Prognostic role of glomerular electron microscopy lesions in IgA nephropathy: "the devil is in the details".

INTRODUCTION: Transmission electron microscopy enables examination of ultrastructural glomerular changes; while this tool has already been applied in IgA nephropathy (IgAN), limited information exists on the prognostic value in this disease. We aimed to systematically investigate ultrastructural lesions and assess their role in predicting the evolution of IgA nephropathy to end-stage kidney disease. METHODS: A single-center retrospective study was performed on 107 consecutive IgAN patients (median age 42 years, 67% male, estimated glomerular filtration rate 46 mL/min, proteinuria 1.0 g/g) between 2010 and 2015, who were followed-up until end-stage kidney disease, death, or end of study (January 2021). A pathologist evaluated the Mesangial hypercellularity (M), Endocapillary hypercellularity (E), Segmental glomerulosclerosis (S), and Tubular atrophy/interstitial fibrosis-Crescents (C) (MEST-C) score and transmission electron microscopy lesions according to a comprehensive protocol that encompassed all glomerular structures. RESULTS: Patients were followed up for a median of 7.1 years; 32 (43%) reached end-stage kidney disease. Patients who reached kidney failure had higher comorbidity score, more frequent arterial hypertension, lower estimated glomerular filtration rate, and higher MEST-C score. In terms of transmission electron microscopy lesions, patients who progressed to end-stage kidney disease had more frequent podocyte activation, effacement, and presence of microvilli; more frequent signs of endothelial cell activation and fenestration; higher mesangial cell proliferation. In the univariate Cox proportional hazard regression, higher MEST-C score and lesions detected by transmission electron microscopy in podocytes, endothelial cells, and mesangial cell proliferation were associated with shorter kidney survival time. In the multivariate Cox proportional hazard regression, only higher MEST-C score, presence of podocytes with microvilli, and mesangial cell proliferation were associated with end-stage kidney disease. CONCLUSION: This study shows that, besides the MEST-C score, the presence of podocytes with microvilli and mesangial cell proliferation are associated with poor kidney survival in IgAN patients, highlighting the prognostic value of lesions detected by transmission electron microscopy.

Bone marrow macrophage iron content and sideroblast count in iron- and ESA-naïve patients with CKD-related anemia.

BACKGROUND: Since in chronic kidney disease (CKD) iron deficiency anemia (IDA) can coexist with inflammation-induced immobilization of iron in macrophages (anemia of chronic disorders - ACD), we assessed the utility of ferritin, transferrin saturation (TSAT), and hepcidin for differentiation of mixed IDA-ACD from ACD, using bone marrow (BM) examination as reference. METHODS: This cross-sectional, single-center study analyzed 162 non-dialysis iron and epoietin-naïve CKD patients (52% males, median age 67 years, eGFR 14.2 mL/min 1.73 m2, hemoglobin 9.4 g/dL). BM aspiration, serum hepcidin (ELISA), ferritin, TSAT, and C-Reactive protein (CRP) were the main studied parameters. RESULTS: ACD was seen in 51%, IDA-ACD in 40%, while "pure" IDA in only 9%. In univariate and binomial analyses, IDA-ACD differed from ACD by lower ferritin and TSAT, but not by hepcidin or CRP. Correspondingly, in receiver operating curve analysis, ferritin and TSAT differentiated IDA-ACD from ACD, at cutoffs of 165 ng/mL and 14%, but with moderate precision (sensitivity and specificity of 72%, and 61%, respectively). CONCLUSION: The mixed pattern IDA-ACD could be more prevalent than estimated in non-dialysis CKD. Ferritin and, to a lesser degree, TSAT are useful in the diagnosis of IDA superimposed on ACD, while hepcidin, although reflecting BM macrophages iron, seems to have limited utility.

Nephrotic Syndrome and Statin Therapy: An Outcome Analysis.

Background and Objectives: Hypercholesterolemia in patients with nephrotic syndrome (NS) may predispose to cardiovascular events and alter kidney function. We aimed to evaluate statins efficiency in NS patients under immunosuppression using four endpoints: remission rate (RR), end-stage kidney disease (ESKD), major cardiovascular events (MACE), and thrombotic complications (VTE). Materials and Methods: We retrospectively examined the outcome at 24 months after diagnosis of 154 NS patients (age 53 (39-64) years, 64% male, estimated glomerular filtration rate (eGFR) 61.9 (45.2-81.0) mL/min). During the follow-up, the lipid profile was evaluated at 6 months and at 1 and 2 years. Results: The median cholesterol level was 319 mg/dL, and 83% of the patients received statins. Patients without statins (17%) had similar age, body mass index, comorbidities, blood lipids levels, NS severity, and kidney function. The most used statin was simvastatin (41%), followed by rosuvastatin (32%) and atorvastatin (27%). Overall, 79% of the patients reached a form of remission, 5% reached ESKD, 8% suffered MACE, and 11% had VTE. The mean time to VTE was longer in the statin group (22.6 (95%CI 21.7, 23.6) versus 20.0 (95%CI 16.5, 23.5) months, p 0.02). In multivariate analysis, statin therapy was not associated with better RR, kidney survival, or fewer MACE; however, the rate of VTE was lower in patients on statins (HR 2.83 (95%CI 1.02, 7.84)). Conclusions: Statins did not improve the remission rate and did not reduce the risk of MACE or ESKD in non-diabetic nephrotic patients. However, statins seemed to reduce the risk of VTE. Further randomized controlled studies are needed to establish statins' role in NS management.

Budd-Chiari syndrome: An unusual complication of an internal jugular tunneled dialysis catheter.

Budd-Chiari syndrome due to the tip of an internal jugular tunneled dialysis catheter malposition in inferior vena cava or hepatic vein is a rare complication. We aimed to present our experience and compare it with the previous reports to highlight the clinical features and the optimal management. A 57-year-old female with history of ANCAp vasculitis, treated by hemodialysis in the last 2 years on a right internal jugular vein tunneled catheter was admitted for pain in the right upper quadrant. A subacute Budd-Chiari syndrome due to catheter malposition was diagnosed. The catheter was removed, and a new tunneled hemodialysis line was inserted in the right internal jugular vein with the tip at the junction of right atrium with superior vena cava. Anticoagulation with apixaban 2.5 mg twice daily was started after catheter replacement and the patient was discharged. At 1 month follow-up the patient had no symptoms, and the ultrasound revealed the absence of the thrombus in the inferior vena cava. Imagining monitoring for malposition after insertion or in a clinical context suggestive for Budd-Chiari syndrome is essential for early diagnosis and treatment. In our case, anticoagulation with apixaban and prompt catheter replacement resulted in Budd-Chiari syndrome resolution.

How useful is kidney biopsy for the management of glomerulopathies in the elderly?

BACKGROUND: The use of kidney biopsy in elderly individuals is still matter of discussion. The purpose of this study is to assess the utility of kidney biopsy for the management of glomerulopathies in an Eastern European cohort, targeting patients older than 65 years. METHODS: This retrospective study included 875 adults (147 older than 65 years), with biopsy-proven glomerulopathies, followed up for 71.1 (95% CI 68.2-73.9) months. The primary endpoint was chronic renal replacement therapy initiation. Statistical evaluation was performed with IBM SPSS software version 20, Analyse-it, and SAS Studio. The Kaplan-Meier method was used to estimate the time to death and the log-rank test was used for comparisons. The multivariate Cox proportional hazard analysis was used to evaluate the risk of death. RESULTS: Secondary glomerulopathies were more frequent in patients aged > 65 years (52.4% vs. 41.9%, p = 0.004). Membranous nephropathy and amyloidosis were the most frequent primary and secondary glomerulopathies in this age group. Kidney biopsy complications were low (< 4%) in both age groups. In 42% of the elderly, the result of biopsy guided the immunosuppressive therapy. While the all-cause mortality rate was higher (OR 4.2; 95% CI 2.7-6.7; p < 0.0001) in elderly individuals, the rate of renal replacement therapy initiation was similar (31.3 vs 26%; p = 0.1) in both age groups. In the competitive risk analysis, kidney survival was similar irrespective of age [CIF 0.4 (95% CI 0.26-0.53) vs. 0.34 (95% CI 0.28-0.39), p = 0.08]. However, after adjusting for the confounding factors, younger age was associated with an increased risk of renal replacement therapy (HR = 1.57, p = 0.01), along with secondary glomerulopathies. CONCLUSION: The diagnosis of an underlying glomerulopathy guided the therapy in almost one-half of the elderly patients who underwent a kidney biopsy, provided important prognostic information and had a low complications rate; kidney biopsy may therefore be considered a safe, reliable procedure in the management of glomerulopathies, even in patients over 65 years of age.

Intravenous Iron-Carbohydrate Nanoparticles and Their Similars. What Do We Choose?

Anemia is highly prevalent worldwide and iron deficiency is the first cause. Iron deficiency has not only hematologic effects but also non-hematologic effects - immune, metabolic, cognitive dysfunctions and poor cardiovascular and renal outcomes - which generally precede anemia. Iron therapy not only significantly improves the hematological parameters but also has non-hematologic benefits. Given that its efficacy and safety has been revealed over the years, intravenous (IV) iron therapy is frequently used. Intravenous iron products are nanoparticles largely consisting in an iron core surrounded by a carbohydrate shell. They are classified as non-biological complex molecules, being different from small commonly used molecules, with properties and biological behavior impossible to be completely characterized only by physicochemical analysis. To date, there is no appropriate regulatory evaluation system for these medicines and several follow-on versions of the IV iron originators (e.g., iron sucrose) were approved using the same regulatory pathway as for generics. Because of this vulnerability in an adequate pathway for approval, both non-clinical and clinical studies suggested no therapeutic equivalence (thus no interchangeability) between iron sucrose originator (Venofer®), and iron sucrose similars. In this review we aimed to underline the importance of intravenous iron therapy as well as raise awareness regarding the differences between nanomedicines and their intended similar but not identical copies. The potential implications of these differences impact patients (safety, efficacy) but also the medical system (higher costs).

Nephrotic Syndrome Complications - New and Old. Part 2.

The nephrotic syndrome consists of heavy proteinuria with hypoalbuminemia. These are the clinical manifestations of several rare kidney disease. Although the population incidence is low (an estimated incidence of three cases per 100 000 patient-years), nephrotic syndrome has been associated with a range of complications including cardiovascular and thromboembolic events, acute kidney injury or systemic infections. These complications are generated by a combination of increased protein urinary losses and greater liver protein synthesis. The current paper aims to present pathophysiological mechanisms and current therapeutic recommendations for hyperlipidemia, acute kidney injury and other complications associated with nephrotic syndrome.

Nephrotic Syndrome Complications - New and Old. Part 1.

Nephrotic syndrome is a rare condition with an incidence of 2-7 cases/100.000 children per year and three new cases/100.000 adults per year. It occurs as a result of severe alteration of the glomerular filtration barrier of various causes, allowing proteins, mostly albumin, to be lost in the urine. Nephrotic syndrome complications are driven by the magnitude of either proteinuria or hypoalbuminemia, or both. Their frequency and severity vary with proteinuria and serum albumin level. Besides albumin, many other proteins are lost in urine. Therefore, nephrotic patients could have low levels of binding proteins for ions, vitamins, hormones, lipoproteins, coagulation factors. The liver tries to counterbalance these losses and will increase the unselective synthesis of all types of proteins. All of these changes will have different clinical consequences. The present paper aims to discuss the pathophysiological mechanism and new therapeutic recommendations for nephrotic syndrome edema and thromboembolic complications.

Negative anti-phospholipase A2 receptor antibody status at three months predicts remission in primary membranous nephropathy.

BACKGROUND: The value of anti-phospholipase A2 receptor antibody (anti-PLA2R ab) monitoring at 3 months after diagnosis in membranous nephropathy (MN) remains uncertain. METHODS: We retrospectively examined the outcome on 1 August 2020 of 59 adult patients (age 54 (44, 68) years, 69% male, SCr 1.0 (0.9, 1.3) mg/dL) diagnosed with MN (kidney biopsy, positive serum anti-PLA2R ab). The outcomes were: kidney survival; partial and/or complete remission. RESULTS: Most of the studied patients (97%) received immunosuppression, cyclophosphamide regimens were the most frequent (87%), followed by cyclosporine (10%). The median time to remission was 12.0 months and the cumulative remission rates were 34% at 6, 54% at 12, and 73% at 24 months. Forty (69%) patients had negative anti-PLA2R ab at 3 months, they had similar age, serum creatinine, albumin, proteinuria, and treatment with the group with positive ab at 3 months. In the Cox proportional hazard model, three months anti-PLA2R ab negativization (HR 0.4 (95%CI 0.1, 0.9)) was an independent predictor for remission, while baseline hypoalbuminemia (HR 3.0 (95%CI 1.5, 5.7)) was associated with absence of remission. Six (10%) patients died, mostly due to cardiovascular disease and infections. A total of five (9%) patients started dialysis. Mean kidney survival time was 50.3 months and there was no survival difference in relation to baseline anti-PLA2R ab titer (p .09) or 3 months negativization (p .8). CONCLUSIONS: Three months anti-PLA2R ab negativization seems to be a late predictor of remission, and lower serum albumin at diagnosis is an early marker for remission absence. Abbreviations: anti-P LA2R ab, anti-phospholipase A2 receptor antibody; eGFR, estimated glomerular filtration rate; ESKD, end stage kidney disease; MN, membranous nephropathy; NELL-1, neural epidermal growth factor-like 1 protein; RAAS: renin-angiotensin-aldosterone system; RBC: red blood cells; RRT, renal replacement therapy; T HSD7A, thrombospondin type-1 domain containing 7A.

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.

Hydroxychloroquine in IgA nephropathy: a systematic review.

BACKGROUND: Hydroxychloroquine (HCQ) has recently been reported to be a promising and safe anti-proteinuric agent for IgA nephropathy (IgAN) patients. In the present systematic review, we aimed to summarize the evidence concerning the benefits and risks of HCQ therapy in IgAN. METHODS: Electronic databases were searched for randomized, cohort, or case-control studies with IgAN biopsy-proven patients comparing the effects of HCQ with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or immunosuppression on proteinuria reduction. RESULTS: Five studies, one randomized and three observational, involving a total of 504 patients, were eligible for inclusion. Overall, there was a tendency of HCQ treatment to reduce proteinuria. In the studies where the control arm was supportive therapy, HCQ significantly reduced proteinuria at 6 months. However, in the studies that compared HCQ to immunosuppressive therapy, we found no difference in proteinuria reduction. HCQ had no impact on eGFR. CONCLUSION: HCQ seems to be an efficient alternative therapy for patients with IgAN who insufficiently respond to conventional therapy. However, ethnically diverse randomized controlled studies with long-term follow-up are needed.

Long-Term Intravenous Iron Therapy and Morbidity in Hemodialysis Patients.

Objective: The aim of this study was to describe long-term intravenous iron therapy-associated morbidity in hemodialysis patients from a single Hemodialysis Center. Material and methods: We conducted an observational retrospective cohort study from 01 January to 31 December 2015. Two hundred and twenty prevalent patients on maintenance hemodialysis therapy for at least 12 months (mean age 53±13 years, 56% males, median hemodialysis vintage 5 (1-26) years) were included. Diabetic nephropathy as primary kidney disease, pregnancy and incomplete data records regarding study aims were exclusion criteria. We compared the frequency, duration and causes of hospitalizations in iron sucrose-treated versus gender and age-matched iron non-treated patients. Differences between groups were assessed using Chi-square and Kruskal-Wallis H tests. A p value µ0.05 was considered statistically significant. Results: From the entire cohort, 68% were iron-treated. One in five patients were treated with higher doses (400 mg monthly), and lower doses were used (100-200 mg monthly) in 80% of patients. There were no differences regarding the rates of admission between the two groups (56/100 patient-years in the iron sucrose-treated vs. 50/100 patient-years in the iron-untreated group, p=0.1). Still, the hospitalization rate significantly increased with the administered iron dose (0.4 vs. 0.7 vs. 0.8/100 patient-years for 100 mg vs. 200 mg vs. 400 mg monthly, respectively, p=0.006). Hospitalization rates due to infectious and cardiovascular diseases were similar for both groups (12/100 patient-years vs. 5.7/100 patient-years, p=0.3 and 11.3/100 patient-years vs. 4.3/100 patient-years, p=0.2, respectively). Conclusion: Higher doses of intravenous iron sucrose appear to be associated with an elevated risk of hospitalization. Nonetheless, long-term intravenous iron therapy seems to have a limited influence in terms of specific cause of morbidity in non-diabetic hemodialysis patients.

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.

IgA nephropathy with serum ANCA positivity: case series and literature review.

The co-occurrence of IgA nephropathy (IgAN) and positive anti-neutrophil cytoplasmic autoantibodies (ANCA) serology is uncommon. In the present case series and literature review, we aimed to clarify the impact of ANCA on pathogenesis, clinical and histopathology presentation, and outcome in IgAN patients. We report four patients with an overlap lesion of IgAN-ANCA positive. Also, we performed a narrative review of all biopsy-proven published case series. Only 1.2% patients had ANCA in our 330-biopsy-proven IgAN cohort. We compared our data with previous reports-6 case series and 3 small retrospective studies-a total of 103 patients. All patients but one had eGFR below 15 mL/min at diagnosis. Besides rapidly decreasing eGFR, all presented with proteinuria around 1.5 g/day and dysmorphic microhematuria, suggesting glomerular inflammation. Systemic symptoms suggestive for ANCA vasculitis were seen in half of our patients, but only one patient had hemorrhagic alveolitis. Patients from our cohort responded to the intensive immunosuppressive regimens used in ANCA-positive vasculitis with renal involvement. However, in the follow-up, one patient had a relapse followed by septic shock related to immunosuppression and one patient started hemodialysis. In the review, we found that IgAN-ANCA -positive patients are characterized by vasculitis-like lesions and clinically by a rapidly progressive decline in kidney function, which was reversed by an aggressive induction immunosuppressive protocol used in ANCA vasculitis. Checking ANCA serology seems useful in patients with rapidly progressive IgAN for therapeutic and prognostic reasons.

Low-salt low-protein diet and blood pressure control in patients with advanced diabetic kidney disease and heavy proteinuria.

PURPOSE: To assess the associations between effects of low salt, low protein diet supplemented with keto-analogues (sLPD)-on salt intake, blood pressure (BP) and cardiovascular events (CVEs) in patients with advanced diabetic kidney disease (DKD) and heavy proteinuria. METHODS: Prospective, single-center study (total duration of 15 months), enrolling 92 patients with advanced DKD (median eGFR 11.7 ml/min) and heavy proteinuria (median 4.8 g/g creatininuria). The intervention consisted in a low salt-low protein (0.6 g/kg-day) diet (sLPD) under intensive nutritional counselling, and adjustment of antihypertensive therapy. The endpoints of this sub-analysis were a salt intake ≤ 5 g/day, a mean blood pressure (MAP) ≤ 97 mmHg, corresponding to KDIGO target of 130/80 mmHg, and the rate of CVEs. RESULTS: Salt intake decreased with 2.5 g/day and the proportion of patients reaching the salt intake endpoint increased with 58%. A salt intake ≤ 5 g/day was associated with a reduced MAP, BMI, proteinuria, fractional excretion of sodium, and eGFR, suggesting a salt-related volume contraction but was not related to protein intake. Mean arterial pressure decreased with 13 mmHg. MAP ≤ 97 mmHg was associated with lower proteinuria, salt, and protein intake, but the contribution of salt intake cannot be differentiated from that of protein intake. CVEs occurred in 20% of patients and were independently related to a lower age and MAP, and increased comorbidities. eGFR only minimally declined and no renal adverse events were noted. sLPD was nutritionally safe. CONCLUSIONS: The multifactorial personalized intervention allowed a stable MAP reduction to KDIGO recommended levels (≤ 97 mmHg), related to the decrease in salt and protein intake. However, BP lower than 130/80 mmHg increased the cardiovascular but not the renal risk in heavy proteinuric patients with advanced DKD. TRIAL REGISTRATION NUMBER: 0341507433: NCT03415074. Registered 02/02/2015 in US National Library of Medicine, ClinicalTrials.gov (NCT).

Adult-onset minimal change disease: the significance of histological chronic changes for clinical presentation and outcome.

INTRODUCTION: Data on pathologic features with prognostic utility in adults with minimal change disease (MCD) are limited. We assessed the relationship between histologic chronic changes and clinical presentation and outcomes. METHODS: The consecutive records of 79 patients with MCD and minimum of 6 months follow-up were retrospectively reviewed. Kidney survival was the primary endpoint (doubling serum creatinine or dialysis initiation). Secondary endpoints were time to remission and relapse. Total chronicity score was the sum of glomerulosclerosis (0-3), interstitial fibrosis (0-3), tubular atrophy (0-3), and arteriolosclerosis (0/1). RESULTS: The median renal chronicity score was 1; 77% had minimal (0-1), 18% mild (2-4), and 5% moderate (5-7) chronicity. Fifty percent had a null score; they were younger, had higher eGFR, similar proteinuria, better renal survival, and lower mortality. Mean kidney survival time was 5.7 (95% CI 5.2-6.2) years; 89% reached a form of remission at a median of 8 weeks; 31% relapsed at a mean of 26 months. Chronic changes severity predicted both relapses and kidney survival, each one-point increase in score raised with 27% the risk of relapse and with 31% the risk of dialysis initiation. Acute kidney injury (AKI) was present in 42% of the patients; they had more often mesangial proliferation, interstitial inflammation, tubular atrophy, arteriosclerosis, podocyte villous hypertrophy, and higher chronicity score. CONCLUSION: Standardized grading of chronicity was a predictor of kidney survival and disease relapse and was related to AKI. Older patients with severe nephrotic syndrome and with increased chronicity score could represent a high-risk category.

Non-diabetic glomerular lesions in diabetic kidney disease: clinical predictors and outcome in an Eastern European cohort.

PURPOSE: Since patients' prognosis depends on the lesions identified by kidney biopsy (KB), we aimed to evaluate predictors of non-diabetic kidney disease (NDKD) in diabetic subjects and to assess their kidney outcome as compared to diabetic nephropathy (DN). METHODS: 180 adults diagnosed by KB with DN (n = 120) or NDKD (n = 60), over a 10 year time-span, were retrospectively included and followed for a mean of 48.1 (95% CI 43.1-53.1) months. Patients with superimposed specific lesions over DN and with steroid-induced diabetes were excluded. The primary endpoint was renal replacement therapy (RRT) initiation. Only subjects who were alive at the end of follow-up (73 with DN and 38 with NDKD) entered the kidney survival analysis. RESULTS: Membranous nephropathy (9%) was the most common NDKD. Predictors for NDKD were shorter duration of diabetes (OR 0.88; 95% CI 0.81-0.96, p = 0.004), absence of diabetic retinopathy (OR 0.08; 95% CI 0.01-0.44, p = 0.003), and nephrotic syndrome at presentation (OR 3.55; 95% CI 1.39-9.04, p = 0.008). Subjects with NDKD needed RRT later as those with DN [82 (95% CI 67-97.1) vs. 45 (95% CI 34-56.5) months, p = 0.001]. In an adjusted Cox model, biopsy diagnosed DN independently predicted RRT (OR 4.43; 95% CI 1.54-12.7, p = 0.006). Other predictors were lower eGFR, higher proteinuria, and absence of renin-angiotensin inhibitor therapy. CONCLUSION: As one-third of the investigated subjects had NDKD, and NDKD was associated with a better kidney survival, independently predicted by the type of glomerular lesion, KB appears the most reliable tool to guide therapy and to assess outcome in patients with diabetic kidney disease.

Is There a Role for IgA/C3 Ratio in IgA Nephropathy Prognosis? An Outcome Analysis on An European Population.

INTRODUCTION: Serum immunoglobulin A (IgA)/C3 ratio has been reported as a predictor of histological lesions and prognosis in asian patients with IgA nephropathy (IgAN). Since its validity in other populations is unclear, we aimed to evaluate the relationship between IgA/C3 ratio and renal outcome in Caucasian European patients with biopsy-proven IgAN. METHODS: We conducted a retrospective, observational study on 95 patients with primary IgAN patients diagnosed between 2010 to 2017 (70% male, age 41 (34 to 49) years, eGFR 39.4 (25.2 to 56.5) mL/ min, proteinuria 1.7 (0.8 to 3.0) g/g). The primary study composite end-point was doubling of serum creatinine, ESRD (dialysis or renal transplant) or death, whichever came first. RESULTS: Median follow-up was 30 (95% CI: 27.5 to 32.4) months; 11% developed ESRD, 10% experienced serum creatinine doubling, and 1% died. The endpoint was reached by 21% of the patients. They had lower eGFR, higher proteinuria and hematuria, and lower serum albumin. The distribution in Oxford classes was alike. The AUROC for IgA/C3 ratio was 0.60 (95% CI: 0.45 to 0.74) and generated an optimal cut-off of 2.91 (sensitivity 68%, specificity 55%). The mean event-free survival of the whole cohort was 5.2 (95% CI: 4.7 to 5.8) years. Patients with IgA/C3 ratio < 2.9 had a tendency to better renal survival (P > .05). In Cox proportional hazard ratio model, the independent predictors of a poorer eventfree survival were higher serum creatinine, higher proteinuria and increased IgA/C3 ratio, while renin angiotensin system inhibitors predicted better outcome. CONCLUSION: Our study reports evidence that supports IgA/C3 ratio as a reasonable predictor of IgAN prognosis in European patients.

Results from the ERA-EDTA Registry indicate a high mortality due to COVID-19 in dialysis patients and kidney transplant recipients across Europe.

The aim of this study was to investigate 28-day mortality after COVID-19 diagnosis in the European kidney replacement therapy population. In addition, we determined the role of patient characteristics, treatment factors, and country on mortality risk with the use of ERA-EDTA Registry data on patients receiving kidney replacement therapy in Europe from February 1, 2020, to April 30, 2020. Additional data on all patients with a diagnosis of COVID-19 were collected from 7 European countries encompassing 4298 patients. COVID-19-attributable mortality was calculated using propensity score-matched historic control data and after 28 days of follow-up was 20.0% (95% confidence interval 18.7%-21.4%) in 3285 patients receiving dialysis and 19.9% (17.5%-22.5%) in 1013 recipients of a transplant. We identified differences in COVID-19 mortality across countries, and an increased mortality risk in older patients receiving kidney replacement therapy and male patients receiving dialysis. In recipients of kidney transplants ≥75 years of age, 44.3% (35.7%-53.9%) did not survive COVID-19. Mortality risk was 1.28 (1.02-1.60) times higher in transplant recipients compared with matched dialysis patients. Thus, the pandemic has had a substantial effect on mortality in patients receiving kidney replacement therapy, a highly vulnerable population due to underlying chronic kidney disease and a high prevalence of multimorbidity.

Kidney Involvement in Hypocomplementemic Urticarial Vasculitis Syndrome-A Case-Based Review.

Hypocomplementemic urticarial vasculitis syndrome (HUVS), or McDuffie syndrome, is a rare small vessel vasculitis associated with urticaria, hypocomplementemia and positivity of anti-C1q antibodies. In rare cases, HUVS can manifest as an immune-complex mediated glomerulonephritis with a membranoproliferative pattern of injury. Due to the rarity of this disorder, little is known about the clinical manifestation, pathogenesis, treatment response and outcome of such patients. We describe here three cases of HUVS with severe renal involvement. These patients had a rapidly progressive form of glomerulonephritis with severe nephrotic syndrome against a background of a membranoproliferative pattern of glomerular injury with extensive crescent formation. Therefore, these patients required aggressive induction and maintenance immunosuppressive therapy, with a clinical and renal response in two patients, while the third patient progressed to end-stage renal disease. Because of the rarity of this condition, there are few data regarding the clinical presentation, pathology and outcome of such patients. Accordingly, we provide an extensive literature review of cases reported from 1976 until 2020 and place them in the context of the current knowledge of HUVS pathogenesis. We identified 60 patients with HUVS and renal involvement that had adequate clinical data reported, out of which 52 patients underwent a percutaneous kidney biopsy. The most frequent renal manifestation was hematuria associated with proteinuria (70% of patients), while one third had abnormal kidney function on presentation (estimated glomerular filtration (GFR) below 60 mL/min/1.73 m2). The most frequent glomerular pattern of injury was membranoproliferative (35%), followed by mesangioproliferative (21%) and membranous (19%). Similar to other systemic vasculitis, renal involvement carries a poorer prognosis, but the outcome can be improved by aggressive immunosuppressive treatment.