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Background and objectives: Urothelial carcinoma is now considered to be the most important tumor of the urinary bladder in Egypt especially after decreased prevalence of schistosomiasis. Due to few available therapeutic approaches and partial success in improving patients' survival, novel immunotherapeutic agents such as immune checkpoint inhibitors become a promising hope especially after PD-1 and CTLA-4 being clinically relevant. TIM-3 which is another immune checkpoints molecule is recently appeared to be associated with immune suppression in many tumors and has been reported to be aberrantly expressed in several human malignancies including urothelial carcinoma. One of the TIM-3 discovered ligands is CEACAM-1. The latter has been linked to malignancy progression and metastatic spread and has been expressed in many tumor types. The aim of our work is to evaluate the expression of TIM-3 and CEACAM-1 in bladder urothelial carcinoma and analyse their correlations with clinical and pathological related factors. Methods: Different TIM-3 and CEACACM-1 expressions were evaluated in immunohistochemically stained paraffin embedded sections from 60 Egyptian patients with bladder urothelial carcinoma. Expression was correlated with the available clinical and pathological data. Results: Both TIM-3 and CEACAM-1 were expressed in cancer cells, tumor infiltrating lymphocytes and endothelial cells. TIM-3 expression by cancer cells showed significant correlation with tumor necrosis and TIM-3 expression by TILs. TIM-3 expression by TILs significantly related to TIM-3 expression by endothelial cells. Endothelial CEACAM-1 positivity significantly correlated to tumor grade, associated inflammation, tumor necrosis, muscle invasion and tumor differentiation. CEACAM-1 expression by TILs was significantly related to its expression in tumor cells and absent vascular emboli. Regarding correlations between the both studied markers, expression of TIM-3 by cancer cells was significantly correlated to CEACAM-1 expression by both TILs and endothelial cells. In addition, TIM-3 and CEACAM-1 expressions by TILs were significantly positively correlated. Conclusion: The expressions of TIM-3 and CEACAM-1 in urothelial cancer cells and TILs suggest a potential role for these molecules in cancer development and progression and introduce them as a novel targets in bladder cancer therapy. In addition, endothelial CEACAM-1 expression could be a marker of tumor progression and invasiveness.

Objective: To present the first Egyptian clinical practice guideline for kidney transplantation (KT). Methods: A panel of multidisciplinary subspecialties related to KT prepared this document. The sources of information included updates of six international guidelines, and review of several relevant international and Egyptian publications. All statements were graded according to the strength of clinical practice recommendation and the level of evidence. All recommendations were discussed by the panel members who represented most of the licensed Egyptian centres practicing KT. Results: Recommendations were given on preparation, surgical techniques and surgical complications of both donors and recipients. A special emphasis was made on the recipient’s journey with immunosuppression. It starts with setting the scene by covering the donor and recipient evaluations, medicolegal requirements, recipient’s protective vaccines, and risk assessment. It spans desensitisation and induction strategies to surgical approach and potential complications, options of maintenance immunosuppression, updated treatment of acute rejection and chemoprophylactic protocols. It ends with monitoring for potential complications of the recipient’s suppressed immunity and the short- and long-term complications of immunosuppressive drugs. It highlights the importance of individualisation of immunosuppression strategies consistent with pre-KT risk assessment. It emphasises the all-important role of anti-human leucocyte antigen antibodies, particularly the donor-specific antibodies (DSAs), in acute and chronic rejection, and eventual graft and patient survival. It addresses the place of DSAs across the recipient’s journey with his/her gift of life. Conclusion: This guideline introduces the first proposed standard of good clinical practice in the field of KT in Egypt. Abbreviations: Ab: antibody; ABMR: Ab-mediated rejection; ABO: ABO blood groups; BKV: BK polyomavirus; BMI: body mass index; BTS: British Transplantation Society; CAN: chronic allograft nephropathy; CDC: complement-dependent cytotoxicity; CKD: chronic kidney disease; CMV: cytomegalovirus; CNI: calcineurin inhibitor; CPRA: Calculated Panel Reactive Antibodies; (dn)DSA: (de novo) donor-specific antibodies; ECG: electrocardiogram; ESWL: extracorporeal shockwave lithotripsy; FCM: flow cytometry; GBM: glomerular basement membrane; GN: glomerulonephritis; HIV: human immunodeficiency virus; HLA: human leucocyte antigen; HPV: human papilloma virus; IL2-RA: interleukin-2 receptor antagonist; IVIg: intravenous immunoglobulin; KT(C)(R): kidney transplantation/transplant (candidate) (recipient); (L)(O)LDN: (laparoscopic) (open) live-donor nephrectomy; MBD: metabolic bone disease; MCS: Mean channel shift (in FCM-XM); MFI: mean fluorescence intensity; MMF: mycophenolate mofetil; mTOR(i): mammalian target of rapamycin (inhibitor); NG: ‘not graded’; PAP: Papanicolaou smear; PCN: percutaneous nephrostomy; PCNL: percutaneous nephrolithotomy; PKTU: post-KT urolithiasis; PLEX: plasma exchange; PRA: panel reactive antibodies; PSI: proliferation signal inhibitor; PTA: percutaneous transluminal angioplasty; RAS: renal artery stenosis; RAT: renal artery thrombosis;:rATG: rabbit anti-thymocyte globulin; RCT: randomised controlled trial; RIS: Relative MFI Score; RVT: renal vein thrombosis; TB: tuberculosis; TCMR: T-cell-mediated rejection; URS: ureterorenoscopy; (CD)US: (colour Doppler) ultrasonography; VCUG: voiding cystourethrogram; XM: cross match; ZN: Ziehl–Neelsen stain

Background: Membranous glomerulonephritis (MGN) considered as the most common causes ofnephrotic syndrome (NS) in the world. Eighty percent of cases are classified as primary MGN. PrimaryMGN is an autoimmune disease in which autoantibodies against podocyte antigens forming subepithelialimmune deposits and result in NS. Autoantibodies against M-type phospholipase A2 receptor (PLA2R)were found in 70-80% of patients with primary MGN but not in those with secondary MGN or other renaldiseases. So, we aim to identify PLA2R associated primary MGN.Patient and methods: Out of 5000 native biopsies received from 2014-17, 600 were diagnosed as MGN,out of which 62 were stained for anti-PLA2R by immunoperoxidase. Nine cases of Lupus (SLE) Class V,12 of hepatitis C&B Virus MGN (10 HCV+ve and 2 HBV+ve) were used as controls. Positive wasdetermined as diffuse glomerular capillary wall staining.Results: Anti-PLA2R was positive in 61%(38/62) of cases (33 idiopathic cases and 5 cases of the control group3:HCV, 1 HBV, 1 SLE). None of theclinical parameters showed significance difference but nephrotic range proteinuria in the anti-PLA2R +vegroup was more (66% vs 46%). Histologically, onlymesangial matrix expansion was significantlydifferent in the aPLA2R –ve group (33% vs 10%, p=0.04).Conclusion: anti-PLA2R tissue staining is a reliable and specific method to identify primary MGN andshould be done routinely in all MGN cases even those identified as secondary on clinical basis.

Background & Objectives: In Egypt, most patients diagnosed as urothelial carcinoma (UC) have high grade and muscle-invasive tumors that are commonly associated with schistosomal cystitis. CD44 and p53 may represent potential targets for anticancer treatment. We aimed to assess the expression of CD44 & p53 and to determine their association in high grade, muscle-invasive tumors. Materials and Methods: Thirty four cystectomy cases with high-grade muscle-invasive UC were collected. Sections were stained for CD44 and p53 taking 10% and 20% positivity as cutoff values, respectively. Results: Median age was 60.5 years. Male/female ratio was 4:1.Fourteen cases were T2, 12 were T3, and 8 were T4. Nodal metastasis was evident in 8 cases. Conventional histology was seen in 38%, followed by squamous differentiation in 24%. Twenty patients had bilharzial cystitis. CD44 was positive in 8.8% of cases whereas p53 immunopositivity was noted in 76.5%. CD44 and p53 expression had no statistical association with stage (p =0.52 and 0.97) or bilharzial infestation (p=0.34 and 0.16). There was no significant association between CD44 expression and that of p53, p= 0.06. Conclusion: High-grade muscle-invasive Schistosomal associated urothelial carcinomas are common, but with limited CD44 and p53 co-expression.

Background and Aims Observational studies suggest that acute kidney injury may occur in up to 15% of patients treated with sofosbuvir based regimens. Histological findings show features of acute interstitial nephritis (AIN) or acute tubular necrosis (ATN). Here, we report the first case of small vessel vasculitis following sofosbuvir treatment. Method A 65-year-old female with controlled T2DM was recently diagnosed with HCV. She attained sustained viral response (SVR) after a three-month course of (sofosbuvir + daclatasvir + ribavirin). Kidney functions were normal pre and post treatment. Three months later, she presented with puffiness, bilateral lower extremities edema (no rash) and vomiting. Labs showed acute kidney injury (AKI), nephrotic proteinuria and haematuria (table 1). Immunological investigations (C3, C4, ANA, ANCA and anti-GBM), paraproteinemia workup and cryoglobulins were all negative. Renal US was also normal. Kidney biopsy revealed focal necrotizing glomerulonephritis with 70% crescents (figure 3,4). No chronic changes were detected in the glomeruli, interstitium or tubules. The patient received pulse methylprednisolone 0.5 gm for 3 days followed by oral prednisolone 60 mg/day. Oral cyclophosphamide was initiated at 150 mg after biopsy result was obtained. Our patient showed clinical and laboratory improvement (figure 1,2), however, she developed bone marrow suppression that required cessation of cyclophosphamide. Valsartan initiated to control proteinuria with slight increase in serum creatinine to 1.4 mg/dl. The patient is still under close follow up every two weeks, with a plan to introduce rituximab if serum creatinine continued to increase. Results AKI following HCV treatment with DAA has been reported. Explanation includes AIN, ATN and cryoglobulinemic vasculitis (CV). AIN and ATN usually occur during the treatment course, which is not the case in our patient as she developed AKI three months following the end of the treatment, and the biopsy did not show signs of either ATN or AIN. New onset CV has been reported previously in 3 case reports following SVR after DAA treatment. Previous reports explained that HCV can induce B-cell clonal proliferation that may persist independent of viral eradication and produce IgM kappa which will result in cryoglobulinemic GN, again this is not true in our case. Our patient did not have a rash, her serum cryoglobulin was negative and complement levels (C3 and C4) were normal and biopsy did not show evidence of CV. As far as we know, this is the first case with suspected sofosbuvir associated small vessel vasculitis to be reported. Despite the patient had a negative serum ANCA levels, we suspect that this is a case of drug induced vasculitis. Drug induced vasculitis has been reported with hydralazine, propylthiouracil and cocaine, none of these drugs were used in our case. Also, there is no reported case of vasculitis associated with ribavirin or daclatasvir. Thus, we suspect Sofosbuvir is the cause of drug induced vasculitis in this patient. Conclusion Crescentic GN following HCV treatment using DAA is a serious complication that should be promptly diagnosed and managed. Physicians treating HCV infected patients should be aware of this possible complication and monitor for kidney function even after achieving SVR.

AIM Doppler ultrasonography can be used to assess the progression of vascular (arterial sclerosis) and parenchymal (glomerular sclerosis and crescents) renal damage. The aim of this study was to evaluate the significance of some sonographic and Doppler parameters as non-invasive markers of glomerular filtration rate (GFR) and renal histopathological damage in children. METHODS A cohort of 84 children were enrolled in a case-control study (42 with CKD stages 2-5 and 42 healthy children). GFR was assessed using new improved equation using serum creatinine and cystatin C. Sonar guided renal specimen was obtained and evaluated for the severity of global sclerosis (GS), segmental sclerosis (SS), tubular atrophy (TA), interstitial fibrosis (IF), arterial sclerosis (AS) and arteriolar hyalinosis (AH). The following sonographic and Doppler parameters were assessed in both patients and control group: resistivity index (RI), pulsatility index (PI), atrophic index (AI), mean renal volume, mean renal density, time average velocity (TAV) and body surface area related volume perfusion (BSARVP). RESULTS There was significant difference in renal density (P

Introduction: Lupus nephritis (LN) is a serious manifestation of systemic lupus erythematosus (SLE) and histologically evident even in those without clinical manifestations of renal disease. Aim of the work: To assess C4d on erythrocytes (E-C4d) and glomerular deposits (G-C4d) in SLE patients and study its association to LN and disease activity. Patients and methods: 61 subjects were enrolled including 15 with LN (study group); 15 with renal disease not due to SLE (control A group); 16 SLE patients with no renal affection (control B group) and 15 healthy individuals (control C group). Flow cytometry system was used for C4d immunohistochemical staining. SLE disease activity index (SLEDAI) was assessed for SLE patients. Results: The age was comparable among groups; for LN patients was 28.3 ± 8.2 years; group A (35.9 ± 13.3); group B (27.1 ± 8.8) and group C (29.4 ± 7.1) (p = .06). Patients were mostly females. The disease duration of LN patients was 1–2 years; group A (3–5 years) and group B (5–10 years). E-C4d and G-C4d deposits were significantly higher in LN patients (8.08 ± 2.93 and 2.3 ± 0.97) in comparison to the control groups (A/B/C) (A: 3.78 ± 0.38 and 0.6 ± 1.12; B: 3.72 ± 0.32; C: 3.55 ± 0.44 p

Background/aim: Cisplatin-induced nephrotoxicity in large proportion of patients. The aim of this work is to clarify the effect of combination of sildenafil and gemfibrozil on cisplatin-induced nephrotoxicity either before or after cisplatin treatment and determination of nephrotoxicity predictors among the measured tissue markers. Methods: Thirty two adult male albino rats were divided into four equal groups (G) GI control, GII received cisplatin, GIII received sildenafil and gemfibrozil before cisplatin, GIV received sildenafil and gemfibrozil after cisplatin. Creatinine and urea were measured and animals were sacrificed and kidney was taken for histopathology. The following tissue markers were measured, heme oxygenase-1 (HO-1) activity, reduced glutathione, quantitative (real-time polymerase chain reaction) RT-PCR for gene expression of tumor necrosis factor alpha (TNF-α) and endothelial nitric oxide synthase (ENOS) level. Results: GII developed AKI demonstrated by significantly high urea and creatinine and severe diffuse (80–90%) tubular necrosis. TNF-α was highly and significantly elevated while the rest of tissue markers were significantly reduced in GI1 compared to other groups. GIV showed better results compared to GIII. There was a significant positive correlation between creatinine and TNF-α when combining GI and GII while there were significant negative correlation between creatinine and other tissue markers in same groups. Linear regression analysis demonstrated that HO-1 was the independent predictor of AKI demonstrated by elevated creatinine among GI and GII. Conclusions: Combination of sildenafil and gemfibrozil can be used in treatment of cisplatin-induced nephrotoxicity. HO-1 is a promising target for prevention and/or treatment of cisplatin-induced nephrotoxicity.

Pediatric kidney transplantation is a multidisciplinary therapy that needs special consideration and experience. In this study, we aimed to present CUCH experience; over a 10-year period, as a specialized center of kidney transplantation in children. We studied 148 transplantations performed at a single center from 2009 to 2018. Pretransplant and follow-up data were collected and graft/patient survival rates were evaluated. A total of 48 patients developed at least one rejection episode during 688 patient-years of follow-up. Infections, recurrence of original disease, and malignancy were the most important encountered medical complications (20%, 2%, and 1.4%, respectively). One-year patient survival was 94.1%, while graft and patient survival was 91.9%. Graft/patient survival at 5, 7, and 9 years was 90%, 77%, and 58%, respectively. Infections were the main cause (69%) of mortality. Death with a functioning graft and CR were the main causes of graft loss (48% and 33%, respectively). Pediatric kidney transplantation in Egypt is still a challenging yet successful experience. Rejections and infections are the most frequent complications. Short-term outcomes surpass long-term ones and graft survival rates are similar to the international standard.

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

The association of bilharziasis with membranous nephropathy (MN) has long been debated. The relatively recent use of antibodies against the M-type phospholipase A2 receptor (PLA2R) has been proposed as a valuable tool to discriminate the idiopathic from secondary MNs. Anti-PLA2R antibodies are found in sera from about 70% of iMN patients, in contrast to patients with secondary MN, in whom serum anti-PLA2R antibodies could not be detected. In the current case report, we detected anti-PLA2R antibodies both in serum and renal biopsy from a patient with MN associated with Schistosoma mansoni. This finding confirms the idiopathic nature of the MN and excludes schistosomiasis as the triggering agent of MN. After treating bilharziasis, Ponticelli regimen was initiated without a significant improvement.

Introduction The role of intrinsic pathway of apoptosis in pathogenesis of lupus nephritis (LN) is still not clear. We investigated the relation between the expression of two major proteins of the intrinsic pathway of apoptosis; bcl2 as an antiapoptotic protein and bax as a proapoptotic one; in renal tissue of LN. Methods The study included fifty paraffin embedded renal tissue obtained from renal biopsy specimens of LN patients (8 cases class II, 10 cases class III, 21 cases class IV and 11 cases class V) and five paraffin embedded apparently normal renal tissue obtained from nephrectomy specimens due to renal neoplasms as a control group. Immunohistochemical staining for bcl2 and bax antibodies was done. Ki67 immunohistochemical staining was done for class III and IV to assess the degree of proliferation. The number of intraglomerular bcl2, bax and ki67 positive cells per glomerular cross section was evaluated for each case. The results were analysed in different LN classes and correlated to different glomerular lesions. Results: The expression of bax and bcl2 proteins was higher in LN glomeruli compared to normal. The expression of bcl2 was significantly higher in class IV and was correlated to the degree of endocapillary hypercellularity. The bax to bcl2 ratio was significantly correlated to the percentage and degree of glomerular sclerosis. Conclusion The intrinsic pathway of apoptosis interfere in the pathogenesis of lupus glomerulonephritis. The balance between bax and bcl2 proteins might have a role in regulating the progression of glomeruli from proliferative to sclerotic state.

Background Polyomavirus nephropathy (PVN) mainly caused by BK polyomavirus (BKPyV) remains the most common productive viral infection of the kidney in immunosuppressed patients. The diagnosis of PVN is based on the detection of BK viruria and BK viremia in conjunction with histological findings in the graft biopsy. Methods Our study was aimed to estimate the prevalence of productive BKPyV infection among renal transplant patients within the first year post-transplant and identify those at risk of developing PVN. Our cross-sectional study was conducted on 134 kidney transplant patients. Evidence of BKPyV replication was assessed by viral quantification of blood and urine samples of studied patients using a quantitative real-time polymerase chain reaction (Q-PCR)PCR), detection of decoy cells in urine cytology smears, histological examination of graft biopsies from Q-PCR BKPyV-positive patients, and immunohistochemical staining by simian virus 40 (SV40) antibody. Results Significant BKPyV infection was prevalent in 8% (n = 11) of our patients, with a peak of BKPyV infection about 8 months post transplant. BKPyV viral load by Q-PCR assay in these patients varied from 1350 to 20,000,000 (1.35 × 10(3) to 2 × 10(7) ) copies/mL for urine samples and 935 to 18,920 (9.35 × 10(2) to 1.89 × 10(4) ) copies/mL for blood samples. All the 11 patients were positive for decoy cells but only 3 developed PVN based on histology and positive SV40 staining. BKPyV infection was more prevalent in older patients. All patients responded to reduction in their immunosuppressive regimens, apart from 2 patients who required replacement of calcineurin inhibitors-based regimen with mammalian target of ramapycin inhibitors with an overall good response. Conclusion Protocol screening programs based on detection of viral replication by viruria, viremia, and decoy cells in urine are necessary to shed light on patients with high virus replication and hence increased risk of developing PVN, and to allow early diagnosis and intervention.

Large case series of renal amyloidosis subtypes have recently been published in the United States and Europe showing AL amyloidosis to be the predominant subtype in this part of the world. However, the most common subtypes of renal amyloidosis throughout the rest of the world are unknown. We present here the first large case series detailing the subtypes of renal amyloidosis among Egyptians. In this population, AA amyloidosis was the most common type of amyloidosis on renal biopsy at 48%. The newly described leukocyte chemotactic factor 2 amyloidosis (ALECT2) was the second most common type and represented nearly one-third of renal amyloid cases at 31%. AL accounted for only 20% of cases. The pathologic findings in ALECT2 cases were similar to those previously described in other case series. Thus ALECT2, which was initially thought to affect mainly Hispanics in the United States, appears to represent an important and likely underrecognized etiology of chronic kidney disease among Egyptians and probably in other ethnic groups around the world.

Obstacles to morbidity-free long-term survival after liver transplantation (LT) include complications of immunosuppression (IS), recurrence of the original disease and malignancies, and unexplained chronic hepatitis and graft fibrosis. Many programs attempt to minimize chronic exposure to IS by reducing dosages and stopping steroids. A few programs have successfully weaned a highly select group of recipients from all IS without apparent adverse consequences, but long-term follow-up is limited. Patients subjected to adjustments in IS are usually followed by serial liver chemistry tests, which are relatively insensitive methods for detecting allograft damage. Protocol biopsy has largely been abandoned for hepatitis C virusnegative recipients, at least in part because of the inability to integrate routine histopathological findings into a rational clinical management algorithm. Recognizing a need to more precisely categorize and determine the clinical significance of findings in long-term biopsy samples, the Banff Working Group on Liver Allograft Pathology has reviewed the literature, pooled the experience of its members, and proposed working definitions for biopsy changes that (1) are conducive to lowering IS and are compatible with operational tolerance (OT) and (2) raise concern for closer follow-up and perhaps increased IS during or after IS weaning. The establishment of guidelines should help us to standardize analyses of the effects of various treatments and/or weaning protocols and more rigorously categorize patients who are assumed to show OT. Long-term follow-up using standardized criteria will help us to determine the consequences of lowering IS and to define and determine the incidence and robustness of OT in liver allografts. Liver Transpl 18:1154-1170, 2012. (c) 2012 AASLD.