Renal Biopsy Research Articles

P43 Unmasking posterior reversible encephalopathy syndrome: a hidden threat in juvenile lupus

Abstract Introduction Posterior reversible encephalopathy syndrome (PRES) is a neurological condition identifiable through clinical presentation and magnetic resonance imaging (MRI). While PRES has been rarely documented in children as a complication of juvenile lupus, it remains a potentially reversible condition. However, it can be complicated by vasculopathy, infarction, or haemorrhage. The pathogenesis of PRES is still unclear. In juvenile lupus, the risk factors for PRES are multifaceted and interact with each other, including vasculitis, lupus nephritis, chronic kidney disease (CKD) leading to renal-origin hypertension, and iatrogenic hypertension caused by several hypertension-inducing drugs commonly used as first-line treatments for lupus. Case description A 14-year-old girl diagnosed with lupus presented with persistent fatigue, lower limb oedema, and abdominal symptoms (vomiting and diarrhoea). She experienced two episodes of PRES, three months apart. Active SLE was confirmed through clinical and laboratory findings, including positive autoimmune and serologic results for ENA antibody screen, high levels of anti-double-stranded DNA (>400), and low complements C3 (0.15 g/L) and C4 (<0.03 g/L). Urine analysis revealed 2+ RBCs, 3+ proteins, and an estimated glomerular filtration rate (eGFR) of ∼21 ml/min/1.73 m² with a plasma creatinine of 226 micromol/L. Renal biopsy identified lupus nephritis class IV and chronic kidney disease (CKD) changes, leading to a diagnosis of CKD stage 4. Initial treatment included a course of pulse methylprednisolone (1 g daily for 3 days) alongside rituximab and MMF for remission induction followed by high-dose oral prednisone (2 mg/kg/d). Her blood pressure started to increase following the first methylprednisolone pulse. In addition, two weeks later, severe fluid overload necessitated dialysis. Despite dialysis and the use of four antihypertensive agents (lisinopril, amlodipine, atenolol, doxazosin), her blood pressure fluctuated and remained uncontrolled. A week later, she experienced focal seizures. While a CT brain scan showed no abnormalities, an MRI revealed multifocal areas of bilateral cerebral hemispheric cortico-subcortical signal and diffusion alteration, indicating evolving PRES. A steroid weaning plan was implemented, and IV cyclophosphamide was initiated according to the National Institutes of Health protocol. Eight weeks later, she had another PRES episode, presenting with seizures confirmed by MRI findings. On both occasions, hypertensive encephalopathy was promptly recognized, and she was transferred to the PICU. Fortunately, her symptoms completely resolved within 12 hours of anticonvulsant and antihypertensive therapies. Discussion Common triggers of PRES include autoimmune conditions such as systemic lupus erythematosus (SLE), hypertensive encephalopathy, and drug toxicities (mainly cytotoxic and immunosuppressive drugs), all of which interact in lupus patients. However, it remains unclear how each factor contributes to the development of PRES. Additionally, the exact pathophysiological mechanism behind PRES is still debated. The two most widely accepted hypotheses involve: firstly, increased arterial blood pressure overwhelming cerebral autoregulatory mechanisms, leading to vascular leakage and vasogenic oedema. Secondly, endothelial dysfunction, where endothelial damage caused by circulating toxins enhances the release of vasoactive and immunogenic agents, altering vascular permeability. Our patient’s development of PRES is multifactorial, with lupus nephritis being a primary cause, aggravated by chronic kidney disease, leading to salt and water retention, which was further exacerbated by prednisolone. Other drugs, such as rituximab and cyclophosphamide, might have also been implicated in causing hypertension. PRES following rituximab infusion has been documented, with onset ranging from immediately after infusion to up to four weeks later. Proposed mechanisms include compromised blood-brain barrier integrity and immune dysregulation. Intravenous cyclophosphamide has also been identified as a potential trigger for PRES in patients with and without SLE, though the exact reason for this remains unclear. The dual role of these drugs in potentially precipitating life-threatening risks like PRES while being therapeutic agents presents a confusing dilemma. Much remains to be learned to enable the prevention and prompt response to PRES. Key learning points • Juvenile lupus with PRES is an uncommon neurological manifestation influenced by multiple factors. • Risk factors for PRES in juvenile lupus include lupus nephritis, CKD secondary to lupus, and iatrogenic hypertension including steroids, rituximab, and cyclophosphamide. These factors commonly exist and interplay together. • The pathogenesis of PRES in lupus, including the role of drugs, remains unclear. • Patients with lupus should be closely monitored, particularly their blood pressure. • Early diagnosis and prompt treatment of PRES can reverse radiologic and neurologic findings, leading to a favourable prognosis.

P49 Belimumab as a potential therapy for lupus enteritis – a case report

Abstract Introduction Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with varied clinical manifestations. Gastrointestinal (GI) complaints are common in 40–60% of SLE patients. Most are mild; however severe life-threatening manifestations may occur. Lupus enteritis (LE) is a rare but severe GI manifestation of SLE, characterised by vasculitis or inflammation of the bowel. Belimumab is a recombinant human monoclonal antibody against the soluble B-lymphocyte stimulator protein (BLyS) and was the first licensed treatment for SLE and lupus nephritis. Herein, we report a case of lupus enteritis that responded well to belimumab therapy. Case description We present a 42-year-old Sri Lankan woman who was diagnosed with SLE in 2015 based on arthritis, Raynaud’s, haemoproteinuria, positive antinuclear antibodies (ANA), anti-double stranded DNA (dsDNA), and anti-Ro antibodies with low complements C3, C4. Renal biopsy confirmed class III a+c lupus nephritis. She was managed with prednisolone, mycophenolate mofetil, hydroxychloroquine and ramipril. She responded well to treatment. She was admitted in August 2018 with recurrent abdominal pains, distension, diarrhoea, nausea, vomiting, 20kg unintentional weight loss, arthritis, lymphadenopathy, and peripheral oedema. Over the last 12 months, she had 5 admissions with similar GI symptoms, which were managed as viral gastroenteritis. Investigations showed nephrotic range proteinuria - urine PCR 330 (0-15 mg/mmol), low albumin = 27 (40-52 g/L), positive anti-dsDNA antibodies = 211 (0-10 IU/ml), CRP 7 (0-4 mg/L), ESR 44 (0-12 mm/hr) with low complements C3 0.36 (0.90-1.80 g/L) and C4 0.07 (0.10-0.40 g/L). Contrast enhanced computed tomography (CECT) scan of the abdomen revealed diffuse oedema of the large bowel extending from the splenic flexure to the rectum, several areas of small bowel thickening, peritoneal enhancement, and moderate volume ascites. Infective causes for colitis were ruled out including abdominal tuberculosis. Sigmoidoscopy and biopsy ruled out inflammatory bowel disease, whereas surgical and gastroenterology reviews ruled out other causes for her presentation. She was diagnosed with lupus enteritis with flare of lupus nephritis and managed with pulsed intravenous methylprednisolone followed by tapering high dose oral prednisolone. Her symptoms gradually improved, and she was discharged. Unfortunately, over the next month, she had recurrent admissions with flares of lupus enteritis requiring further intravenous methylprednisolone. As a result, she was commenced on monthly IV belimumab. Since starting belimumab, she has not had any further flares of lupus enteritis and her anti-dsDNA antibody and complements C3, C4 levels have normalised. Discussion Lupus enteritis (LE) presents with non-specific GI symptoms such as abdominal pain (most common), nausea, vomiting, diarrhoea and ascites. In most cases, it develops months to years after SLE diagnosis but in some cases, may be the presenting feature. Its pathogenesis remains unknown; however, mesenteric vasculitis and/or thromboses are thought to play a role. Contrast enhanced computed tomography (CECT) abdomen is the gold-standard investigation and usually shows bowel wall oedema, dilated bowel loops (>3 cm), bowel wall thickening with peripheral enhancement (“target sign”/”double halo sign”), engorgement of mesenteric vessels with a palisade pattern (“comb-sign”), increased attenuation of mesenteric fat and/or ascites. Laboratory investigations usually reveal markers of active lupus. Significant proteinuria (>0.5 g/24 h) is usually found in around 50% of patients. LE is very steroid responsive, with most patients achieving disease remission with steroids alone. Additional immunosuppression (such as cyclophosphamide, MMF, azathioprine, HCQ or rituximab) may be used concomitantly, for other manifestations of SLE or in those with relapsing or refractory disease. Belimumab has previously been licensed for use in SLE and lupus nephritis; however, there is sparse literature about its use in lupus enteritis. Our patient responded very well to belimumab, with both clinical and immunological remission. Key learning points • Lupus enteritis is a rare but severe gastrointestinal (GI) manifestation of SLE that presents with non-specific GI symptoms such as abdominal pain (most common), nausea, vomiting, diarrhoea and ascites. Clinicians managing SLE patients should have a high index of suspicion regarding the diagnosis, else it may be easily missed leading to recurrent admissions and delayed treatment. • Contrast enhanced CT abdomen is the gold-standard investigation and shows characteristic changes - bowel wall oedema, dilated bowel loops (>3 cm), bowel wall thickening with peripheral enhancement (“target sign”/”double halo sign”), engorgement of mesenteric vessels with a palisade pattern (“comb-sign”), increased attenuation of mesenteric fat and/or ascites • Lupus enteritis is very steroid responsive, with most patients achieving disease remission with steroids alone. Some patients with other SLE manifestations, or relapsing/refractory disease may require additional immunosuppression. Belimumab may be another option to consider in such patients.

P38 Lupus enteritis as a first presentation of systemic lupus erythematosus in a previously well patient: a very rare occurrence

Abstract Introduction Lupus enteritis is an anecdotally rare condition (with no formal estimates of incidence) which can pose a diagnostic challenge, especially when presenting without other lupus-related symptoms and signs. Here, we present an unusual case where lupus enteritis was the first manifestation of systemic lupus erythematosus (SLE). Case description A 65-year-old South Asian female presented with a 6-month history of intermittent nausea, vomiting and abdominal pain, with the only systemic feature being worsening fatigue. She had no connective tissue disease features, previous miscarriage or venous thromboembolism (VTE). Over six months, she had multiple hospitalisations in different hospitals with recurrent attacks of episodic abdominal pain and vomiting, associated with migratory and reversible intestinal inflammation on serial imaging. Initial investigations revealed lymphopenia (0.99x109/L) and hypoalbuminaemia (25 g/L). During a two-month admission at our centre, she underwent detailed gastrointestinal investigations, including four abdomino-pelvic CT scans during transient episodes of pain and vomiting, showing diffuse wall thickening affecting different parts of the gastrointestinal tract at different times. Following discussion at specialist radiology and inflammatory bowel disease multidisciplinary meetings, these CT scans and an MRI small bowel study were confirmed to demonstrate a transient, migratory, reversible pattern of bowel inflammation affecting the ileum, jejunum and colon at different time points; there were no clinical, endoscopic, histological or imaging features of inflammatory bowel disease. Gastro-duodenal biopsies were normal and negative for amyloidosis and tuberculosis. Colonic biopsies excluded inflammation. C1 esterase inhibitory deficiency was excluded. A vasculitis screen was negative, but immunology was positive for anti-nuclear and anti-chromatin antibodies, with positive crithidia, but normal dsDNA. C3 was normal, but C4 was low at 0.04 g/L. Urinalysis showed significant albuminuria (413.8 mg/mmol). Following multidisciplinary discussion between gastroenterology, clinical immunology and rheumatology, a diagnosis of SLE was made, with an initial presentation of lupus enteritis. She received a tapering dose of corticosteroids and hydroxychloroquine. The patient suffered from a right-sided multi-segmental pulmonary embolus with infarction, but this was felt to be due to her nephrotic syndrome (negative anti-cardiolipin and β2-glycoprotein antibodies). Renal biopsy revealed class I lupus nephritis with podocytopathy. The patient was duly commenced on tacrolimus as a steroid-sparing agent. Discussion Lupus enteritis is a rare, poorly-defined condition, with only small amounts evidence regarding treatment and management in the literature, although a narrative review of 58 papers has recently been published. However, the average time between diagnosis of SLE and presentation with lupus enteritis is around 44 months, meaning that isolated enteritis as a first presentation of SLE is extremely rare. Only two out of 150 patients reviewed by Janssens et al (from a single tertiary lupus centre) presented with enteritis prior to a diagnosis of SLE. Lupus enteritis is potentially serious if left untreated, and can lead to life-threatening complications such as intestinal necrosis and/or perforation. This rare presentation highlights the importance of considering lupus enteritis in the differential in any patient presenting with non-specific gastrointestinal symptoms and a migratory pattern of intestinal inflammation on radiological investigations. This can enable prompt diagnosis and timely management. Key learning points • Lupus enteritis can be a first presentation of SLE without any other classical manifestations. • Lupus enteritis is extremely rare, but can be life-threatening if not identified and rapidly treated. • Radiology can demonstrate transient, migratory bowel inflammation on serial imaging.

What is the spectrum of kidney pathology associated with COVID-19?

Kidney involvement occurs in almost one third of patients hospitalised with coronavirus disease 2019 (COVID-19) and is associated with increased disease severity. This review aims to outline the spectrum of kidney pathology involved in COVID-19. Literature was reviewed systematically on the databases Medline OVID and Scopus in search of case reports, case series, cohort studies and autopsy studies of patients with COVID-19 who underwent kidney biopsies. Studies were published between August 2020 and November 2021. Fourteen studies consisting of 159 patients were included in this review. Acute tubular necrosis is the most common pathology followed by collapsing glomerulopathy, occurring in 40.1% and 28.9% of patients respectively. Of the 46 patients with collapsing glomerulopathy, 44 were of African descent with high-risk apolipoprotein L1 genotypes. Less common glomerular diseases include membranous nephropathy, secondary focal segmental glomerulosclerosis, minimal change disease and primary focal segmental glomerulosclerosis occurring in 5%, 4.4%, 3.1% and 2.5% of patients respectively. Glomerulonephritis occurred in a minority of patients. Direct viral infection has not been found as a definitive aetiology. Acute kidney injury occurs frequently in hospitalised COVID-19 patients and is associated with increased morbidity and mortality. The mechanisms underpinning acute kidney injury are multifactorial. Acute tubular necrosis is the most common. Collapsing glomerulopathy is the most common glomerular injury and is strongly linked to apolipoprotein L1 genotypes. Improved understanding of COVID-19-related kidney pathologies can guide treatment to improve patient outcomes and reduce progression of chronic kidney disease. The longitudinal impact of COVID-19-related kidney disease requires further research.

The Difficulties of Treating Complement-3–Mediated Glomerulopathy

Background: C3 glomerulopathy (C3G) is a rare disease affecting the complement alternative pathway, categorized into dense deposit disease and C3 glomerulonephritis. Dense deposit disease predominantly affects younger individuals, while C3 glomerulonephritis tends to manifest in older populations. The diseases are characterized by dysregulation of the complement alternative pathway, leading to the deposition of complement components in the glomeruli and subsequent renal dysfunction. Notably, the incidence of C3G in the United States is low, with 1–3 cases per 1,000,000 and a prevalence of 5 cases per 1,000,000. Areas of Uncertainty: Numerous uncertainties persist in comprehending the etiology and pathophysiology of C3G. While biomarkers such as C3 nephritic factor, autoantibodies, and relevant genetic mutations have been identified, their pathogenicity and clinical utility remain unclear. Standard workups involve complement assays and autoantibody panels, yet the definitive diagnostic test remains a kidney biopsy. Nuanced challenges lie in deciphering the sensitivity and specificity of these diagnostic tools, especially in the presence of phenotypical variations among individuals. Therapeutic Advancement: Current therapeutic approaches, albeit lacking robust evidence, encompass a spectrum ranging from supportive care to targeted B-cell therapy and immunosuppression with mycophenolate mofetil and glucocorticoids. For severe and refractory cases, the monoclonal antibody eculizumab, targeting C5 in the complement cascade, is recommended. These treatments, while offering some relief, pose challenges related to their cost and obtaining insurance approval. Exploratory avenues delve into the potential of plasma exchange and innovative treatments such as oral complement inhibitors, reflecting the ongoing quest for effective therapeutic modalities. Trials investigating various complement inhibitors underscore the dynamic landscape of therapeutic advancements in C3G management. Conclusion: In conclusion, the article highlights the complexities of C3G management. The need for further understanding, large-scale trials, and ongoing investigations into disease etiology and pathophysiology is emphasized.

Application of spatial-omics to the classification of kidney biopsy samples in transplantation.

Improvement of long-term outcomes through targeted treatment is a primary concern in kidney transplant medicine. Currently, the validation of a rejection diagnosis and subsequent treatment depends on the histological assessment of allograft biopsy samples, according to the Banff classification system. However, the lack of (early) disease-specific tissue markers hinders accurate diagnosis and thus timely intervention. This challenge mainly results from an incomplete understanding of the pathophysiological processes underlying late allograft failure. Integration of large-scale multimodal approaches for investigating allograft biopsy samples might offer new insights into this pathophysiology, which are necessary for the identification of novel therapeutic targets and the development of tailored immunotherapeutic interventions. Several omics technologies - including transcriptomic, proteomic, lipidomic and metabolomic tools (and multimodal data analysis strategies) - can be applied to allograft biopsy investigation. However, despite their successful application in research settings and their potential clinical value, several barriers limit the broad implementation of many of these tools into clinical practice. Among spatial-omics technologies, mass spectrometry imaging, which is under-represented in the transplant field, has the potential to enable multi-omics investigations that might expand the insights gained with current clinical analysis technologies.

Lupus Nephritis: Redefining the treatment goals

The course of proliferative lupus nephritis (LN) is characterized by flares of activity alternating with periods of quiescence, against a background of chronic immune dysregulation. An accurate assessment of disease activity is of unassailable importance to tailor therapy. In the present communication, we discuss the available clinical, serological and histological tools to evaluate disease activity and how they may be applied to redefine the treatment goals in LN. Traditionally, treatment response is judged by the degree of proteinuria reduction and improvement of kidney function, but this fails to differentiate ongoing inflammatory disease from chronic damage. Despite intensive research, no novel biomarker has proved useful for clinical practice, and we continue to rely on anti-double-stranded DNA antibody levels (anti-dsDNA) to assess serological activity. Repeat kidney biopsies sometimes reveal persistent inflammation despite apparent clinical remission, giving credibility to the conviction that histological remission should be a treatment goal and protocol biopsies part of the decision-making process. However, the discrepancies between clinical and histological responses to therapy can be explained by persistent systemic autoimmunity with low-grade immune complex deposition or, alternatively, by delayed clearance of intrarenal inflammation once immunological remission has been achieved. Since persistent immune dysregulation is the motor of disease activity in LN, it should be the principal focus of therapy and monitoring. We propose to replace the traditional induction-remission maintenance protocol by a more dynamic and individualized approach, and aim for 3 treatment goals, concomitantly rather than sequentially: 1) Clinical remission, by attenuating renal inflammation, using microscopic hematuria, proteinuria, eGFR and complement levels as biomarkers; 2) Immunological remission, by decreasing immune complex generation, using anti-dsDNA as biomarker; 3) Preservation of kidney function, by curtailing chronic kidney damage, using eGFR slope as biomarker.

Proteinuria and proximal tubular epithelial cells: correlation between immunofluorescence, histology, and degree of proteinuria.

Proteins are filtered from the blood through the glomerular filtration barrier. Filtered proteins are reabsorbed by proximal tubular epithelial cells (PTECs), which have been shown to possess the ability to regulate protein reabsorption. Histologically, these reabsorbed proteins are seen as tubular protein reabsorption droplets (TPRDs). Experimental studies indicate that PTECs play an important role in regulating proteinuria but the correlations between TPRD and the degree of proteinuria in human kidney biopsies have not been investigated in detail. Consecutive native kidney biopsies with non-proliferative glomerular disease performed at the OSUWMC for a 1-year period were analyzed. Cases with acute glomerular diseases and inadequate biopsies were excluded. The staining intensity and the percentage of TPRDs, as well as other morphologic parameters, were assessed. A total of 109 kidney biopsies were included in the study. A reverse correlation was identified between the percentage of albumin TPRDs and proteinuria (p = 0.047). There were positive correlations between proteinuria and the staining intensity for IgG TPRDs (p = 0.05) and the degree of acute tubular necrosis (ATN) (p = 0.015). In patients with no ATN, positive correlations between proteinuria and albumin and IgG TPRDs were seen, whereas in patients with ATN, these correlations were lost. A positive correlation was seen between proteinuria and chronic kidney injury. A strong correlation was noted between the degree of proteinuria and podocyte foot process effacement. Our data indicate that PTECs regulate proteinuria by absorbing proteins from the urine filtrate. Therefore, based on the human renal biopsy material, our study confirms that well-functioning renal PTECs play an important role in the regulation of proteinuria.

Lupus anticoagulant-hypoprothrombinemia syndrome with lupus nephritis in a girl misdiagnosed with immunoglobulin A nephropathy: a case report

Distinguishing lupus nephritis (LN) from other glomerulopathies, such as immunoglobulin A nephropathy (IgAN), poses a diagnostic challenge owing to overlapping clinical and histopathologic findings. Lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) is a rare and potentially fatal disorder characterized by the presence of lupus anticoagulant and acquired factor II deficiency. We report a pediatric case of LN with LAHPS, which was initially diagnosed as IgAN. An 8-year-old girl presented with gross hematuria with nephrotic syndrome. Based on the kidney biopsy results, treatment for IgAN with membranoproliferative pattern was initiated. Two months later, she developed left upper extremity swelling with multiple vein thromboses requiring anticoagulation; treatment led to remission, allowing discontinuation of immunosuppressants within 8 months. Gross hematuria recurred 10 months later and was accompanied by hypocomplementemia; positive antinuclear, anti-double stranded DNA, and triple antiphospholipid antibodies; and factor II deficiency, prompting revision of the diagnosis to LN and LAHPS. Initial delay in LN diagnosis was attributed to the patient’s young age, nonspecific symptoms, and inconclusive laboratory and histopathological findings. Immunosuppressive therapy for IgAN partially improved LN, further complicating the diagnosis. This case emphasized the importance of clinical suspicion; integrating clinical, serological, and histopathological data; and considering LAHPS in differential diagnosis of glomerulonephritis with coagulopathy.

Acute tubulointerstitial nephritis following coronavirus disease 2019 mRNA vaccination: a pediatric case report.

Coronavirus disease 2019 (COVID-19) mRNA vaccines have been linked to various kidney adverse events including acute tubulointerstitial nephritis (ATIN). This report describes a 15-year-old female who developed persistent fever and fatigue 54days after receiving her second dose of the BNT162b2 2 SARS-CoV-2 vaccine. She presented with elevated serum creatinine and urinary β2-microglobulin (β2MG) levels. Kidney biopsy revealed mononuclear infiltrate with some eosinophils, confirming the diagnosis of ATIN. Repeatedly positive lymphocyte transformation test results for the vaccine suggested a relationship between the vaccine and interstitial nephritis. Initially, treatment with prednisolone was effective. However, an increase in urinary β2MG level was observed 7months later, and the introduction of mycophenolate mofetil (MMF) allowed for the gradual reduction and eventual cessation of prednisolone. This case represents one of the rare pediatric instances of ATIN following COVID-19 vaccination. MMF can be an effective alternative in corticosteroid-dependent cases.

The prognostic role of activation of the complement pathways in the progression of advanced IgA nephropathy to end-stage renal disease

IntroductionThe role of complement system in late stage of IgA nephropathy (IgAN) remains unknown. We therefore investigated the effects of complement system on worsening kidney function in advanced (stage 4 CKD) IgAN.MethodsRenal specimens of 69 IgAN patients who underwent renal biopsy during stage 4 CKD between 2010 and 2021, were stained using immunofluorescence (IF) and immunohistochemistry (IHC) for glomerular complement components. The primary outcome was progression to end-stage renal disease (ESRD). Associations of complement components with baseline clinicopathological characteristics and outcomes were assessed using multivariable Cox regression and Spearman analyses.ResultsDuring a median follow-up of 18.0 months, 26 (37.7%) patients progressed to ESRD and none died. C1q and C3 deposition were detected in 12 and 66 patients, respectively. Higher eGFR [hazards ratio (HR), 0.852, 95% confidence interval (CI), 0.756–0.959; P = 0.008], higher C3 intensity (HR, 2.955, 95%CI, 1.063–8.220; P = 0.038) and T1-2 score (HR, 2.576, 95%CI, 1.205–5.576, P = 0.015) were predictive of time to ESRD in CKD 4 stage IgAN. Significant expressions of C1q (P = 0.005), C4d (P < 0.001), factor B (P < 0.001), C3 (P = 0.042) and C5b-9 (P = 0.004) were identified in ESRD group than in non-ESRD group by IHC, while MBL expression was low. Although they were not associated with baseline 24 h-UP, higher factor B and C1q expressions were both correlated with a lower baseline eGFR (P < 0.001 and = 0.04, respectively) and the deterioration of kidney function during follow-up (P = 0.046 and 0.015, respectively).ConclusionComplement deposition in IgAN patients with stage 4 CKD portends a faster deterioration of kidney function. Activation of classical and alternative complement pathways plays a major role in this stage.

C3 glomerulopathy is highly prevalent in French Polynesia

ObjectiveTo compare the natural history of C3 glomerulopathy (C3G) to acute post-infectious glomerulonephritis (APIGN) in a cohort of patients with a relative homogeneity of environment conditions and genetic background. MethodsWe retrospectively reviewed the characteristics of all patients with biopsy proven C3G or APIGN referred in 2013–2019 to the only renal unit in French Polynesia. ResultsPoint prevalence of C3G is ∼23 cases per 100,000 inhabitants. A recurrent variation of CFI (p.Arg406His) was identified at the heterozygous state in 4/8 (50 %) patients with C3G but its pathogenicity remain elusive. Characteristics at presentation and kidney outcomes were roughly similar between C3G (n = 16) and APIGN (n = 20), excepted for the presence of humps on kidney biopsy. ConclusionsC3G is highly prevalent in French Polynesia suggesting specific genetic or environmental susceptibility factors. Systematic diagnosis workflow should be proposed to all patients with C3 predominant glomerulonephritis.

Clinicopathological Features of Membranous Nephropathy Complicated by IgA Nephropathy: A Retrospective Analysis of Seven Cases.

Aims/Background Both membranous nephropathy (MN) and immunoglobulin A nephropathy (IgAN) are immune complex-mediated glomerular diseases, but the concurrent occurrence of these two conditions in the same patient is not common, a phenomenon that is currently not supported by clinical data in terms of treatment and prognosis. This study explores the clinical and pathological characteristics, as well as the treatment outcomes, of patients affected by MN and IgAN simultaneously. Methods The clinical data, pathological features, and diagnostic and therapeutic information of seven cases of MN complicated by IgAN, treated between December 2015 and December 2022, were retrospectively analyzed. Results Among the seven cases, there were two male and five female patients, with an average age of 57.3 ± 9.2 years. All patients presented with clinical manifestations of proteinuria and edema upon admission, with an average 24-hour urine protein of 3716.6 ± 1519.4 mg/24 h. Phospholipase A2 receptor (PLA2R) expression was detected in all seven cases, and nephrotic syndrome was clinically diagnosed in five cases. Additionally, all seven cases showed microscopic hematuria, with intermittent gross hematuria in two cases. All seven patients included in this study underwent renal biopsy. After disease staging, the patients had MN stages I-III and IgAN stages II-III. Pathological findings revealed abnormal glomerular basement membrane (GBM) and diffuse immunoglobulin G (IgG) deposition in the subepithelial space, predominantly of the IgG4 subtype. Simultaneously, there was diffuse mesangial zone deposition of immunoglobulin A (IgA) to varying degrees, co-localization of complement component C3 and IgA, and mesangial cell proliferation. Treatment strategies included angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) in combination with steroids or immunosuppressive therapies such as tacrolimus, cyclophosphamide, and rituximab. After 2-6 months of treatment, all patients achieved complete remission with a favourable prognosis. Conclusion MN accompanied by IgAN tends to occur more frequently in middle-aged and elderly individuals, with a relatively low incidence. The latent feature of the comorbidities manifests as a form of IgAN superimposed on the background of MN. Utilizing ACEI or ARB in combination with steroids or various immunosuppressive therapies represents a potentially effective treatment strategy.

DOT1L protects against podocyte injury in diabetic kidney disease through phospholipase C-like 1

BackgroundPodocyte injury causes proteinuria and accelerates glomerular sclerosis during diabetic kidney disease (DKD). Disruptor of telomeric silencing 1-like (DOT1L), an evolutionarily conserved histone methyltransferase, has been reported in preventing kidney fibrosis in chronic kidney disease models. However, whether DOT1L exerts beneficial effects in diabetes induced podocyte injury and the underlying molecular mechanisms need further exploration.MethodsThe expression of DOT1L was confirmed by Western blotting in MPC-5 cells and cortex of kidney from db/db mice, as well as immunofluorescence staining in human renal biopsy samples. The effect of DOT1L on podocyte injury was obtained using MPC-5 cells and db/db mice. The potential target genes regulated by DOT1L was measured by RNA-sequencing. Then, a series of molecular biological experiments was performed to investigate the regulation of PLCL1 by DOT1L in MCP-5 cells and db/db mice. Lipid accumulation was assessed by UPLC-MS/MS analysis and Oil Red O staining.ResultsDOT1L expression was significantly declined in high glucose (HG)-treated MPC-5 cells, podocyte regions of kidney tissues from db/db mice and human renal biopsy samples. Subsequent investigations revealed that upregulation of DOT1L ameliorated HG-induced cell apoptosis in MPC-5 cells as well as primary podocytes. Furthermore, podocyte-specific DOT1L overexpression inhibited diabetic podocyte injury in db/db mice. Mechanistically, we revealed that DOT1L upregulated phospholipase C-like 1 (PLCL1) expression by mediating H3K79me2 at its promoter and PLCL1 silencing suppressed the protective role of DOT1L on podocyte injury. Moreover, DOT1L improved diabetes induced abnormal fatty acid metabolism in podocytes and PLCL1 knockdown reversed its protective effects.ConclusionsTaken together, our results indicate that DOT1L protects podocyte injury via PLCL1-mediated fatty acid metabolism and provides new insights into the therapeutic target of DKD.

Shear-Wave Elastography Improves Diagnostic Accuracy in Chronic Kidney Disease Compared to Conventional Ultrasound.

Non-invasive tests are increasingly demanded for diagnosing and prognostication of chronic kidney disease (CKD). Shear-wave elastography (SWE), an emerging technique for measuring tissue stiffness, shows promise for distinguishing between individuals with different stages of renal fibrosis. This study aimed to compare the diagnostic accuracy of two-dimensional SWE (2D-SWE) and conventional ultrasound for detecting CKD, employing renal biopsy as the gold standard. From May 2020 to October 2023, this prospective study included 30 healthy volunteers and 169 patients with CKD who had undergone 2D-SWE and conventional ultrasound of both kidneys. Cortical and medullary stiffness, cortical pixel intensity, renal length, parenchymal and cortical thickness, interlobar artery peak systolic velocity, end-diastolic velocity (EDV), and resistive index were measured. The diagnostic accuracy of 2D-SWE and conventional ultrasound was compared using the receiver operating characteristic curve (ROC) and Delong test. For diagnosing CKD, the area under the ROC (AUC) of cortical stiffness (0.96 [95% CI, 0.93, 0.99]) was significantly higher than that of all conventional ultrasound parameters, including EDV (0.78 [95% CI, 0.71, 0.86]) and cortical thickness (0.74 [95% CI, 0.67, 0.80]). The sensitivity of cortical stiffness (91%) was significantly higher than that of EDV (68%) and cortical thickness (53%). No significant difference was found in the specificity of cortical stiffness (96%) compared to that of EDV (79%) and cortical thickness (100%). Two-dimensional SWE showed higher diagnostic accuracy than that of conventional ultrasound for detecting CKD.

Native kidney biopsy in pregnancy and postpartum: A single centre experience from India

Native kidney biopsy in pregnancy and postpartum: A single centre experience from India

C/EBPα-mediated ACSL4-dependent ferroptosis exacerbates tubular injury in diabetic kidney disease

Diabetic kidney disease (DKD) is a prevalent and debilitating complication of diabetes characterized by progressive renal function decline and a lack of effective treatment options. Here, we investigated the role of the transcription factor CCAAT/enhancer binding protein alpha (C/EBPα) in DKD pathogenesis. Analysis of renal biopsy samples revealed increased C/EBPα expression in patients with DKD. Using RNA sequencing and proteomics, we explored the mechanisms through which the C/EBPα contributes to DKD. Our findings demonstrated that C/EBPα exacerbated tubular injury by promoting acyl-CoA synthetase long-chain family member 4 (ACSL4)-dependent ferroptosis. We identified that C/EBPα upregulated ACSL4 expression by binding to its transcription regulatory sequence (TRS), leading to elevated lipid peroxidation and ferroptosis. Furthermore, inhibition or genetic ablation of C/EBPα attenuated ferroptosis and mitigated tubular injury in DKD. These results highlighted the C/EBPα-ACSL4-ferroptosis pathway as a promising therapeutic target for DKD treatment.

Tubulointerstitial nephritis with IgM-positive plasma cells complicated by liver failure.

Tubulointerstitial nephritis (TIN) is characterized by inflammation of the renal interstitium with the infiltration of immune cells, mainly consisting of T cells. Recently, patients with TIN with the predominant infiltration of immunoglobulin M (IgM)-positive plasma cells were reported, coined IgMPC-TIN. Here we report the case of a 70-year-old woman diagnosed with Fanconi syndrome and renal tubular acidosis. Renal biopsy revealed IgMPC-TIN. Her renal dysfunction and clinical findings improved after corticosteroid therapy. However, the patient died of progressive liver failure and spontaneous bacterial peritonitis. In laboratory tests, viral hepatitis was excluded, and autoantibodies associated with liver diseases were negative. Generally, IgMPC-TIN is often complicated by primary biliary cholangitis (PBC), whereas her autopsy revealed the local infiltration of IgM-positive plasma cells, obliterative portal venopathy, and nodular regenerative hyperplasia in liver. This case is the first demonstration that IgMPC-TIN is also seen in liver disease with nodular regenerative hyperplasia, although IgMPC-TIN is more common in anti-M2 antibody-positive disease.

Male systemic lupus erythematosus, rapidly progressive glomerulonephritis, and iatrogenic acute bone marrow failure: a case report

Lupus nephritis (LN) is a significant complication of systemic lupus erythematosus (SLE), marked by kidney inflammation due to autoimmune activity, leading to proteinuria, hematuria, and potentially renal failure. Rapidly progressive glomerulonephritis (RPGN) is a rare, critical manifestation of LN characterized by a rapid decline in kidney function. This condition can lead to irreversible renal damage and is often fatal without prompt treatment. In this case, a 62-year-old man initially presented with fever, cough, and body aches, which were treated as an acute upper respiratory infection. Despite initial improvement, he developed persistent nausea, vomiting, and signs of renal dysfunction. Laboratory investigations revealed anemia, high erythrocyte sedimentation rate (ESR), electrolyte imbalances, and elevated creatinine. Imaging and endoscopy ruled out malignancy, and a differential diagnosis of multiple myeloma was excluded through plasma protein electrophoresis. Serological tests confirmed SLE, and subsequent renal biopsy revealed LN with RPGN features. Despite aggressive treatment with corticosteroids and cyclophosphamide, the patient’s condition rapidly deteriorated, leading to respiratory distress and intensive care unit (ICU) admission. He ultimately succumbed to his illness, underscoring the unpredictable and severe nature of RPGN in LN. This case highlights the importance of early diagnosis and intensive management to prevent rapid disease progression and improve patient outcomes.

Archetypal Analysis of Kidney Allograft Biopsies Using Next-generation Sequencing Technology.

In kidney transplantation, molecular diagnostics may be a valuable approach to improve the precision of the diagnosis. Using next-generation sequencing (NGS), we aimed to identify clinically relevant archetypes. We conducted an Illumina bulk RNA sequencing on 770 kidney biopsies (540 kidney recipients) collected between 2006 and 2021 from 11 European centers. Differentially expressed genes were determined for 11 Banff lesions. An ElasticNet model was used for feature selection, and 4 machine learning classifiers were trained to predict the probability of presence of the lesions. NGS-based classifiers were used in an unsupervised archetypal analysis to different archetypes. The association of the archetypes with allograft survival was assessed using the iBox risk prediction score. The ElasticNet feature selection reduced the number of the genes from a range of 859-10 830 to a range of 52-867 genes. NGS-based classifiers demonstrated robust performances (precision-recall area under the curves 0.708-0.980) in predicting the Banff lesions. Archetypal analysis revealed 8 distinct phenotypes, each characterized by distinct clinical, immunological, and histological features. Although the archetypes confirmed the well-defined Banff rejection phenotypes for T cell-mediated rejection and antibody-mediated rejection, equivocal histologic antibody-mediated rejection, and borderline diagnoses were reclassified into different archetypes based on their molecular signatures. The 8 NGS-based archetypes displayed distinct allograft survival profiles with incremental graft loss rates between archetypes, ranging from 90% to 56% rates 7 y after evaluation (P < 0.0001). Using molecular phenotyping, 8 archetypes were identified. These NGS-based archetypes might improve disease characterization, reclassify ambiguous Banff diagnoses, and enable patient-specific risk stratification.