Digital Spatial Profiling of Glomerular Gene Expression in Pauci-Immune Focal Necrotizing Glomerulonephritis.

Pauci-immune focal necrotizing glomerulonephritis (piFNGN) involves asynchronous onset and progression of injurious lesions in biopsies. Pathologists can describe this heterogeneity within a biopsy, but translating the information into prognostic or expression analyses is challenging. Understanding the underlying molecular processes could improve treatment; however, bulk or single-cell transcriptomic analyses of dissociated tissue disregard the heterogeneity of glomerular injury. We characterize protein and mRNA expression of individual glomeruli in 20 biopsies from 18 patients with antineutrophil cytoplasmic antibody-associated piFNGN using the NanoString digital spatial profiling (DSP) platform. For this purpose, circular annotations of glomeruli were analyzed using protein, immuno-oncology RNA, and Cancer Transcriptome Atlas panels (n=120, 72, and 48 glomeruli, respectively). Histologic evaluation of glomerular patterns of injury was performed in adjacent serial sections. Expression data were processed by log2 transformation, quantile normalization, and batch adjustment. DSP revealed distinct but overlapping gene expression profiles relating to the morphological evolution of injurious lesions, including dynamic expression of various immune checkpoint regulators. Enrichment analysis indicated deregulated pathways that underline known and highlight novel potential mechanisms of disease. Moreover, by capturing individual glomeruli, DSP describes heterogeneity between and within biopsies. We demonstrate the benefit of spatial profiling for characterization of heterogeneous glomerular injury, indicating novel molecular correlates of glomerular injury in piFNGN.

Pathologic Correlation with Renal Dysfunction after Intravitreal Injections of Vascular Endothelial Growth Factor Antagonists.

OBJECTIVE: Vascular endothelial growth factor (VEGF) antagonists have been used for treating metastatic neoplasms. It has also been known that one of its side effects is to cause proteinuria and renal failure in the setting of thrombotic microangiopathy (TMA). The underlying mechanism is likely due to the inhibition of VEGF production in podocytes, resulting in diffuse fusion of foot processes and impaired glomerular endothelial fenestrations, and leading to massive proteinuria and subsequent glomerular endothelium injury. Intravitreal injection of VEGF antagonists (IIVA) has been also used to treat macular degeneration and diabetic retinal neo-vascular proliferation. The majority of patients tolerate the treatment well. However, IIVA can lead to renal dysfunction including proteinuria and gradual renal failure as a rare side effect. The goal of this study was to report two cases related to the nephrotoxicity of IIVA and review the literature associated with this topic. CASE REPORT: The first diabetic patient had elevated serum creatinine at 3.25 mg/dl and proteinuria/creatinine ratio at 6.1 after 48-month treatment of IIVA. The first renal biopsy revealed thrombotic microangiopathy that was correlated with his increased serum creatinine and nephrotic range of proteinuria. The second diabetic patient had increased serum creatinine up to 1.89 mg/dl but low proteinuria. The second biopsy showed acute tubular necrosis that was correlated with his elevated serum creatinine. CONCLUSION: Intravitreal injection of VEGF antagonist can be associated with thrombotic microangiopathy and acute tubular necrosis, leading to renal dysfunction.

Renal Morphology in Coronavirus Disease: A Literature Review.

Renal biopsy is useful to better understand the histological pattern of a lesion (glomerular, tubulointerstitial, and vascular) and the pathogenesis that leads to kidney failure. The potential impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the kidneys is still undetermined, and a variety of lesions are seen in the kidney tissue of coronavirus disease patients. This review is based on the morphological findings of patients described in case reports and a series of published cases. A search was conducted on MEDLINE and PubMed of case reports and case series of lesions in the presence of non-critical infection by SARS-CoV-2 published until 15/09/2020. We highlight the potential of the virus directly influencing the damage or the innate and adaptive immune response activating cytokine and procoagulant cascades, in addition to the genetic component triggering glomerular diseases, mainly collapsing focal segmental glomerulosclerosis, tubulointerstitial, and even vascular diseases. Kidney lesions caused by SARS-CoV-2 are frequent and have an impact on morbidity and mortality; thus, studies are needed to assess the morphological kidney changes and their mechanisms and may help define their spectrum and immediate or long-term impact.

Multiparametric ultrasound findings in acute kidney failure due to rare renal cortical necrosis.

Renal cortical necrosis (RCN) is a rare cause of acute kidney failure and is usually diagnosed on the basis of characteristic enhancement patterns on cross-sectional imaging. Contrast-enhanced ultrasound (CEUS) offers benefits in patients with kidney failure in the clinical setting including the use of a nonnephrotoxic intravascular contrast agent and the fact that it can be performed at the bedside in critical cases. Therefore, the aim of this study is to investigate whether CEUS can reliably identify typical imaging features of RCN. We retrospectively analyzed 12 patients with RCN examined in our department and confirmation of the diagnosis by either histopathology, other contrast-enhanced cross-sectional imaging tests, and/or CEUS follow-up. Assessed parameters in conventional US were reduced echogenicity, loss of corticomedullary differentiation, length and width of kidney, hypoechoic rim, resistance index and in CEUS delayed wash-in of contrast agent (> 20 s), reverse rim sign, maximum nonenhancing rim and additional renal infarction. Furthermore, imaging features in RCN were compared with the findings in renal vein thrombosis (RVT), among them echogenicity, corticomedullar differentiation, hypoechoic rim, RI value, delayed cortical enhancement, total loss of cortical perfusion and enhancement of renal medulla. All 12 patients showed the reverse rim sign, while a hypoechogenic subcapsular rim was only visible in four patients on B-mode ultrasound. A resistance index (RI) was available in 10 cases and was always less than 1. RI was a strong differentiator in separating RVT from RCN (RI > 1 or not measurable due to hypoperfusion as differentiator, p = 0.001). CEUS showed total loss of medullary enhancement in all cases of RVT. With its higher temporal resolution, CEUS allows dynamic assessment of renal macro- and microcirculation and identification of the typical imaging findings of RCN with use of a nonnephrotoxic contrast agent.

Systemic complement activation in anti-neutrophil cytoplasmic antibody-associated vasculitis and necrotizing glomerulonephritis.

AIM: Due to the accumulating evidence of complement activation in anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV), we decided to investigate the possibility of systemic complement activation in patients with Necrotizing Glomerulonephritis secondary to AAV. METHODS: Clinical, laboratory and histological findings, and serum levels of complement components, C3a, C5a and Bb fragment of Factor B and C4d, were estimated in patients with AAV and glomerulonephritis, at time of diagnosis, before any treatment had been applied. All patients were treated with the same immunosuppressive protocol and followed up for total 24 months. Twenty age and sex matched healthy individuals served as controls. RESULTS: Serum levels of all complement components were significantly increased in patients, compared to controls; C5a: 19.9(0.02-48) vs 9.06(2.1-16.3)pg/mL, P = .002, Bb: 7.3(0.02-31.4) vs 0.2(0.02-1.6)pg/mL, P < .0001, C3a: 4.7(0.4-7.2) vs 2.4(1.09-5)pg/mL, P = .05 and C4d: 11.6(0.07-70) vs 0.7(0.07-8.2)pg/mL, P = .001, respectively. There was strong correlation between serum Bb levels and eGFR and FFS2009 score at time of diagnosis (r = -.41, P = .002 and r = .41, P = .003 respectively). Also, serum Bb levels were increased in patients with severe interstitial infiltration (P = .04) and focal necrosis (P = .01) on renal biopsy. Serum Bb levels could also predict renal function outcome during the acute phase of disease, but not at the end of follow up. CONCLUSION: We provided strong evidence of systemic activation of complement alternative pathway in the development and progression of AAV and glomerulonephritis. Serum Bb seem to play a critical role in the induction, also predicting disease activity and outcome, yet activation of classical pathway cannot be excluded.

Towards a simplified renal histopathological prognostic score in glomerular nephropathies.

AIMS: An important role of native kidney biopsy evaluation is to predict renal prognosis. We aimed to develop a simplified chronicity score based solely on pathological features that are easily recognisable and can be found in all glomerular nephropathies (GN). In this retrospective study, observational cohort study we included 625 patients with GN diagnosis after native kidney biopsy in a tertiary unit between 1 January 2010 and 31 December 2015. METHODS AND RESULTS: Presence of global glomerulosclerosis (GG), tubular atrophy (TA), interstitial fibrosis (IF) and fibrocellular/fibrous crescents (FC) in any grade was scored with one point; a final score was between 0 and 4 (i.e. 'absent' 0 score, 'moderate' 1-2 score, 'severe' 3-4 score). The primary endpoint was renal replacement therapy (RRT) initiation. Mean baseline estimated glomerular filtration rate (eGFR) was 55.9 ± 29.6 ml/min; during the follow-up (median = 27 months), 78 patients started RRT. The total mean renal survival time was 60.1 (58.0-62.1) months. GG (41%) was the most frequent lesion, followed by IF (25%), TA (18%) and FC (17%). Patients with absent (65.7; 63.6-67.8 months) chronicity had better renal survival than those with moderate (59.1; 56.1-62.2 months) or severe (42.7; 35.6-49.7 months) chronicity. The score was associated with renal survival [hazard ratio (HR) = 1.33; 1.08-1.64)] independently of the classical prognostic factors. Patients with moderate and severe chronicity had a two- and threefold increase in risk of RRT initiation. CONCLUSION: Our score was correlated with renal survival independently of the traditional risk factors, and could improve outcome prediction in patients with GN by reducing the interobserver variability.

Cyclophilin Inhibition Protects Against Experimental Acute Kidney Injury and Renal Interstitial Fibrosis.

Cyclophilins have important homeostatic roles, but following tissue injury, cyclophilin A (CypA) can promote leukocyte recruitment and inflammation, while CypD can facilitate mitochondrial-dependent cell death. This study investigated the therapeutic potential of a selective cyclophilin inhibitor (GS-642362), which does not block calcineurin function, in mouse models of tubular cell necrosis and renal fibrosis. Mice underwent bilateral renal ischemia/reperfusion injury (IRI) and were killed 24 h later: treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. In the second model, mice underwent unilateral ureteric obstruction (UUO) surgery and were killed 7 days later; treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. GS-642362 treatment gave a profound and dose-dependent protection from acute renal failure in the IRI model. This protection was associated with reduced tubular cell death, including a dramatic reduction in neutrophil infiltration. In the UUO model, GS-642362 treatment significantly reduced tubular cell death, macrophage infiltration, and renal fibrosis. This protective effect was independent of the upregulation of IL-2 and activation of the stress-activated protein kinases (p38 and JNK). In conclusion, GS-642362 was effective in suppressing both acute kidney injury and renal fibrosis. These findings support further investigation of cyclophilin blockade in other types of acute and chronic kidney disease.

Renal Cortical Necrosis; Five Consecutive Cases within Short Span of Time.

Renal cortical necrosis (RCN) is characterized by patchy or diffuse destruction of all the elements of renal cortex resulting from significantly diminished renal arterial perfusion due to vascular spasm and microvascular injury. It is a rare cause of acute kidney injury (AKI) in developed countries with frequency of 1.9%-2% of all patients of AKI. In contrast, the incidence of RCN is higher in developing countries ranging from 6%-7%. Obstetric complication is the main cause of RCN, earlier it was about 20%-30% which has been declining to 5% in the Indian subcontinent during the past two decades. The aim of this study is to review five consecutive cases of RCN diagnosed within very short span of time. Histopathologically, diagnosed five cases of RCN during one-month span in September 2016 at Armed Forces Institute of Pathology, Dhaka were included in this study. All the cases were referred cases from a tertiary level obstetric center of Dhaka city; the mean age was 24.2 ± 3.4 years. All the cases had the history of postpartum hemorrhage followed by septicemia. They all presented with acute renal failure dependent on hemodialysis for >21 days. On histological examination, three (60%) had patchy RCN and two (40%) had diffuse RCN. Two (40%) showed coagulative necrosis of all the glomeruli, two (40%) showed coagulative necrosis of >50% of glomeruli, and in one (20%) case necrosis of about 25% of glomeruli. One of the glomeruli showed global sclerotic change of most of the glomeruli. In all the cases, interstitium showed moderate focal lymphocytic infiltration and mild edema. Among all, one (20%) was found with immunoglobulin A nephropathy as an associated diagnosis. RCN is still encountered as an obstetric complication in our setting and this type of grave consequences should be prevented by better monitoring of pregnancies.

Histopathology and Long-Term Outcome of Kidneys Transplanted From Donors With Severe Acute Kidney Injury.

BACKGROUND: Acute kidney injury is a treatable entity although difficult to recognize without diagnostic biopsy. We investigated the potential association between clinically defined deceased donors and acute kidney injury with preimplantation histological findings and recipient outcomes. METHODS: Kidney biopsies from donors were classified using the Acute Kidney Injury Network criteria and assessed for percentage glomerulosclerosis, tubular atrophy, interstitial fibrosis, and vascular narrowing with the Remuzzi score and for acute tubular necrosis. Differences in incidence rates of delayed graft function (DGF) and cumulative rejection episodes were compared between recipients transplanted with normal and 3 levels of acute kidney injury using the analysis of variance with Bonferroni correction ( P = .0012). RESULTS: Sixteen out of 335 donors showed a severe acute kidney injury level 3 with a median serum creatinine of 458 µmol/L. Fourteen (88%) had 0-3 Remuzzi score and were used for single kidney transplantation and 2 (12%) were used for dual kidney transplantation (score: 4-6). Recipients who received a kidney from a donor with level 3 acute kidney injury had a higher percentage of DGF (47%) without statistical significance ( P = .008). The rate of cumulative rejection (45%) at 2 years was not significantly increased ( P = .09). CONCLUSIONS: Recipients receiving level 3 acute kidney injury kidneys, selected with Remuzzi histopathological score and acute tubular necrosis assessment, had a greater incidence of DGF but a similar long-term cumulative rejection compared to no injury and level 1 and level 2 acute kidney injury donors. The application of the histopathological examination allowed expansion of the kidney donor pool.

HIVAN associated tubular pathology with reference to ER stress, mitochondrial changes, and autophagy.

Human immunodeficiency virus associated nephropathy (HIVAN) is a unique form of a renal parenchymal disorder. This disease and its characteristics can be accredited to incorporation of DNA and mRNA of human immunodeficiency virus type 1 into the renal parenchymal cells. A proper understanding of the intricacies of HIVAN and the underlying mechanisms associated with renal function and disorders is vital for the potential development of a reliable treatment for HIVAN. Specifically, the renal tubule segment of the kidney is characterized by its transport capabilities and its ability to reabsorb water and salts into the blood. However, the segment is also known for certain disorders, such as renal tubular epithelial cell infection and microcyst formation, which are also closely linked to HIVAN. Furthermore, certain organelles, like the endoplasmic reticulum (ER), mitochondria, and lysosome, are vital for certain underlying mechanisms in kidney cells. A paradigm of the importance of said organelles can be seen in documented cases of HIVAN where the renal disorder results increased ER stress due to HIV viral propagation. This balance can be restored through the synthesis of secretory proteins, but, in return, the secretion requires more energy; therefore, there is a noticeable increase in mitochondrial stress. The increased ER changes and mitochondrial stress will greatly upregulate the process of autophagy, which involves the cell's lysosomes. In conjunction, we found that ER stress and mitochondrial changes are associated in the Tg26 animal model of HIVAN. The aim of our review is to consolidate current knowledge of important mechanisms in HIVAN, specifically related to the renal tubules' association with ER stress, mitochondrial changes and autophagy. Although the specific regulatory mechanism detailing the cross-talk between the various organelles is unknown in HIVAN, the continued research in this field may potentially shed light on a possible improved treatment for HIVAN.

Patterns of renal involvement in a cohort of patients with inflammatory bowel disease in Egypt.

BACKGROUND AND STUDY AIM: Renal complications are frequent extraintestinal manifestations in inflammatory bowel disease (IBD). We aimed in our study to describe the spectrum of renal affection in our IBD patients. PATIENTS AND METHODS: This study is a retrospective analysis of renal biopsies done for IBD patients who developed renal diseases, at Cairo University Hospital, from June 2005 to Jan. 2016. Results : Among 896 IBD patients, 218 patients (24.3%) developed renal affection. The onset of renal disease mandated renal biopsy at 5.6 ± 7.4 years after IBD diagnosis. Nephrotic range proteinuria was the most common indication for a renal biopsy [81 (37.15%) patients]. Amyloidosis was the most common renal pathological diagnosis [56 patients (25.7%)] followed by immunoglobulin A (IgA) nephropathy [35 patients (16.1%)], focal segmental glome- rulosclerosis (FSGS) [32patients (14.7%)], crescentic glomerulonephritis (CGN) [32 patients (14.7%)], membranous nephropathy (MN) [18 patients (8.25%)], minimal change disease [17 patients (7.7%)], chronic interstitial nephritis (CIN) [10 patients (4.6%)], acute tubular necrosis (ATN) [8 patients (3.7%)], thrombotic microangiopathy (TMA) [6 patients (2.75%)], and acute interstitial nephritis (AIN)[4 patients (1.8%)]. Variable renal histopathology diagnoses did not correlate with age, duration of IBD diagnosis, or drugs used for IBD treatment. Crescentic GN was significantly correlating with ASCA, ANCA-p, and ANCA-c in serum. CONCLUSION: Amyloidosis is a common renal pathological diagnosis in our patients, and is followed by IgA nephropathy, and FSGS.

Renal outcomes in primary IgA nephropathy patients with segmental glomerular necrosis: a case-control study.

The renal prognosis and treatment of primary IgA nephropathy (IgAN) patients with segmental glomerular necrosis (SGN) remain controversial. Patients with primary IgAN confirmed by renal biopsy were enrolled. Patients with SGN on renal biopsy were selected as the necrosis group, and a propensity score matching method was used to match a control group according to age, gender, weight, height and follow-up time. A total of 825 IgAN patients were enrolled in the present study. Seventy-three (8.8%) patients with SGN were selected as the necrosis group, and 292 patients without SGN were matched as the control group. Compared to the control group, a significantly increased serum fibrinogen level (3.97 g/L vs 3.54 g/L, P=.002) and proportion of patients with macroscopic hematuria (35.6% vs 14.7%, P<.001) was observed in the necrosis group. According to the new IgA pathological classification system, crescent formation was more pronounced in the necrosis group (P=.001). The average estimated glomerular filtration rate was obviously higher in the necrosis group and decreased more slowly during follow-up. However, the time-averaged urine protein-to-creatinine ratio remained low in the necrotic group, whereas it gradually increased in the control group. SGN suggests an active renal inflammatory state, but it was not an independent risk factor for a poor renal outcome in patients treated with immunosuppressive therapy. Furthermore, patients with SGN had a more stable renal function and low urinary protein excretion during follow-up, which may be attributable to aggressive immunotherapy.

Expression of cleaved caspase-3 in renal tubular cells in Plasmodium falciparum malaria patients.

AIM: In Plasmodium falciparum malaria, the clinical manifestation of acute kidney injury (AKI) is commonly associated with acute tubular necrosis (ATN) in the kidney tissues. Renal tubular cells often exhibit various degrees of cloudy swelling, cell degeneration, and frank necrosis. To study individual cell death, this study evaluates the degree of renal tubular necrosis in association with apoptosis in malarial kidneys. METHODS: Kidney tissues from P. falciparum malaria with AKI (10 cases), and without AKI (10 cases) were evaluated for tubular pathology. Normal kidney tissues from 10 cases served as controls. Tubular necrosis was assessed quantitatively in kidney tissues infected with P. falciparum malaria, based on histopathological evaluation. In addition, the occurrence of apoptosis was investigated using cleaved caspase-3 marker. Correlation between tubular necrosis and apoptosis was analyzed. RESULTS: Tubular necrosis was found to be highest in P. falciparum malaria patients with AKI (36.44% ± 3.21), compared to non-AKI (15.88% ± 1.63) and control groups (2.58% ± 0.39) (all p < 0.001). In the AKI group, the distal tubules showed a significantly higher degree of tubular necrosis than the proximal tubules (p = 0.021) and collecting tubules (p = 0.033). Tubular necrosis was significantly correlated with the level of serum creatinine (r = 0.596, p = 0.006), and the occurrence of apoptosis (r = 0.681, p = 0.001). CONCLUSION: In malarial AKI, the process of apoptosis occurs in ATN.

Purtscher's retinopathy and renal cortical necrosis: two rare vaso-occlusive complications in a patient with acute pancreatitis: a case report.

BACKGROUND: Purtscher's retinopathy and renal cortical necrosis are two rare vaso-occlusive complications of acute pancreatitis. Purtscher's retinopathy causes sudden impairment of vision, which was first reported in a patient with head trauma. Subsequently, it was also reported as a complication of acute pancreatitis and few other clinical conditions. Acute pancreatitis also rarely causes renal cortical necrosis leading to acute kidney injury. However, the simultaneous presence of both complications is rarely reported. CASE PRESENTATION: A 20-year-old Bengali man presented to our hospital with a history of acute upper abdominal pain, vomiting, anuria, and disorientation. He was ultimately found to have bilateral complete blindness due to Purtscher's retinopathy and acute kidney injury due to renal cortical necrosis, as sequelae of acute pancreatitis. He became dialysis-dependent, his vision did not recover, and he died 16 months after diagnosis. CONCLUSIONS: This case highlights Purtscher's retinopathy and renal cortical necrosis might be considered as a recognized pair complication of acute pancreatitis.

Clinical Scenarios in Acute Kidney Injury-Parenchymal Acute Kidney Injury - Vascular Diseases.

Acute cortical necrosis and hemolytic uremic syndrome (HUS) are 2 clinical scenarios of parenchymal acute kidney injury (AKI) related to renal microvascular injury. Acute cortical necrosis is a rare condition related to an ischemic necrosis of renal cortex. Necrotic lesions can be due to several injuries and may be focal, multifocal or diffuse. Renal necrotic lesions become visible with ultrasound only after renal recovery. HUS is a rare disease characterized by hemolytic anemia, thrombocytopenia and AKI. Color Doppler ultrasound is useful during diagnostic and follow-up phase. Renal artery thrombosis and renal vein thrombosis may also cause parenchymal AKI. Acute renal infarction is a rare pathological condition that occurs due to clots or cholesterol aggregates occluding renal artery or its branches. Several causes may lead to partial or massive kidney ischemic necrosis. Contrast-enhanced CT allows definitive diagnosis in 80% of cases and, at present, it is the first imaging technique used. Ultrasound (US) sensitivity and specificity significantly increases with color Doppler and contrast-enhanced US (CEUS). In AKI patients, in whom the use of iodinated contrast media is contraindicated, color Doppler and CEUS may be valid alternatives for the diagnosis of acute renal infarction. Renal vein thrombosis may be primary or secondary to retroperitoneal neoplasm or inflammatory diseases. It rarely causes an acute worsening of renal function because of the presence of several anastomosis that prevent parenchymal necrosis due to venous congestion. Color Doppler US could detect thrombus within the lumen and document the absence of venous flow.