mm being associated with increased risks for coronary heart disease, acute coronary syndrome and cardiovascular death. CONCLUSIONS: The prevalence of traditional cardiovascular risk factors in these peritoneal dialysis patients is extremely high, but there are also some other factors involved, especially malnutrition and inflammation. Age higher than 55 years, smoking, albumin less than 3.5 g/dl, iPTH less than 150 pg/ml and nephroangiosclerosis were associated with highest odds ratio for coronary heart disease. An increasing CRP levels was associated with an increasing gradient for coronary heart disease risk.