Morphological Spectrum and Novel Necrotizing Crescentic Pattern in Microfilaria-Induced Renal Injury: A Case Series

Glomerular diseases vary with age, and it is important to investigate the spectrum of glomerular diseases in pediatric patients to help in a more precise clinical diagnosis and optimize the management of patients. We aimed to study the clinicopathologic pattern of pediatric glomerular diseases in North India. This is a 5-year retrospective, single-center cohort study. The database was searched to identify all pediatric patients with glomerular diseases in their native kidney biopsies. About 2890 native renal biopsies were studied, of which 409 were pediatric glomerular diseases. The median age was 15 years with a male preponderance. Nephrotic syndrome was the most common presentation (60.8%), followed by non-nephrotic proteinuria with hematuria (18.5%), rapidly proliferative glomerulonephritis (7%), isolated hematuria (5.3%), acute nephritic syndrome (3.4%), non-nephrotic proteinuria (1.9%), and advanced renal failure (0.7%). Minimal change disease (MCD) was the most common histological diagnosis, followed by focal segmental glomerulosclerosis (17.4%), IgA nephropathy (IgAN; 10%), membranous nephropathy (6.6%), lupus nephritis (5.9%), crescentic glomerulonephritis (2.9%), and C3 glomerulopathy (2.9%). Diffuse proliferative glomerulonephritis (DPGN) was the most common histological diagnosis in patients with hematuria and non-nephrotic as well as nephrotic range proteinuria. The most common histological diagnoses for isolated hematuria and acute nephritic syndrome were IgAN and postinfectious glomerulonephritis (PIGN), respectively. MCD and lupus nephritis are the most common pediatric primary and secondary histopathologic diagnoses, respectively. The adolescent-onset glomerular diseases have a higher frequency of IgAN, membranous nephropathy, and DPGN. PIGN is still an important differential in our pediatric patients presenting with acute nephritic syndrome.

The fenestrated endotheliocyte of peritubular and glomerular capillaries in rat and mouse kidneys were observed with SEM and TEM. In the glomerular capillary, so-called "pored-domes" were found not only at the fenestrated areolae but also at the nuclear region of the endotheliocyte. At the region between filtration surface and nuclear region, they accumulated to construct a sponge-like structure. The endotheliocyte of peritubular capillary also showed small "pored-domes". The size and morphology of the pores in the "pored-domes" of glomerular and peritubular capillaries were similar to those of areolae fenestratae of the respective capillary. Based on the findings, we assumed that pored-domes and the sponge-like structure are the reservoir for the fenestrated area of the endotheliocyte to accommodate the rapid expansion of capillary lumen.

Vascular endothelial growth factor (VEGF) is essential for maintenance of the glomerular capillary network. The present study investigated the effects of VEGF in rats with progressive crescentic glomerulonephritis (GN). Necrotizing and crescentic GN was induced in rats by injection of anti-rat glomerular basement membrane (GBM) antibody. The alterations of glomerular capillaries and glomerular VEGF expression were assessed. In addition, the effects of continuous VEGF165 administration (10 microg/100 g per d) on glomerular capillaries, glomerular inflammation, and the course of crescentic GN were examined. The appropriate timing of VEGF administration in progressive GN also was evaluated. In anti-GBM GN, necrotizing and crescentic glomerular lesions occurred by day 7, and newly formed necrotizing lesions reoccurred by week 3. Expression of VEGF was markedly reduced in necrotizing and crescentic lesions. Capillary repair was impaired after capillary destruction in necrotizing and crescentic glomeruli, which rapidly progressed to sclerotic glomeruli with chronic renal failure. In contrast, in the rats that received VEGF165 administration from day 7, the necrotizing and crescentic lesions recovered and renal function significantly improved in week 4. This was evident by proliferating endothelial cells and glomerular capillary repair. In addition, VEGF administration decreased intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 expression in glomeruli (particularly on endothelial cells), reduced glomerular infiltrating CD8-postive and ED-1-positive cells, and inhibited the newly formed necrotizing lesions. VEGF administration was apparently effective against both the inflammatory and necrotizing glomerular lesions. These results suggest that VEGF administration resolves glomerular inflammation and accelerates glomerular recovery in the progressive necrotizing and crescentic GN. The therapeutic application of VEGF may be clinically useful for severe GN accompanied by extensive glomerular inflammation and endothelial injury.

Endemic Fungal Infections in Solid Organ Transplant Recipients

Overlapping pathways to transplant glomerulopathy: chronic humoral rejection, hepatitis C infection, and thrombotic microangiopathy

Changes in renal microcirculation in patients with nephrotic and nephritic syndrome: The role of resistive index

Pattern of kidney diseases varies across geographies due to multiple factors. There is a paucity of information from South Asia due to the absence of nationwide/regional biopsy registries. This study aimed to delineate the spectrum of renal parenchymal diseases in our region. Records of kidney biopsies done in our nephrology department between 2006 and 2016 were analysed. Clinico-pathological correlation was done from the available records. Of the 3275 biopsy evaluated, 61.9% were males, and mean age was 33.2 ± 14.2 years. 6.2% patients were elderly (age ≥ 60 years). Nephrotic syndrome (60.3%) was the commonest indication for biopsy. On histology, 73.0% patients had primary glomerulonephritis (GN), 15.5% secondary GN, 5.3% tubulo-interstitial and 3.7% vascular disease. Focal segmental glomerulosclerosis (FSGS) was the commonest primary GN accounting for 18.2% of all GNs, followed by minimal change disease (16.8%), membranous nephropathy (MN) (16.0%) and IgA nephropathy (10.4%). Lupus nephritis (10.6%) and amyloidosis (3.7%) were the commonest secondary GN. The commonest cause of nephrotic syndrome was minimal change disease (22.9%), acute nephritic syndrome was lupus nephritis (30.6%), rapidly progressive renal failure was pauci-immune crescentic GN (24.5%). IgA nephropathy was the commonest etiology of asymptomatic urinary abnormalities (26.3%) and gross haematuria (50%). About 60.9% patients of undetermined chronic kidney disease had glomerular diseases, and 13.6% had chronic tubulointerstitial nephritis. Lupus nephritis and acute cortical necrosis were significantly more common in females compared with males. This is one of the largest cohorts of kidney biopsies from India, and it delineates the unique features and differences in the pattern of kidney disease in our population.

Postinfectious glomerulonephritis (PIGN) comprises a large group of glomerulonephridities that are caused by infectious agents. Acute glomerulonephritis is a term that defines a pathological lesion that may be asymptomatic or it may be manifested clinically with the acute nephritic syndrome, or the nephrotic syndrome, or with a rapidly progressive renal failure. In this chapter we will deal with the most common glomerulonephridities that result from bacterial infections: poststreptococcal glomerulonephritis, IgA-dominant glomerulonephritis associated with staphylococcal infections, and glomerulonephritis associated with bacterial endocarditis, infected atrial ventricular shunts, syphilis, and deep-seated infections. Since poststreptococcal glomerulonephritis is the best known of the acute postinfectious glomerulonephritis and its most frequent clinical picture is the acute nephritic syndrome, the terms poststreptococcal glomerulonephritis, acute glomerulonephritis, and acute nephritic syndrome are often, and incorrectly, used interchangeably. The incidence of PIGN is declining in affluent societies where most cases now occur in elderly individuals, many with comorbid debilitating conditions such as alcoholism, HIV infection, drug abuse, and diabetes. Nevertheless, PIGN, and specifically poststreptococcal glomerulonephritis, is still frequent in children in poor communities with limited access to medical care. Postinfectious glomerulonephritis results from antigen–antibody reactivity. Nephritogenic immune complexes are formed in the circulation or, in situ, in the glomerular basement membrane (GBM) and, in either case, cause local activation of the complement system and the coagulation cascade. Classic experimental studies in the acute (one-shot) and chronic serum sickness models [1–3] have demonstrated that glomerular deposition of circulating immune complexes depend on the size of the complexes (300–500 kDa) and on antigen load and the intensity of the antibody response (antigen/antibody ratio). The development of glomerular inflammation and severity, as well as the progression to chronic renal lesions, depends, on a large measure, on the duration of antigen exposure and the host’s capacity to remove the deposited complexes. In situ formation of immune complexes results from the deposition of the inciting antigen in the GBM and its penetration to the epithelial side of the GBMwhere it is met by the corresponding antibody to form immune complexes that present characteristic subepithelial electron-dense deposits. In situ formation of immune complexes occurs in conditions of antigen excess and is typical of cationic antigens that have electrostatic charge-facilitated penetration of the polyanionic GBM [4]. In specific types of glomerulonephritis, the pathogenesis involves the participation of bacterial wall superantigens causing intense Tcell activation that recruit cytokine-mediated polyclonal B cell responses; this is the case in glomerulonephritis associated with staphylococcal infection and predominant IgA deposition.

### Box 1—Manifestations of glomerular disease * Asymptomatic proteinuria * Asymptomatic haematuria * The nephrotic syndrome * The nephritic syndrome * Acute/rapidly progressive renal failure * End stage chronic renal failure * Hypertension #### Summary points There is a spectrum of disease, from such asymptomatic urinary abnormalities to the nephritic and nephrotic syndromes and indeed some patients have features of both. The nephritic syndrome is the abrupt onset of haematuria (often with red blood cell casts), proteinuria (usually moderate), reduced renal function, and salt and water retention causing oedema and hypertension. The nephrotic syndrome is heavy proteinuria (> 3.5 g/24 h) associated with hypoproteinaemia, distinct oedema, and often hypercholesterolaemia. Although the history, examination, urine analysis, and blood investigations (box 2) may suggest a likely cause, definitive diagnosis requires a renal biopsy. Underlying glomerulonephritis is also considered to be the cause of end stage renal failure in about a quarter of patients accepted on to dialysis programmes. As the progression of glomerulonephritis may be insidious some patients present in chronic renal failure with small smooth kidneys. By this time renal biopsy is more hazardous and less …

The associations of glomerular capillary and endothelial injury with the formation of necrotizing and crescentic lesions in cases of crescentic glomerulonephritis (GN) have not been evaluated in detail. Glomerular capillary and endothelial cell injury were assessed in renal biopsy specimens of crescentic GN, including those from patients with anti-neutrophil cytoplasmic autoantibodies (ANCA) -associated GN (n=45), anti-glomerular basement membrane (GBM) GN (n=7), lupus GN (n=21), and purpura GN (n=45) with light and electron microscopy and immunostaining for CD34. In ANCA-associated GN, anti-GBM GN, lupus GN, and purpura GN, almost all active necrotizing glomerular lesions began as a loss of individual CD34-positive endothelial cells in glomerular capillaries, with or without leukocyte infiltration. Subsequently, necrotizing lesions developed and were characterized by an expansive loss of CD34-positive cells with fibrin exudation, GBM rupture, and cellular crescent formation. With electron microscopy, capillary destruction with fibrin exudation were evident in necrotizing and cellular crescentic lesions. During the progression to the chronic stage of crescentic GN, glomerular sclerosis developed with the disappearance of both CD34-positive glomerular capillaries and fibrocellular-to-fibrous crescents. In addition, the remaining glomerular lobes without crescents had marked collapsing tufts, a loss of endothelial cells, and the development of glomerular sclerosis. The loss of glomerular capillaries with endothelial cell injury is commonly associated with the formation of necrotizing and cellular crescentic lesions, regardless of the pathogeneses associated with different types of crescentic GN, such as pauci-immune type ANCA-associated GN, anti-GBM GN, and immune-complex type GN. In addition, impaired capillary regeneration and a loss of endothelial cells contribute to the development of glomerular sclerosis with fibrous crescents and glomerular collapse.

Endothelial deposition of the complement split product C4d is an established marker of antibody-mediated acute renal allograft rejection. A contribution of alloantibody-dependent immune reactions to chronic rejection is under discussion. In this study, the association of immunohistochemically detected endothelial C4d deposition in peritubular capillaries (PTC) with morphologic features of chronic renal allograft injury was investigated in a large study cohort. C4d deposits in PTC were detected in 73 (34%) of 213 late allograft biopsies performed in 213 patients more than 12 mo after transplantation (median, 4.9 yr) because of chronic allograft dysfunction. Endothelial C4d deposition was found to be associated with chronic transplant glomerulopathy (CG) (P < 0.0001), with basement membrane multilayering in PTC (P = 0.01), and with an accumulation of mononuclear inflammatory cells in PTC (P < 0,001). Furthermore, C4d deposits in PTC (in biopsies with normal glomerular morphology) were associated with development of CG in follow-up biopsies. Other morphologic features of chronic allograft nephropathy (with exception of tubular atrophy) were not associated with C4d deposits in PTC. Analyses of previous and follow-up biopsies revealed that C4d deposits may occur de novo and may also disappear at any time after transplantation. In conclusion, the data suggest that complement activation in renal microvasculature, indicating humoral alloreactivity, contributes to chronic rejection characterized by chronic transplant glomerulopathy and basement membrane multilayering in PTC.

37-Year-Old Woman With Bilateral Lower Extremity Edema, Proteinuria, and Microscopic Hematuria

In situ multiplex immunofluorescence analysis of the inflammatory burden in kidney allograft rejection: A new tool to characterize the alloimmune response.

Background There is a paucity of registries on diseases found on renal biopsies, especially in Egypt. Therefore, in this study, we have attempted to identify the pattern of renal pathology among renal biopsy (RB) specimens and to study the clinicopathological correlation of RB in the Alexandria area, which is considered the biggest second city in Egypt after Cairo, with around six million inhabitants, as a step toward generating a national RB registry. Methods We evaluated all the available adult native renal biopsies that were performed in the Alexandria area during the years 2012 and 2015 from the two main nephropathology centers. Clinical presentations were asymptomatic urinary abnormalities, nephrotic syndrome (NS), nephritic syndrome, and unexplained acute kidney injury. Renal diseases were divided into four major categories: (a) primary glomerulonephritides (GN); (b) secondary GN; (c) tubulointerstitial nephropathies (TIN); and (d) vascular nephropathies. The distinction between primary and secondary GN was not established by a single histological approach, but by association of the morphological findings and available clinical data. A RB forum was designed to collect the clinical and pathological data. Results 861 native renal biopsies were included; the most common age interval during which RB was performed was 20–30 years (32.6%); female gender (51%) was slightly more prevalent than male sex (49%). The renal specimen was inadequate in 14.1% of the cases. Of all biopsies, primary GN was the most frequent (64.3%), followed by secondary GN (27.8%), TIN (4.2%), and vascular nephropathies (1.2%), where end stage renal disease (ESRD) cases represented 2.4%. The most common clinical syndrome as an indication for RB was NS (57.8%), followed by acute kidney injury (21.6%), chronic kidney disease (CKD) (9.3%), asymptomatic urinary abnormalities (8.9%), nephritic syndrome (1.2%), and nephritic nephrotic syndrome (1.2%). At the time of the biopsy, 53.2% of the patients presented with elevated kidney functions. Mesangioproliferative GN was the most common primary GN (24.8%), followed by membranoproliferative GN (23.7%), focal and segmental glomerulosclerosis (21.4%), membranous nephropathy (10.3%), IgA nephropathy (8.8%), minimal change disease (5.7%), and crescentic GN (5.3%). Lupus nephritis was the most common cause of secondary GN (56.3%), followed by amyloidosis (14.6%), diabetic nephropathy (12.6%), nodular GN (6.8%), cast nephropathy (4.4%), cryoglobulinemia (2.9%), gouty nephropathy (1.9%), and lymphomatous infiltration (0.5%). Acute TIN represented 65.5% of the TIN cases and chronic TIN represented 35.5%. Thrombotic microangiopathy represented 66.6% of the vascular diseases and hypertension (HTN) nephrosclerosis represented 33.3%. Conclusion Our RB registry represents an important contribution toward understanding the epidemiology of renal diseases in Alexandria city. We are hoping that this registry will be the basis for developing a national registry. Establishment of a trusted national registry that will help in preventing and treating renal diseases requires good cooperation between nephrologists and pathologists, with collection of all clinical, serological, and pathological data.

Progressive ascending telangiectasias