Disease modification achievement in patients with lupus nephritis in a real-life setting: mission impossible?

OBJECTIVE: A preliminary definition of disease modification (DM) in lupus nephritis (LN) was recently developed focusing on long-term remission and damage prevention, with minimal treatment-associated toxicity. We aimed to further specify aspects of DM criteria in LN, assess DM achievement in a real-world setting and examine potential DM predictors and long-term outcomes. METHODS: We collected clinical/laboratory and histological inception cohort data from biopsy-proven LN patients (82% females) with ≥72 months follow-up at two joint academic centres. Specific criteria for 24-hour proteinuria, estimated glomerular filtration rate (eGFR), renal flares and glucocorticoids dose were set at three time frames (months 0-12, 13-60 and 72) to assess DM. In the first model, DM was achieved if patients fulfilled all four criteria at all three time frames (achievers). In the second model, the continued glucocorticoids reduction criterion was excluded. Logistic regression analyses were performed. Possible different trends in DM achievement between past and recent decades were also investigated. RESULTS: DM was achieved by 60% of patients, increased to 70% when glucocorticoids excluded from DM criteria. 24-hour proteinuria at 9 months predicted DM achievement (OR 0.72, 95% CI 0.53 to 0.97, p=0.03), but none of baseline characteristics. Among patients with >72 month follow-up, non-achievers had worse renal outcomes (flares, >30% proteinuria increase, eGFR decline) than achievers at the end of follow-up (median 138 months). Patients diagnosed between 1992 and 2005 were found to have significantly lower percentages of DM achievement and met less often the glucocorticoids dose reduction criterion in all three time frames, compared with those diagnosed between 2006 and 2016 (p=0.006 and p<0.01, respectively). CONCLUSIONS: DM was achieved by only 60% of LN patients in a real-life setting, partly due to lack of glucocorticoids dose target attainment, while DM failure was associated with worse long-term renal outcomes. This may imply limitations in the effectiveness or implementation of current LN treatments, supporting the need for novel therapeutic strategies.

Impaired cerebral autoregulation in Fabry disease: A case-control study.

BACKGROUND AND PURPOSE: Cerebral small vessel disease is a common manifestation among patients with Fabry disease (FD). As a biomarker of cerebral small vessel disease, the prevalence of impaired cerebral autoregulation as assessed by transcranial Doppler (TCD) ultrasonography was evaluated in FD patients and healthy controls. METHODS: TCD was performed to assess pulsatility index (PI) and vasomotor reactivity expressed by breath-holding index (BHI) for the middle cerebral arteries of included FD patients and healthy controls. Prevalence of increased PI (>1.2) and decreased BHI (<0.69) and ultrasound indices of cerebral autoregulation were compared in FD patients and controls. The potential association of ultrasound indices of impaired cerebral autoregulation with white matter lesions and leukoencephalopathy on brain MRI in FD patients was also evaluated. RESULTS: Demographics and vascular risk factors were similar in 23 FD patients (43% women, mean age: 51 ± 13 years) and 46 healthy controls (43% women, mean age: 51 ± 13 years). The prevalence of increased PI (39%; 95% confidence interval [CI]: 20%-61%), decreased BHI (39%; 95% CI: 20%-61%), and the combination of increased PI and/or decreased BHI (61%; 95% CI: 39%-80%) was significantly (p < .001) higher in FD patients compared to healthy controls (2% [95% CI: 0.1%-12%], 2% [95% CI: 0.1%-12%], and 4% [95% CI: 0.1%-15%], respectively). However, indices of abnormal cerebral autoregulation were not associated independently with white matter hyperintensities and presented a low-to-moderate predictive ability for the discrimination of FD patients with and without white matter hyperintensities. CONCLUSIONS: Impaired cerebral autoregulation as assessed by TCD appears to be highly more prevalent among FD patients compared to healthy controls.

Τhe Impact of Pre-Transplant Kidney Biopsy on the Evaluation of Prospective Living Kidney Donors.

Living kidney donation contributes to increasing the donor pool. Since safety and excellent outcomes of living kidney donors (LKD) are essential, renal biopsy must be part of the pre-transplant evaluation in donors with isolated urine abnormalities or other risk factors. We retrospectively collected data on potential living donors evaluated in the pre-transplant outpatient clinic of Laiko General Hospital of Athens between 2007 and 2022, who underwent a pre-transplant biopsy. Biopsy indications included microscopic hematuria, borderline proteinuria and comorbidities suggestive of chronicity. Those with glomerular diseases or chronic lesions were excluded from donation. We identified 59 potential living donors who underwent renal biopsy. Of these, 10 (16.9%) were male. Median age was 58 (IQR 51-63) years, while 23 (39%) were older than 60 years. 49 out of 59 (83%) had glomerular hematuria, 10 (16.7%) had proteinuria (150-300 mg/d). Out of the 59 donors, 21 (35.6%) were hypertensive, three (5.1%) had impaired glucose tolerance and seven (11.9%) had a BMI > 30 kg/m2. A total of 32 (54.2%) potential donors were accepted for donation. Eight (13.6%) had IgA nephropathy, 10 (16.9%) TBMD and nine (15.3%) had increased chronicity including secondary FSGS. When compared with a control group of donors who did not need a pre-transplant biopsy, those 32 who donated were more frequently hypertensive (p = 0.003), but had similar eGFR [61.3 (±10.4) vs. 61.9 (±13.8), p = 0.866] after a follow-up of 79 (36-114) months. Renal biopsy is a useful tool in the evaluation of prospective LKD. Thorough assessment of donors with isolated urine abnormalities and marginal donors is critical to ensure good post-donation outcomes.

Treatment of HIV-Associated Lupus-like Membranous Nephropathy with Tacrolimus: A Case Report and Review of the Literature.

Renal complications of HIV infection are common and histologically diverse. Besides HIV-associated nephropathy, which is the most well-defined glomerular disorder, immune-complex-mediated glomerulonephritis (HIVICK) is also encountered in the setting of HIV infection and may occasionally present with "lupus-like" features by light microscopy and immunofluorescence. Management of HIVICK remains controversial and mainly focuses on HIV viremia suppression with combined antiretroviral therapy. Immunosuppressive therapy may be used in order to mitigate the renal inflammation induced by the immune complex deposition. Data regarding the use of immunosuppressants in HIVICK are very limited, mostly including corticosteroids and mycophenolate acid analogues. Herein, we present the case of a 40-year-old HIV-infected Caucasian man with nephrotic syndrome, renal impairment, and a "lupus-like" membranous pattern in the kidney biopsy, who achieved a partial response of his proteinuria with a tacrolimus-based regimen in combination with antiretroviral therapy.

D313Y Variant in Fabry Disease: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: There is accumulating evidence in the literature indicating a strong correlation between Fabry disease (FD) phenotypes and specific sequence variations in the Galactosidase Alpha (GLA) gene. Among them, the potential pathogenicity and clinical relevance of D313Y variation in patients with FD remain debated. METHODS: We performed a systematic review and meta-analysis of studies reporting D313Y as single occurring variant in the GLA gene and sought to evaluate (1) the prevalence of D313Y variation in different populations with or without clinical manifestations of FD, (2) the clinical FD phenotype in D313Y-positive patients, and (3) the proportion of D313Y-positive patients presenting abnormal laboratory findings (alpha-galactosidase-A deficiency or globotriaosylceramide accumulation). RESULTS: Forty cohorts comprising 211 individuals with D313Y variation among 42,723 participants with available GLA gene-sequencing data were included. Patients highly suspected for FD had a higher prevalence of D313Y variation (4.9%, 95% CI 1.6%-9.9%; I2 = 95.5%) compared with the general population (0%, 95% CI 0%-0.1%; I2 = 1.9%; p = 0.004). The prevalence of D313Y variation was 0.6% (95% CI 0.3%-1%; I2 = 74.1%), 0.4% (95% CI 0.2%-0.7%; I2 = 0%), and 0.3% (95% CI 0.2%-0.4%; I2 = 0%) in patients presenting with neurologic, cardiac, or renal manifestations, respectively. D313Y was associated with a milder, late-onset FD phenotype, as indicated by the mean patient age of 51 years (95% CI 44-59; I2 = 94%) and the evidence of alpha-galactosidase A deficiency and globotriaosylceramide accumulation in 26.7% (95% CI 15.3%-40%; I2 = 34%) and 16.2% (95% CI 8%-26.4%; I2 = 35%) of cases, respectively. D313Y-positive patients displayed predominantly neurologic FD manifestations (58.1%, 95% CI 37.7%-77.1%; I2 = 78%), with central and peripheral nervous system (CNS/PNS) involvement noted in 28.2% (95% CI 15.4%-43.2%; I2 = 51%) and 28.5% (95% CI 17.8%-40.5%; I2 = 61%) of cases, respectively. DISCUSSION: D313Y variation seems to correlate with an atypical, mild late-onset phenotype with predominantly neurologic FD manifestations. Monitoring for CNS/PNS involvement is thus paramount to identify D313Y-positive patients with latent or early-FD pathology, which may qualify for enzyme-replacement therapy or chaperone treatment.

Predictors of Early Response, Flares, and Long-Term Adverse Renal Outcomes in Proliferative Lupus Nephritis: A 100-Month Median Follow-Up of an Inception Cohort.

Objective: To define predictors of response, time to response, flares, and long-term renal outcome in an inception cohort of proliferative lupus nephritis (PLN). Methods: We included 100 patients (80% female; mean age 31 ± 13 years) with biopsy-proven PLN (III, IV, III/IV + V). Clinical, laboratory, histological and therapeutical parameters were recorded at baseline, 6, 9, 12, 18, 24, 36, 72 months, time of flare, and last follow-up visit. Logistic and Cox-regression models were applied. Results: After induction treatment (69% received cyclophosphamide (CYC) and 27% mycophenolic acid (MPA)), partial (PR) or complete (CR) response was achieved in 59% (26% CR, 33% PR) and 67% (43% CR, 24% PR) of patients at 3 and 6 months, respectively; median time to PR was 3 months (IQR 5) and median time to CR was 6 months (IQR 9). Baseline proteinuria <1.5 g/day correlated with a shorter time to CR (HR 1.77) and with CR at 3, 6, and 9 months (OR 9.4, OR 5.3 and OR 3.7, respectively). During 100-month median follow-up, 33% of patients had ≥1 renal flares (median time: 38 months). Proteinuria >0.8 g/day at 12 months was associated with a higher risk of flares (OR 4.12), while MPA and mixed classes with lower risk (OR 0.14 and OR 0.13, respectively). Baseline proteinuria >2 g/day and 12-month proteinuria >0.8 g/day correlated with a shorter time to flare (HR 2.56 and HR 2.57, respectively). At the end of follow-up, 10% developed stage 3-4 chronic kidney disease (CKD), and 12% end-stage renal disease (ESRD). Twelve-month proteinuria >0.8 g/day (OR 10.8) and interstitial fibrosis/tubular atrophy >25% (OR 7.7) predicted CKD or ESRD at last visit. Conclusions: Baseline proteinuria <1.5 g/day predicted time to CR. Twelve-month proteinuria >0.8 g/day correlated with flares (ever) and time to flare and, along with baseline interstitial fibrosis/tubular atrophy >25%, predicted CKD or ESRD at the last visit.

New Insights Into an Overlooked Entity: Long-Term Outcomes of Membranous Lupus Nephritis From a Single Institution Inception Cohort.

Introduction: Pure membranous lupus nephritis (MLN) accounts for 10-20% of total cases of lupus nephritis and is generally associated with a better patient and renal survival compared to proliferative classes. Studies of MLN are limited by small sample size and heterogeneity of included populations since patients with pure MLN and those with mixed classes are usually examined together. Aim of the Study: To describe clinical and laboratory characteristics of patients with pure MLN, therapeutic regimens, response to treatment, renal relapses, and their long-term renal survival and to define prognostic factors of remission and relapse. Methods: We retrospectively studied an inception cohort of 27 patients with histologically proven pure MLN. Clinical, laboratory and therapeutical parameters were recorded at diagnosis, at different time points (3-6-9-12-18-24-36-72 months) during the course of the disease, at time of renal flare, and at last follow up visit. Results: 48.1% (13/27) of patients were treated with mycophenolic acid (MPA), 29.6% (8/27) with cyclophosphamide (CYC), and 3.7% (1/27) with cyclosporine (all in combination with corticosteroids). Five patients (18.5%) did not receive any immunosuppressive treatment. Mean duration of treatment was 4.7 ± 2.3 years. Median time to complete remission was 9 months (IQR = 7) and median time to partial remission was 4 months (IQR = 4). No clinical or laboratory parameter was found to be significantly associated with time to remission. Time to remission was not significantly affected by either of the two treatment regimens (CYC and MPA) (p = 0.43). Renal flare was observed in 6 (22%) of the 27 patients in a median time of 51 months (IQR = 63). Proteinuria >1 g/24 h at 1 year significantly correlated with risk of flare (OR 20, p = 0.02). After a median follow up period of 77 months, all patients had an eGFR > 60 ml/min/1.73 m2 (mean eGFR 100 ± 32 ml/min/1.73 m2). Conclusions: In a small cohort of patients with pure MLN, long-term renal survival was very good. With the limitation of the small sample size, we could not find any baseline clinical, biochemical or therapeutic factor that could predict time to remission. Proteinuria > 1 g/24 h at 1 year should be further examined in larger cohorts as a possible predictor of flare.

Validation of the International IgA Nephropathy Prediction Tool in the Greek Registry of IgA Nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is among the commonest glomerulonephritides in Greece and an important cause of end-stage kidney disease (ESKD) with an insidious chronic course. Thus, the recently published International IgAN prediction tool could potentially provide valuable risk stratification and guide the appropriate treatment module. This study aimed to externally validate this prediction tool using a patient cohort from the IgAN registry of the Greek Society of Nephrology. METHODS: We validated the predictive performance of the two full models (with or without race) derived from the International IgAN Prediction Tool study in the Greek Society of Nephrology registry of patients with IgAN using external validation of survival prediction models (Royston and Altman). The discrimination and calibration of the models were tested using the C-statistics and stratified analysis, coefficient of determination ( R D 2 ) for model fit, and the regression coefficient of the linear predictor (ßPI), respectively. RESULTS: The study included 264 patients with a median age of 39 (30-51) years where 65.2% are men. All patients were of Caucasian origin. The 5-year risk of the primary outcome (50% reduction in estimated glomerular filtration rate or ESKD) was 8%. The R D 2 for the full models with and without race when applied to our cohort was 39 and 35%, respectively, and both were higher than the reported R D 2 for the models applied to the original validation cohorts (26.3, 25.3, and 35.3%, respectively). Harrel's C statistic for the full model with race was 0.71, and for the model without race was 0.70. Renal survival curves in the subgroups (<16th, ~16 to <50th, ~50 to <84th, and >84th percentiles of linear predictor) showed adequate separation. However, the calibration proved not to be acceptable for both the models, and the risk probability was overestimated by the model. CONCLUSIONS: The two full models with or without race were shown to accurately distinguish the highest and higher risk patients from patients with low and intermediate risk for disease progression in the Greek registry of IgAN.

Pregnancy in Women With Preexisting Glomerular Diseases: A Single-Center Experience.

AIM: Women with glomerular diseases are often of childbearing age. Besides lupus nephritis, data regarding pregnancy in patients with glomerular diseases are limited, posing a challenging task to attending nephrologists. This study aimed to investigate the pregnancy outcomes and the impact on the underlying glomerular disease among women followed in our institution. METHODS: A single-center retrospective cohort study of women with biopsy-proven glomerular diseases who experienced pregnancy between 2010 and 2020. We analyzed data before, during, and after gestation. RESULTS: A total of 22 women, 13 women with primary and 9 women with secondary glomerular diseases, were included in this study. Most patients (82%) had received immunosuppressive treatment at various times before pregnancy. All the women were in remission, either complete (62%) or partial (38%), with well-preserved renal function (82%) before conception. A total of 30 live births and 1 stillbirth were recorded; the rate of preterm delivery was 23%. Renal function and proteinuria remained stable during pregnancy. Preeclampsia was observed in 6.7% of patients and disease relapse in 6.9% of the pregnancies. CONCLUSION: Pregnancy was associated with a low frequency of adverse events in women with underlying glomerular diseases, provided they have quiescent disease and preserved renal function.

Clinicopathologic features and treatment outcomes of patients with fibrillary glomerulonephritis: A case series.

ABSTRACT: Fibrillary glomerulonephritis (FGN) is a diverse glomerular disease with poor renal prognosis. The optimal therapeutic approach remains undetermined, as treatment outcomes vary across different studies.We retrospectively reviewed the medical data of 10 patients diagnosed with biopsy-proven FGN at our center between 2004 and 2019. Clinical and histological features, as well as therapeutic regimens and treatment response, are reported.The patients were predominantly men (2.5/1 men-female ratio) with a mean age at diagnosis of 46.5 years (IQR: 41.5-59.5). The median proteinuria and creatinine levels at presentation were 2.55 g/day (IQR: 0.4-8.9) and 1.35 mg/dl (IQR: 0.94-1.88), respectively. Four out of 10 patients presented with nephrotic syndrome, 5 patients with nephritic syndrome and 1 with isolated microscopic hematuria. Light microscopy showed mesangial proliferative (n = 7), membranoproliferative-like (n = 2), and diffuse sclerosing patterns (n = 1). Rituximab was used in 7/10 patients, either as monotherapy (n = 3) or combined with cyclophosphamide and corticosteroids (n = 4). Patients who were treated with immunosuppression had higher median levels of creatinine (1.40 mg/dl) and proteinuria (3.5 g/d) compared to those who received supportive treatment alone (0.94 mg/dl and 0.6 g/d, respectively). After a median follow-up of 30 months (IQR:18-66.5), 4 out of 7 patients (57%) treated with immunosuppression achieved a clinical response, 1 had persistent renal dysfunction and 2 patients progressed to end-stage renal disease.The present case series extends the existing literature on the clinical features and outcomes of FGN, as well as the use of rituximab-based regimens for the treatment of the disease. Further research is needed to establish the proper management of the disease.

Clinical impact of repeat renal biopsies in patients with lupus nephritis: Renal biopsy is essential especially later in the course of the disease.

OBJECTIVE: The clinical impact of repeat renal biopsies in patients with lupus nephritis (LN) is still debatable. The aim of this retrospective analysis was to assess whether repeat renal biopsy is a reliable tool in guiding therapeutic decisions. METHODS: Laboratory and histological parameters and therapeutic changes in 35 patients with LN and repeat renal biopsies were retrospectively analyzed. Biopsies were performed in the presence of clinical evidence of an active glomerular disease. Biopsy specimens were retrospectively re-assessed by two renal pathologists and were compared according to the last International Society of Nephrology/ Renal Pathology Society classification. RESULTS: Thirty-five patients had two, 13 had three, 5 had four, 4 had five, and 1 had six renal biopsies. Fifty-eight comparisons of renal biopsies were made. Median times between the first and second, second and third, third and fourth, and fourth and fifth biopsies were 31, 27, 34, and 28 months, respectively. The mean activity indices from the first to the fifth biopsy were 8.7, 6.6, 7.8, 9.4, and 4.7, whereas the mean chronicity indices were 1.7, 2.3, 4.3, 5.2, and 7.7, respectively. Conversion was observed in 65.5% of cases with the most frequent (21%) being between classes III and IV. Conversion to a more severe type of nephritis occurred in 19% of cases. There was no correlation of laboratory parameters to the type of nephritis upon conversion. In 79% of cases, immunosuppressive therapy was modified after repeat biopsy. CONCLUSION: Repeat biopsy is a reliable tool for monitoring the activity and chronicity status of LN and for tailoring immunosuppressive therapy to the needs of the patient, especially late in the course of the disease.

IgA nephropathy in Greece: data from the registry of the Hellenic Society of Nephrology.

BACKGROUND: Natural history, predisposing factors to an unfavourable outcome and the effect of various therapeutic regimens were evaluated in a cohort of 457 patients with immunoglobulin A nephropathy (IgAN) and follow-up of at least 12 months. METHODS: Patients with normal renal function and proteinuria <1 g/24 h as well as those with serum creatinine (SCr) >2.5 mg/dL and/or severe glomerulosclerosis received no treatment. Patients with normal or impaired renal function and proteinuria >1 g/24 h for >6 months received daily oral prednisolone or a 3-day course of intravenous (IV) methylprednisolone followed by oral prednisolone per os every other day or a combination of prednisolone and azathioprine. The clinical outcome was estimated using the primary endpoints of end-stage renal disease and/or doubling of baseline SCr. RESULTS: The overall 10-year renal survival was 90.8%, while end-stage renal disease and doubling of baseline SCr developed in 9.2% and 14.7% of patients, respectively. Risk factors related to the primary endpoints were elevated baseline SCr, arterial hypertension, persistent proteinuria >0.5 g/24 h and severity of tubulointerstial fibrosis. There was no difference in the clinical outcome of patients treated by the two regimens of corticosteroids; nevertheless, remission of proteinuria was more frequent in patients who received IV methylprednisolone (P = 0.000). The combination of prednisolone with azathioprine was not superior to IV methylprednisolone followed by oral prednisolone. Side effects related to immunossuppressive drugs were observed in 12.8% of patients. CONCLUSION: The clinical outcome of patients with IgAN was related to the severity of clinical and histological involvement. The addition of azathioprine to a corticosteroid-based regimen for IgAN does not improve renal outcome.