Sufia Husain

Advances in the Understanding of Transplant Glomerulopathy

Transplant glomerulopathy is a sign of chronic kidney allograft damage. It has poor survival and no effective therapies. This entity develops as a maladaptive repair/remodeling response to sustained endothelial injury and is characterized by duplication/multilamination of capillary basement membranes. This review provides up-to-date information for transplant glomerulopathy, including new insights into underlying causes and mechanisms, and highlights unmet needs in diagnostics. Transplant glomerulopathy is widely accepted as the principal manifestation of chronic antibody-mediated rejection, mostly with HLA antigen class II antibodies. However, recent data suggest that at least in some patients, there also is an association with hepatitis C virus infection, autoimmunity, and late thrombotic microangiopathy. Furthermore, intragraft molecular studies reveal nonresolving inflammation after sustained endothelial injury as a key mechanism and therapeutic target. Unfortunately, current international criteria rely heavily on light microscopy and miss patients at early stages, when they likely are treatable. Therefore, better tools, such as electron microscopy or molecular probes, are needed to detect patients when kidney injury is in an early active phase. Better understanding of causes and effector mechanisms coupled with early diagnosis can lead to the development of new therapeutics for transplant glomerulopathy and improved kidney outcomes.

Phenotypes of antibody-mediated rejection in organ transplants.

Antibody‐mediated hyperacute rejection was the first rejection phenotype observed in human organ transplants. This devastating phenotype was eliminated by reliable crossmatch technologies. Since then, the focus was on T‐cell‐mediated rejection and de novo donor‐specific antibodies were considered an epiphenomenon of cognate T‐cell activation. The immune theory was that controlling the T‐cell response would entail elimination of antibody‐mediated rejection (ABMR). With modern immunosuppressive drugs, T‐cell‐mediated rejection is essentially treatable. However, this did not prevent ABMR from emerging as a significant phenotype in all types of organ transplants. It became obvious that both rejection types require distinct treatment and thus reliable diagnosis. This is the current challenge. ABMR, depending on stage, grade, time course, organ type or prior treatment, can present with a wide spectrum of phenotypes. This review summarizes the current diagnostic consensus for ABMR, describes unmet needs and challenges in diagnostics, and proposes new approaches for consideration.

Strategy for second kidney biopsy in patients with lupus nephritis

BACKGROUND Standard clinical and laboratory parameters have limited predictive values for discriminating between active lupus nephritis and chronic disease. The objective of this study was to examine the predictive utility of a second kidney biopsy in patients with lupus nephritis. METHODS Patients with lupus nephritis were advised to have second kidney biopsies at the end of the maintenance phase of their therapies. Baseline and second renal biopsies were re-classified by pathologists blinded to the clinical data. The relationships between remission status and histological parameters were examined. RESULTS Included in this study were 77 patients followed up for a median duration of 8.7 years (interquartile range, 5.3-10.1 years). Their renal survival rates were 93% for those in complete remission (CR), 69% for partial remission (PR) and 41% for no remission (NR). One-third of the patients with PR and 14% of patients with NR had no histological evidence of active disease on second biopsy. At the second biopsy, but not at the baseline biopsy, activity index was predictive of survival. The 10-year renal survival rate was 100% for those with an activity index of 0, 80% for those with an activity index of 1 or 2 on the second biopsy and 44% for those with an index of >2, regardless of remission status. CONCLUSION Second kidney biopsy at the end of maintenance phase of therapy is an important diagnostic and prognostic tool that could guide physicians to safer practices with better outcomes.

Increasing prevalence of breast cancer among Saudi patients attending a tertiary referral hospital: a retrospective epidemiologic study.

Aim To determine the pattern of breast diseases among Saudi patients who underwent breast biopsy, with special emphasis on breast carcinoma. Methods A retrospective review was made of all breast biopsy reports of a mass or lump from male and female patients seen between January 2001 and December 2010 at the King Khalid University Hospital, Riyadh, Saudi Arabia. Results Of 1035 breast tissues reviewed, 939 specimens (90.7%) were from female patients. There were 690 benign (65.8%) and 345 (34.2%) malignant cases. In women, 603 (64.2%) specimens were benign and 336 (35.8%) were malignant. In men, 87 specimens (90.6%) were benign and 9 (9.4%) were malignant. All malignant cases from male patients belonged to invasive ductal carcinoma and the majority of malignant cases from female patients belonged to invasive/infiltrating ductal carcinoma. The proportion of malignancy was 18% in patients younger than 40 years and 63.2% in patients older than 60 years. The mean age of onset for malignancy was 48.6 years. The annual percentage incidence of malignant breast cancer steadily increased by 4.8%, from an annual rate of 23.5% in 2000 to 47.2% in 2007. Conclusion Among Saudi patients, there is a significant increase in the incidence of breast cancer, which occurs at an earlier age than in western countries. Continued vigilance, mammographic screening, and patient education are needed to establish early diagnosis and perform optimal treatment.

Predictive and prognostic significance of CD8+ tumor‑infiltrating lymphocytes in patients with luminal B/HER 2 negative breast cancer treated with neoadjuvant chemotherapy

The immunobiology of breast cancer (BC) subtypes, including luminal cancer, remains unclear. Cluster of differentiation (CD)8+ tumor-infiltrating lymphocytes (TIL) are essential components of tumor-specific cellular adaptive immunity. However, only few studies have addressed the significance of cluster of differentiation 8+(CD8+) TIL in patients with luminal BC. The present study aimed to evaluate the predictive and prognostic significance of CD8+ TIL in patients with luminal B/human epidermal growth factor receptor 2 (HER 2)-negative BC treated with anthracycline-based neoadjuvant chemotherapy (NC). A total of 31 patients who underwent breast-conserving surgery or mastectomy post-NC were enrolled. Immunostaining for CD8+ TIL was performed using rabbit monoclonal antibodies against human CD8+. Intra- and peritumoral CD8+ TIL expression levels were classified into high and low, based on the median value of each. CD8+ TIL expression data were demonstrated to be correlated with disease-free survival (DFS) and overall survival (OS), using Kaplan-Meier and Coxs proportional hazards regression tests. The results revealed that, among all clinicopathological characteristics, only pathological complete response (pCR) was significantly correlated with intratumoral CD8+ TIL expression (P=0.016). A total of 9/16 patients (56%) with high intratumoral CD8+ TIL expression achieved pCR, in contrast with 2 out of 15 patients (13.3%) with low expression (P=0.016). High expression of intratumoral CD8+ TIL was significantly associated with OS (log-rank test, P=0.023). Multivariate Cox regression analysis revealed that intratumoral expression of CD8+ TIL was an independent prognostic factor for OS [hazard ratio (HR)=2.82; 95% confidence interval (CI)=0.911-4.833, P=0.007], but not for DFS (HR=1.11; 95% CI=0.282-2.078; P=0.508). In conclusion, the results of the present study suggested that high intratumoral CD8+ TIL expression was significantly predictive of pCR post-NC, and represented an independent prognostic factor for improved OS. In contrast, low intratumoral CD8+ TIL expression was a strong predictor of lack of pCR to NC, as well as an independent prognostic factor for poor OS. Assessment of the immune response in conjunction with the usual parameters may aid in the further stratification of patients with luminal B/HER 2-negative BC regarding the prediction of pCR post-NC and overall prognosis.

Molecular subtypes of breast carcinoma in Saudi Arabia. A retrospective study

Objectives: To determine the distribution of various molecular subtypes of breast cancer in Saudi Arabia and to assess the association between these subtypes and age at diagnosis, tumor size, histopathological type, grade, presence of carcinoma in-situ, and lymph node status. Methods: This observational retrospective study, between January 2010 and December 2014, was conducted at King Khalid University Hospital, Riyadh, Saudi Arabia. We classified 359 breast cancers into 4 molecular subtypes, using immunohistochemistry: luminal A (estrogen receptor [ER], or progesterone receptor [PR] positive and human epidermal growth factor receptor 2 [HER2] negative), luminal B (ER and/or PR positive and HER2 positive), HER2-positive (ER and PR negative and HER2 positive), and triple negative (ER, PR, and HER2 negative). We evaluated the relationship between these subtypes and clinicopathological features using Chi square test. Results: The most prevalent subtype was luminal A (58.5%), followed in descending order of frequency by triple negative (14.8%), luminal B (14.5%), and HER2-positive (12.3%). The average age at diagnosis was 49.8 years, and average tumor size at diagnosis was 3.19 cm. Conclusion: Luminal A tumor was the most common molecular subtype and HER2-positive was the least common. Most lobular carcinomas were luminal A tumors. Human epidermal growth factor receptor 2-positive and triple negative tumors had a higher histologic grade and a larger tumor size at diagnosis, and they were more common in women under 50 years. Carcinoma-in-situ was least common in triple negative tumors. We found no association between lymph node status and molecular subtypes.

A 38‐YEAR OLD WOMAN WITH A DURAL BASED LESION

Isolated intracranial xanthogranulomas arising from the dura mater are extremely rare.We present a case of a symptomatic large right frontoparietal dura based intracranial xanthogranuloma in a 38-year-old female. Xanthogranulomas are benign non-Langerhans cell histiocytic lesions. They are frequently described in the skin of infants and children. Extracutaneous manifestations especially in the central nervous system are highly uncommon. Dural xanthogranulomas usually arise in association with familial hypercholesterolemia, with Erdheim Chester disease (ECD), and with Weber-Christian disease. Our case however, had no such associations. In this report, the authors describe the clinical, radiological and microscopic presentation of this case and the differential diagnoses of intracranial xanthogranuloma.

Collapsing glomerulopathy, the Saudi Arabian scenario. A study of 31 cases and a review of literature

Objectives: To compare the clinico-pathological features of collapsing glomerulopathy (CG) at a tertiary hospital in Saudi Arabia with the world literature. Methods: In a retrospective study, all biopsy-diagnosed cases of CG between 2004-2015 were identified and analyzed, at King Khalid University Hospital, King Saud University, Riyadh. The clinico-pathological findings along with prognosis were reviewed and compared with the reported literature. Results: Thirty-one CG patients were identified, most were adult males. All the CG cases were idiopathic, all Arabs, none HIV positive, none of African descent, and none with a history of drug abuse. The number of glomeruli with collapsing lesions per biopsy ranged from 1 to 9. Other types of FSGS lesions (not otherwise specified and perihilar) were also noted. There was extensive podocyte effacement. Upon treatment, remission (complete/partial) was noted in almost half the patients; around one fourth did not respond to treatment; and one fourth progressed to end stage kidney disease (ESKD). The median time taken to develop ESKD from the time of biopsy diagnosis was 23 months. Conclusion: The clinico-pathological and prognostic correlates of CG in Saudi Arabia are comparable with that of the world literature. The management protocol at our center is the same as that practiced in different parts of the world, and the prognosis is overall poor.

Prognostic significance of C1q deposition in serial biopsies for predicating the long-term outcome in patients with proliferative lupus nephritis.

Lupus nephritis (LN) is characterized by a highly variable clinical course. It has been reported that histopathologic lesions are risk factors for the progression of LN. The aim of this study is to investigate the relationship among the co-deposition of C1q, clinicopathological features, and renal outcomes in patients with LN. The clinical and histological parameters were studied in patients with International Society of Nephrology/Renal Pathology Society Class III or IV LN, who underwent two kidney biopsies. The patients were divided into two groups based on the glomerular C1q deposits: C1q-positive and C1q-negative. The impact of C1q status and longterm renal outcome on the doubling of serum creatinine and the rate of remission in the two groups were further investigated. Fifty-three patients had pure proliferative nephritis and 37.7% of these had a co-deposition of C1q. Doubling of serum creatinine was observed in 25% of patients with C1q-positive and 24.2% of patients with C1q-negative deposits. There was no difference between the two groups in terms of achieving complete or partial remission. The renal survival in the two groups was similar (P = 0.75). Upon repeat biopsy, the persistence of C1q positivity was associated with a poor outcome (P = 0.007). C1q deposition in the glomerulus in the baseline biopsy was not associated with a poor renal outcome or severe pathologic features in patients with proliferative LN. However, the persistence of C1q positivity in repeat kidney biopsy is associated with a poor renal outcome.

Focal and segmental glomerulosclerosis in murine models: a histological and ultrastructural characterization with immunohistochemistry correlation of glomerular CD44 and WT1 expression

ABSTRACT Aim: Focal segmental glomerulosclerosis (FSGS) is a common progressive chronic renal disease. Podocyte injury and loss are the postulated pivotal events that trigger FSGS. In this study, the authors aim to examine the evolution of FSGS in murine models histologically, ultrastructurally and immunohistochemically with special emphasis on podocytes and parietal epithelial cells (PECs). Material and methods: FSGS resembling primary FSGS in humans was initiated in Wistar rats using intravenous Adriamycin injections. Blood and urine analysis were performed at 0, 8, and 12 weeks. Both the control kidneys and the test kidneys were harvested at 8 and 12 weeks, examined histologically and ultrastructurally and the findings correlated with the glomerular expression of immunostains specific for podocytes (WT-1) and for activated PECs (CD44). Results: FSGS developed in both 8 and 12 weeks test groups showing progressive proteinuria, podocytopathy and segmental glomerular scarring. There was a decrease in the glomerular expression of WT-1 with a concurrent increase in the glomerular expression of CD44, indicating podocyte loss with synchronous increase in activated PECs. The evolving FSGS correlated negatively with podocytes and positively with activated PECs. Conclusion: Our study shows that with podocyte injury there is podocyte effacement and loss, proteinuria, glomerular segmental adhesion and scarring, all culminating in FSGS. In addition, there is activation, hyperplasia and hypertrophy of PECs. This demonstrates that both podocyte loss and PEC activation promote FSGS. Our findings are consistent with recent investigations. More studies are required to further understand the role of these cells in the evolution of FSGS and subsequently introduce new targeted treatment modalities.