Parietal epithelial cell dysfunction in crescentic glomerulonephritis

Crescentic glomerulonephritis represents a group of kidney diseases characterized by rapid loss of kidney function and the formation of glomerular crescents. While the role of the immune system has been extensively studied in relation to the development of crescents, recent findings show that parietal epithelial cells play a key role in the pathophysiology of crescent formation, even in the absence of immune modulation. This review highlights our current understanding of parietal epithelial cell biology and the reported physiological and pathological roles that these cells play in glomerular lesion formation, especially in the context of crescentic glomerulonephritis.

The Association between Glomerular Diameter and Secondary Focal Segmental Glomerulosclerosis in Chronic Kidney Disease

<b><i>Introduction:</i></b> When nephron loss occurs, the glomerular filtration rate (GFR) is suggested to be maintained by glomerular hypertrophy, but excessive hypertrophy can rather lead to the formation of focal segmental glomerulosclerosis (FSGS), thereby causing progressive kidney damage. However, it is not clear how much glomerular hypertrophy leads to the formation of FSGS. We examined the association between glomerular diameter and FSGS lesions in chronic kidney disease (CKD) patients. <b><i>Methods:</i></b> We recruited 77 patients who underwent renal biopsy during 2016–2017; however, those identified with primary FSGS and glomerulonephritis with active glomerular lesion were excluded. We evaluated the maximal glomerular diameter (Max GD), an indicator of glomerular size, in each renal biopsy specimen and examined its association with FSGS lesion. <b><i>Results:</i></b> The median age, blood pressure, and estimated GFR of the patients were 53 years, 122/70 mm Hg, and 65 mL/min/1.73 m², respectively. The optimal cutoff threshold of Max GD for predicting the presence of FSGS lesions, assessed by receiver operating characteristic curve analysis, was determined to be at 224 μm (area under the curve, 0.81; sensitivity, 81%; specificity, 72%). Multivariate logistic regression analyses demonstrated that Max GD ≥224 μm was significantly associated with the presence of FSGS lesions, independent of other confounding factors (odds ratio, 11.70; 95% confidence interval, 1.93–70.84). <b><i>Discussion/Conclusion:</i></b> Glomerular hypertrophy (Max GD ≥224 μm) has been associated with FSGS lesions in CKD patients and may reflect the limits of the compensatory process.

A Case of Lupus Nephritis Aggravated by Diabetic Nephropathy with a Rapid Decline in Kidney Function

Lupus nephropathy is a glomerular lesion and one of the most severe organ localizations of systemic lupus erythematosus (SLE). Diabetic nephropathy, on the other hand, is a major cause for chronic kidney disease (CKD) as well as for end stage kidney disease (ESKD). We present the case of a 51-year-old woman with nephrotic syndrome diagnosed 4 months previously. Since the diagnosis was made, a rapid decline in renal function was observed – serum creatinine rose from 159 to 200 and to 462 μmol/l. Arterial hypertension was present for 2 years with BP values up to 200/90 mm Hg, as well as newly diagnosed diabetes mellitus which was insulin-treated due to the low renal function. The test for anti-dsDNA-63.3 was positive and ANA titers were 1: 320. The renal biopsy revealed a combination of lupus nephropathy and a nodular variant of diabetic nephropathy. Treatment with methylprednisolone, cyclophosphamide and heparin was initiated. This was followed by improvement in serum creatinine and proteinuria, by reduction of edema, decreased titers of anti-dsDNA and by improvement of the general well-being. A few months later, in the course of another intermittent infection, the patient’s condition deteriorated sharply, necessitating hemodialysis. Nephropathy secondary to lupus erythematosus is rarely seen in combination with diabetic nephropathy, but once they co-occur, a complicated course of the disease will eventually lead to serious kidney damage. The morphological examination of the renal biopsy aspirate is the only reliable mean to assess the nature of the glomerular changes and to make adequate therapeutic decisions.

ANG II and Aldosterone Acting Centrally Participate in the Enhanced Sodium Intake in Water-Deprived Renovascular Hypertensive Rats

Renovascular hypertension is a type of secondary hypertension caused by renal artery stenosis, leading to an increase in the renin–angiotensin–aldosterone system (RAAS). Two-kidney, 1-clip (2K1C) is a model of renovascular hypertension in which rats have an increased sodium intake induced by water deprivation (WD), a common situation found in the nature. In addition, a high-sodium diet in 2K1C rats induces glomerular lesion. Therefore, the purpose of this study was to investigate whether angiotensin II (ANG II) and/or aldosterone participates in the increased sodium intake in 2K1C rats under WD. In addition, we also verified if central AT1 and mineralocorticoid receptor blockade would change the high levels of arterial pressure in water-replete (WR) and WD 2K1C rats, because blood pressure changes can facilitate or inhibit water and sodium intake. Finally, possible central areas activated during WD or WD followed by partial rehydration (PR) in 2K1C rats were also investigated. Male Holtzman rats (150–180 g) received a silver clip around the left renal artery to induce renovascular hypertension. Six weeks after renal surgery, a stainless-steel cannula was implanted in the lateral ventricle, followed by 5–7 days of recovery before starting tests. Losartan (AT1 receptor antagonist) injected intracerebroventricularly attenuated water intake during the thirst test. Either icv losartan or RU28318 (mineralocorticoid receptor antagonist) reduced 0.3 M NaCl intake, whereas the combination of losartan and RU28318 icv totally blocked 0.3 M NaCl intake induced by WD in 2K1C rats. Losartan and RU28318 icv did not change hypertension levels of normohydrated 2K1C rats, but reduced the increase in mean arterial pressure (MAP) produced by WD. c-Fos expression increased in the lamina terminalis and in the NTS in WD condition, and increased even more after WD-PR. These results suggest the participation of ANG II and aldosterone acting centrally in the enhanced sodium intake in WD 2K1C rats, and not in the maintenance of hypertension in satiated and fluid-replete 2K1C rats.

Lupus Nephritis: Renal Biopsy Guiding the Clinician

Systemic lupus erythematosus is a chronic autoimmune disease that affects mostly women. The kidneys are involved in 50% of patients causing a high degree of disease morbidity and mortality with poor prognosis. Early diagnosis of lupus nephritis with prompt therapy correlates with a better outcome. The renal biopsy provides important informations to clinicians to monitor the patients. The patterns of glomerular lesion, degree of activity and chronicity of the disease and extent of lesions to the tubulointerstitial and vascular compartments are fundamental information for the clinician to decide the most appropriate treatment. In order to correlate the kidney disease with clinical manifestations and patient outcome the glomerular lesions are classified according to International Society of Nephrology and Renal Pathology Society Classification (ISN/RPS). The definition of active and chronic lesions was introduced by studies conducted at National Institute of Health (NIH). The ISN/RPS classification and NIH indices have recently been revised by a series of retrospective validation studies to improve and minimize the controversial aspects.

MO1030THE FIRST CASE OF ATYPICAL HEMOLYTIC UREMIC SYNDROME (AHUS) FEATURES IN AN EXPERIMENTAL MODEL

Background and Aims Thrombotic Microangiopathies (TM) are three distinct clinical syndromes presenting the same histological renal pattern: typical and atypical Hemolytic Uremic Syndrome (SEU- aSEU) and Thrombotic Thrombocytopenic Purpura (TTP). So far, the first report of a TM has been generally attributed to Eli Moschowitz. In 1922 he described the case of a 16 years old girl who died after acute onset of fever with petechial lesions and autoptic findings of hyaline thrombosis of terminal arterioles and capillaries, thus profiling the first case of TTP. Only in the 1955, Conrad Gasser described the first medical record of HUS, describing the case of a patient with a manifestation of bilateral necrosis of the renal cortex. We describe the first reported case of a Thrombotic Microangiopathy, in particular an experimentally induced aHUS by Richard M. Pearce in 1909. In this case, the trigger leading to aHUS was represented by snake venom injection in an experimental rabbit model. Method Pearce described acute glomerular lesions produced in the rabbit using dried venom of rattlesnake Crotalus Adamanteus. It was dissolved in salt solution in the proportion of 0.25 of a milligram to one cubic centimeter, rising gradually to two milligrams, and then followed by doses of 0.5 of a milligram of fresh venom at various intervals. The intervals between injections depended on the general condition of the animal and the amount of albuminuria. Results Rabbit kidneys showed well marked hemorrhagic and exudative lesions in the glomeruli; hyaline, granular, blood, and hemoglobin casts in both convoluted and collecting tubules; and granular degeneration of the epithelium of the convoluted tubules and loops of Henle. Pearce also described a “penetration of the cells of the compressed glomerular tuft into the mass of hemorrhage lying either in the tuft itself or in the capsular space” (Figure 1). In animals surviving 20-30 days after the first injection of the venom, the acute lesions were demonstrated to subside at the microscopic examination and their earlier presence was marked by “occasional casts and compressed masses of red cells in the glomerular spaces and tufts”. At the same time other models also showed “extensive granular degeneration of the convoluted tubules and many casts”. The renal autoptic findings presented the features of a vascular nephritis with severe endothelial changes. Conclusion Glomerular and tubular lesions of rabbits’ kidneys induced by crotalus’s venom showed typical features of what is today defined as aHUS. In this first experiment, the author described a glomerular tuft as “more analogous to the organization of a red thrombus than it is to any form of glomerular lesion known in man”, so we can affirm that Pearce described, ante litteram TMA histological features many years before other scientists.

MO307POLYCLONAL FREE LIGHT CHAINS AS A PREDICTOR OF CKD PROGRESSION IN NONPROLIFERATIVE GLOMERULOPATHIES

Background and Aims The mechanism of the epithelial-mesenchymal transition of kidney tubular cells leading to kidney fibrosis formation and CKD progression is well described for monoclonal free light chains (FLC) in patients with monoclonal gammopathies. As far as the interaction of FLC with megalin/cubulin receptors on proximal tubular epithelial cells is considered to be universal we hypothesize that polyclonal free light chains (pFLC) could have the same effect on tubulointerstitial compartment in patients with primary glomerulopathies. This retrospective study was performed to reveal the association of serum pFLC kappa (pFLC-κ) and lambda (pFLC-λ) assessed by Freelite® with clinical and morphological parameters and CKD progression in patients with nonproliferative glomerulopathies. Method 36 patients with morphologically proven diagnosis of nonproliferative glomerulopathies (minimal changed disease (n=11), membranous nephropathy (n=11) and focal segmental glomerulosclerosis (n=14)) were included. Serum levels of pFLC-κ and pFLC-λ were assessed by Freelite® (normal ranges: κ=3.3-19.4 mg/l; λ=5.7-26.3 mg/l; κ/λ ratio=0.26-1.65) at the time of kidney biopsy (KBx) in all cases. Patients with abnormal κ/λ-ratio due to monoclonal gammapathies were excluded. Apart demographical parameters, serum creatinine, estimated GFR (eGFR) by CKD-EPI, serum albumin and 24-hour proteinuria were measured. Morphological findings defined by light microscopy were measured semiquantitatively according to currently accepted criteria (0 - &lt;10%, 1 - 10-25%, 2 – 26-50%, 3 - &gt;50% of tissue involved). Data are presented as median and interquartile range (M (25%; 75%)) and mean and the standard error of mean (m±SEM) for semiquantitative parameters or %. Correlation between parameters was assessed by Spearman’s coefficient. Progression of CKD was determined as decline of eGFR &gt;15% from the initial level at the end of follow-up. Cox proportional hazards regression was used to estimate the association of pFLC and other parameters with CKD progression. Differences were considered statistically significant at p &lt;0.05. Median follow-up was 11 (1; 53) months. Results Demographic and clinical parameters at the time of KBx are shown in the Figure 1. Clinical and morphological parameters as well as correlation analysis data are presented in the Figure 2. Univariant Cox regression shows that pFLC-λ &gt;N (Exp(β)=5.120; 95% CI: 1.011-25.924, p&lt;0.05), both pFLC-κ and pFLC-λ &gt;N (Exp(β)=6.646; 95% CI: 1.327-33.287, p=0.02), κ/λ ratio (Exp(β)=4.656; 95% CI: 1.411-15.362, p=0.01), as well as percent of sclerotic glomeruli (Exp(β)=1.039; 95% CI: 1.006-1.073, p=0.01), glomerular basement membrane segmental thickening (Exp(β)=3.129; 95% CI: 1.213-8.071, p&lt;0.01), mesangial proliferation (Exp(β)=5.177; 95% CI: 1.146- 23.396, p=0.03), interstitial cell infiltration (Exp(β)=3.777; 95% CI: 1.258-11.340, p=0.02) and peritubular capillaritis (Exp(β)=5.177; 95% CI: 1.146- 23.396, p=0.03) were associated with CKD progression. Conclusion In nonproliferative glomerulopathies increased level of pFLC, either kappa or lambda, is associated with glomerular lesion, interstitial inflammation, tubular atrophy and interstitial fibrosis. Moreover, elevated levels of pFLC could be proposed as a predictor of CKD progression in studied patient cohort. The mechanisms of kidney injury by pFLC requires further investigation.

Glomerular Macrophages in Human Auto- and Allo-Immune Nephritis

Macrophages are involved in tissue homeostasis. They participate in inflammatory episodes and are involved in tissue repair. Macrophages are characterized by a phenotypic heterogeneity and a profound cell plasticity. In the kidney, and more particularly within glomeruli, macrophages are thought to play a maintenance role that is potentially critical for preserving a normal glomerular structure. Literature on the glomerular macrophage role in human crescentic glomerulonephritis and renal transplantation rejection with glomerulitis, is sparse. Evidence from preclinical models indicates that macrophages profoundly modulate disease progression, both in terms of number—where depletion has resulted in a reduced glomerular lesion—and sub-phenotype—M1 being more profoundly detrimental than M2. This evidence is corroborated by better outcomes in patients with a lower number of glomerular macrophages. However, due to the very limited biopsy sample size, the type and role of macrophage subpopulations involved in human proliferative lesions is more difficult to precisely define and synthesize. Therefore, specific biomarkers of macrophage activation may enhance our ability to assess their role, potentially enabling improved monitoring of drug activity and ultimately allowing the development of novel therapeutic strategies to target these elusive cellular players.

Prevalence of IgA Nephropathy: A 10 Years’ Experience from Jinnah Postgraduate Medical Centre, Karachi, Pakistan

Background: Immunoglobulin A (IgA) is considered the most frequently dealt primary glomerulonephritis, worldwide. The Berger’s disease or IgA nephropathy is a mesangial proliferative glomerulonephritis characterized by deposition of immunoglobulin A in kidneys. The aim of the study was to report the prevalence of IgA nephropathy and the associated parameters (age, gender, and body mass index) in our population. Methods: This was a retrospective study, accomplished at Jinnah Postgraduate Medical Centre, Karachi, Pakistan, from June 2009-May 2019. The histopathology and immunofluorescence of renal biopsies of 519 patients were studied and the prevalence of biopsy proven IgA nephropathy was determined. The Chi-square test was used for association of biopsy proven IgA nephropathy with age, gender, and body mass index. A p-value of 0.05 or less was considered statistically significant. Results: A total of 519 biopsies were studied, out of those, only 4 (0.8%) had IgA nephropathy with male dominance in the last 10 years at Karachi, Pakistan. Male to female ratio was found to be 3:1. The most common clinical indication for renal biopsy was isolated hematuria in 50% of the cases followed by acute kidney injury and nephritic syndrome with 25% each respectively. Most of the patients suffering from proteinuria (> 3.5gm/24 hours), microscopic hematuria in 80% cases, high blood pressure in 50% cases, with other associated symptoms including edema, gastrointestinal, and skin-related symptoms reported. Conclusion: Immunoglobulin A (IgA) nephropathy is not a commonly diagnosed glomerular lesion. Further large-scale cohorts can aid in determining the other factors associated with a low frequency of IgA nephropathy. Keywords: Biopsy; Glomerulonephritis; Immunoglobulin A; Nephropathy.

A Case Demonstrating the Pathological Relationship between Granulomatous Vasculitis and Glomerular Lesion in Renal Sarcoidosis

We experienced a rare case of tubulointerstitial angiocentric granulomatous vasculitis with focal segmental glomerulosclerosis (FSGS) and associated sarcoidosis. Our patient was an 18-year-old man who presented with exertional cough and dyspnea. He also had overt proteinuria (3.0 g/24 h), normal renal function (eGFR 95 mL/min/1.73 m²), heart failure, and hypertension. He had no previous episode of hypertension. These manifestations immediately improved after the administration of antihypertensive therapy that contained an angiotensin-converting enzyme inhibitor, calcium antagonists, beta antagonists, and diuretics. However, he, later on, developed renal dysfunction, with worsening of both proteinuria and hypertension. Renal biopsy was performed and showed epithelioid cells that were arranged concentrically around small blood vessels in tubulointerstitial granulomas. In the glomeruli, the segmental sclerotic lesions were classified as a perihilar variant of FSGS. There were no inflammatory changes, such as a mesangial lesion, inflammatory cell infiltration, fibrinoid necrosis, or crescent formation, and no glomerular granuloma. In the tubulointerstitial granulomas, the intimal elastic lamina of the interlobular arteries was reduplicated, and the intimal wall thickness of renal arterioles was remarkable. After receiving oral prednisolone therapy, the overt proteinuria resolved, the eGFR recovered from 39.4 to 60.6 mL/min/1.73 m², and hypertension was managed more easily. Thereafter, he did not experience any recurrence. The concurrent improvement of renal function and proteinuria by steroid treatment suggested a relationship between the glomerular lesions and the tubulointerstitial granulomatous vasculitis with associated sarcoidosis.