Thrombotic microangiopathy after kidney transplantation: Expanding etiologic and pathogenetic spectra.

Thrombotic microangiopathy (TMA) is an uncommon but serious complication that not only affects native kidneys but also transplanted kidneys. This review is specifically focused on post-transplant TMA (PT-TMA) involving kidney transplant recipients. Its reported prevalence in the latter population varies from 0.8% to 14% with adverse impacts on both graft and patient survival. It has many causes and associations, and the list of etiologic agents and associations is growing constantly. The pathogenesis is equally varied and a variety of patho genetic pathways lead to the development of microvascular injury as the final common pathway. PT-TMA is categorized in many ways in order to facilitate its management. Ironically, more than one causes are contributory in PT-TMA and it is often difficult to pinpoint one particular cause in an individual case. Pathologically, the hallmark lesions are endothelial cell injury and intravascular thrombi affecting the microvasculature. Early diagnosis and classification of PT-TMA are imperative for optimal outcomes but are challenging for both clinicians and pathologists. The Banff classification has addressed this issue and has developed minimum diagnostic criteria for pathologic diagnosis of PT-TMA in the first phase. Management of the condition is also challenging and still largely empirical. It varies from simple maneuvers, such as plasmapheresis, drug withdrawal or modification, or dose reduction, to lifelong complement blockade, which is very expensive. A thorough understanding of the condition is imperative for an early diagnosis and quick treatment when the treatment is potentially effective. This review aims to increase the awareness of relevant stakeholders regarding this important, potentially treatable but under-recognized cause of kidney allograft dysfunction.

Tumor deposits in axillary adipose tissue in patients with breast cancer: Do they matter?

Tumor deposits (TDs) are defined as discrete, irregular clusters of tumor cells lying in the soft tissue adjacent to but separate from the primary tumor, and are usually found in the lymphatic drainage area of the primary tumor. By definition, no residual lymph node structure should be identified in these tumor masses. At present, TDs are mainly reported in colorectal cancer, with a few reports in gastric cancer. There are very few reports on breast cancer (BC). For TDs, current dominant theories suggest that these are the result of lymph node metastasis of the tumor with complete destruction of the lymph nodes by the tumor tissue. Even some pathologists classify a TD as two lymph node metastases for calculation. Some pathologists also believe that TDs belong to the category of disseminated metastasis. Therefore, regardless of the origin, TDs are an indicator of poor prognosis. Moreover, for BC, sentinel lymph node biopsy is generally used at present. Whether radical axillary lymph node dissection should be adopted for BC with TDs in axillary lymph nodes is still inconclusive. The present commentary of this clinical issue has certain guiding significance. It is aimed to increase the awareness of the scientific community towards this under-recognized problem in BC pathology.

Evolution of human kidney allograft pathology diagnostics through 30 years of the Banff classification process.

The second half of the previous century witnessed a tremendous rise in the number of clinical kidney transplants worldwide. This activity was, however, accompanied by many issues and challenges. An accurate diagnosis and appropriate management of causes of graft dysfunction were and still are, a big challenge. Kidney allograft biopsy played a vital role in addressing the above challenge. However, its interpretation was not standardized for many years until, in 1991, the Banff process was started to fill this void. Thereafter, regular Banff meetings took place every 2 years for the past 30 years. Marked changes have taken place in the interpretation of kidney allograft biopsies, diagnosis, and classification of rejection and other non-rejection pathologies from the original Banff 93 classification. This review attempts to summarize those changes for increasing the awareness and understanding of kidney allograft pathology through the eyes of the Banff process. It will interest the transplant surgeons, physicians, pathologists, and allied professionals associated with the care of kidney transplant patients.

Biopsy-Proven Renal Diseases in the Elderly: A Developing Country Perspective.

Renal diseases are one of the common causes of morbidity and mortality in elderly population. Currently, the spectrum of renal diseases in elderly population in our country is unknown. The aim of this study was to determine the pattern of renal diseases in elderly patients in Pakistan. In this retrospective, observational study, we included all consecutive patients aged ≥60 years, on whom native renal biopsies were performed during a period of 25 years from January 1994 to December 2018. The final histologic diagnosis was categorized into four groups, primary glomerular diseases (PGDs), secondary glomerular diseases (SGDs), tubulointerstitial disease (TID), and vascular diseases (VDs). A total of 324 renal biopsies are performed in the study period. The mean age was 64.6 ± 5.1 years, range of 60-80 years with a male-to-female ratio of 3.26:1. The mean serum creatinine at biopsy was 4.1 ± 2.86 mg/dL. Indications for biopsy were acute kidney injury (AKI) in 141 (43.5%), followed by nephrotic syndrome (NS) in 128 (39.5%). Renal disease category was PGD in 204 (63%), SGD in 42 (13%), TID in 58 (17.9%), and VD in 20 (6.1%). Focal segmental glomerulosclerosis (FSGS) is the leading cause of PGD in 55 (27%). Among SGD, amyloidosis was the most common cause in 27 (64.3%). In patients who were biopsied for AKI, majority were crescentic glomerulonephritis accounting for 28 (19.8%). In conclusion, AKI and NS are the common biopsy indications in our population. Overall FSGS is the most common histologic diagnosis in this cohort.

Allograft bone banking experience in Pakistan.

To share our experience of establishing a bone bank in Pakistan, and the clinical use of these indigenously produced bone grafts. We retrospectively reviewed our experience of the procurement, processing, and storage of bone grafts at a bone bank in Karachi, Pakistan, the first bone bank to be established in a public sector hospital in Pakistan. The bone bank was established at Sindh Institute of Urology and Transplantation (SIUT), Karachi, in collaboration with Department of Orthopaedic Surgery, Dow University of Health Sciences/Civil Hospital, Karachi (CHK) in May, 2015. Since then, a large number of bone grafts from the tissue bank have been used for various orthopedic procedures. This paper describes the problems and challenges faced in establishing and running a tissue bank in a Muslim and a developing country and the progress of the bone bank over the first 4 years. A total of 93 bone grafts were retrieved and preserved in the bone bank over the 4-year period. Among these, 56 (60.2%) bones were retrieved from male donors and 37 (39.8%) from females. The mean age of all donors was 55.9 ± 15.34 years (range: 16-90 years). All bone donors were living patients. No c bones were obtained from deceased donors. Types of bone grafts included: femoral heads, 68; head with neck of femur, 19; radius and ulna, 1; lower femur, knee joint, lower leg and foot bones, 4; and skull bone, 1. All grafts were subjected to aerobic and anaerobic bacterial cultures, as well as fungal cultures. Microbiological contamination was observed in 18/93 (19.35%). All culture positive bones were discarded. Bone grafts issued from the bank and transplanted were 51/93 (54.8%) in all. Bone grafts were used in a variety of tumor and non-tumor orthopaedic procedures in CHK. Nine bone grafts were donated to the other hospitals to be used for revision total hip replacement and tumor surgeries. There were no service charges. Two patients (3.92%) developed infections postoperatively, one superficial and one deep. No other complications were noted. This is the preliminary report on the establishment and functioning of a bone bank in a public sector hospital in Pakistan. The favorable outcome has inculcated confidence in orthopedic surgeons for greater use of bone allografts for a variety of indications in this country.

Borderline Changes on Dysfunctional Renal Allograft Biopsies: Clinical Relevance in a Living Related Renal Transplant Setting.

OBJECTIVES: Our aim was to determine the clinical significance of borderline lymphocytic infiltrates on indicated renal allograft biopsies in a living related renal transplant setting. MATERIALS AND METHODS: The study was conducted at the histopathology department of Sindh Institute of Urology and Transplantation. A retrospective review of 421 renal transplant patients was conducted from October 2007 to September 2008 to identify patients in whom a histologic diagnosis of borderline changes was made on dysfunctional renal allograft biopsies. Demographic, clinical, and laboratory data; biopsy findings; treatments given; and responses to treatment were collected and analyzed. Standard biopsy indications determined the need for graft biopsies. Biopsies were reported according to Banff criteria. RESULTS: Mean age was 26.92 ± 9.14 years (range, 10-45) for recipients and 38.46 ± 9.16 years (range, 19-50) for donors. Males were predominant among recipients (84.6% vs 15.4%), and females were predominant among donors (57.7% vs 42.3%). The best serum creatinine levels were 1.79 ± 1.15 mg/dL (range, 0.83-6.12). These were achieved after a median of 3 days (interquartile range, 2-7.25). Dysfunctional biopsies exhibiting borderline infiltrates were performed at a median duration of 5.5 days (interquartile range, 3-14.25). Mean serum creatinine at the time of biopsy was 2.34 ± 1.43 mg/dL (range, 1.25-8.25). The biopsies showed borderline cellular infiltrates (interstitial inflammation 1 [i1] and tubulitis 1 and [t1] lesions). All recipients except one received antirejection treatment (antithymocyte globulin, n = 5; escalation of mycophenolate mofetil dosage, n = 1; pulse steroids, n = 19); all recipients responded with a decline in serum creatinine toward baseline, with a mean serum creatinine of 1.31 ± 0.42 mg/dL (range, 0.40-2.71). This response was achieved at a median duration of 9.73 ± 5.32 days (range, 1-23) after starting treatment. CONCLUSIONS: The borderline cellular infiltrates on dysfunctional renal allograft biopsies signify evolving phases of acute cellular rejection. These infiltrates responded favorably to antirejection treatment in our setting.

Proliferative Lesions of Parathyroid Glands: An Update for Practicing Pathologists.

Pathological lesions of parathyroid glands encompass a wide range of lesions ranging from developmental anomalies to inflammatory disorders to neoplastic processes. Proliferative lesions of parathyroid glands represent the commonest causes of hyperparathyroidism in clinical practice. However, the parathyroid specimens represent only a tiny fraction of the workload received in a non-specialist histopathology laboratory. As a result, the familiarity of the pathologists with the spectrum of parathyroid lesions is generally limited. An accurate diagnosis of the parathyroid lesions is challenging and a daunting task for both the clinicians and the pathologists. The traditional morphological approaches have limitations. Ancillary techniques of immunohistochemistry and molecular biology are being increasingly employed to resolve the diagnostic dilemmas. This review briefly describes the proliferative pathological lesions affecting the parathyroid glands and provides some useful tips on accurately diagnosing these lesions.

Frequency and clinicopathological correlations of histopathological variants of idiopathic focal segmental glomerulosclerosis in nephrotic adolescents.

OBJECTIVE: To determine the frequency and clinicopathological correlations of focal segmental glomerulosclerosis variants in adolescents with idiopathic nephrotic syndrome. METHODS: All consecutive adolescents (12 to 18 years) who presented with idiopathic nephrotic syndrome in the period, January 2009 to December 2012, and in whom the histological diagnosis of focal segmental glomerulosclerosis was made on renal biopsies, were included in this prospective study. Their clinical, laboratory and histopathological features at the time of presentation or biopsy were noted from the case files and the biopsy reports. RESULTS: Among 50 adolescents, 34 (68%) were males and 16 (32%) females.The mean age was 15.14 +/- 2.3 years. The mean duration of disease was 6.3 +/- 11.2 months.The mean serum creatinine was 0.96 +/- 0.82 mg/dl. The mean 24-hour urinary protein excretion was 3.8 +/- 0.68 grams. Biopsy indications were steroid-resistant nephritic syndrome in 15 (30%), steroid-dependant nephritic syndrome in 19 (38%) and adolescent nephritic syndrome in 16 (32%) cases. Among the focal segmental glomerulosclerosis variants, 40 (80%) were "not otherwise specified", followed by the collapsing variant, which accounted for 8 (16%) cases. The tip and cellular variants, both were found in one (2%) case each. Among the histological features, global glomerulosclerosis was found in 23 (46%) cases, and segmental scarring/collapse in all (100%). A variable degree of tubular atrophy and interstitial fibrosis was noted in 44 (88%) cases. CONCLUSION: The results from this study indicate that the pattern of focal segmental glomerulosclerosis variants differs markedly in adolescents compared with younger children.

Immunoglobulin M nephropathy in adults: a clinicopathological study.

INTRODUCTION: There is no data specifically on the clinical and immunopathologic features of Immunoglobulin M nephropathy (IgMN) in adults with kidney diseases in Pakistan. MATERIALS AND METHODS: We retrospectively reviewed our adult native renal biopsy records from May 2001 to April 2010 and identified 57 cases out of a total of 1,753 records labeled as IgMN on final histopathological analysis. Among these, 41 cases were included in the present analysis. Their relevant data items were collected from the case files and biopsy reports. RESULTS: The mean age of this cohort was 30.21 ± 10.12 years. The male-female ratio was 1.15:1. The most common presentation was idiopathic nephrotic syndrome. Hematuria and hypertension at presentation were noted in 24 (58.5%) and 10 (24.4%) patients, respectively. The most common morphologic change was glomerular mesangial cell proliferation, found in 28 biopsies (68.3%). Mesangial matrix expansion was noted in 16 (39%). Minor glomerular alterations were noted in 5 cases (12.2%) and focal segmental glomerulosclerosis in 4 (9.8%). Immunofluorescence microscopy showed diffuse mesangial positivity of IgM in all specimens. Subdominant IgA was noted in 6 cases (14.6%). Complements C3 and C1q were found in 28 (68.3%) and 21 (51.2%) patients, respectively. CONCLUSIONS: Our results show that IgMN is not very common in adults. Its clinicopathological spectrum is similar to that described from the neighboring countries, showing a spectrum of morphologic changes ranging from minor changes to focal segmental glomerulosclerosis.

Frequency and clinicopathological characteristics of variants of primary focal segmental glomerulosclerosis in adults presenting with nephrotic syndrome.

BACKGROUND: There is no information on the frequency and clinicopathological presentation of the variants of primary focal segmental glomerulosclerosis (FSGS) in adults presenting with idiopathic nephrotic syndrome (INS) in Pakistan. OBJECTIVES: The aim of this study was to determine the frequencies of different histologic variants of primary FSGS with INS at our center and to compare our findings with those published in literature. PATIENTS AND METHODS: All consecutive adults (≥18 years) with INS, and diagnosis of FSGS on renal biopsies, were included. Their clinicopathological features at the time of presentation were retrieved and compared among the variants. RESULTS: There were 120 (65.2%) males and 64 (34.8%) females. The mean age was 30.62±12.02 years. The mean 24-hr urinary protein excretion was 4.69±2.36 grams. Microscopic hematuria was found in 30 (16.3%) patients. The mean serum creatinine was 1.58±0.87 mg/dL. At presentation, 128 (69.6%) patients were normotensive, while 56 (30.4%) exhibited hypertension. FSGS, not otherwise specified (NOS) was the predominant variant, comprising 76.6% of all; collapsing variant comprised 12%, tip variant, 9.8%, perihilar, 1.1%, and cellular, 0.5%. The mean number of glomeruli involved by segmental scarring was 3.41±2.87 and there was significant difference among the variants (p= 0.001). Arteriolopathy was found in 23.4 % cases and fibrointimal thickening of arteries in 18.5%. Tubular atrophy and interstitial fibrosis (IF/TA) was noted in 93% of cases. There was no significant difference in vasculopathy and IF/TA among the variants. CONCLUSIONS: Collapsing variant was the second most common variant following NOS and these findings are different from other regional studies.

The prevalence and clinicopathological profile of IgM nephropathy in children with steroid-resistant nephrotic syndrome at a single centre in Pakistan.

BACKGROUND: There is little information on the clinicopathological characteristics of IgM nephropathy (IgMN) in paediatric steroid-resistant nephrotic syndrome (SRNS) and its response to calcineurin inhibitors (CNI). MATERIAL AND METHODS: This study was conducted at Sindh Institute of Urology and Transplantation, from January 2009 to August 2011. All SRNS children who received renal biopsies were included. Relevant data were compared among minimal change disease (MCD) and IgMN. The response to CNI was analysed in detail in IgMN by groups (group 1: complete or partial remission; group 2: no response). RESULTS: The frequency of IgMN in 147 children with SRNS was 13.6%. Compared with MCD, there was a male preponderance in IgMN. Blood urea and serum creatinine both at presentation and at last follow-up were significantly higher in IgMN. Regarding subgroups of IgMN, systolic blood pressure (SBP), blood urea and serum creatinine were significantly higher in group 2 at presentation, while at last follow-up, SBP, diastolic blood pressure and proteinuria were higher in group 2. The prevalence and degree of mesangial proliferation, global glomerulosclerosis, interstitial fibrosis and tubular atrophy were significantly higher in group 2. CONCLUSIONS: IgMN is a common cause of paediatric SRNS and is significantly different from MCD. There is also a significant difference in clinical and laboratory parameters among responders and non-responders to CNI in IgMN.

The spectrum of histopathological lesions in children presenting with steroid-resistant nephrotic syndrome at a single center in Pakistan.

Steroid-resistant nephrotic syndrome (SRNS) is a common problem in pediatric nephrology practice. There is currently little information in the literature on the spectrum of histopathologic lesions in children presenting with SRNS in Pakistan. This study was designed to determine the histopathologic lesions in children presenting with SRNS at our center. The study was conducted at the Histopathology Department, Sindh Institute of Urology and Transplantation (SIUT) from January 2009 to August 2011. All children (≤ 16 years) presenting with SRNS, in whom renal biopsies were performed, were included. Their demographic, clinical, laboratory, and histopathological data were retrieved from files and original renal biopsy forms. The results were analyzed by SPSS version 10.0. A total of 147 children were included. Of these, 91 (61.9%) were males and 56 (38.1%) females, with male-to-female ratio of 1.6 : 1. The mean age was 7.03 ± 4.0 years (range: 6 months-16 years). The histopathological lesions seen on renal biopsies comprised of focal segmental glomerulosclerosis (FSGS) (38.5%), followed by minimal change disease (MCD) (23.2%), IgM nephropathy (IgMN) (13.6%), idiopathic mesangial proliferative GN (10.2%), membranous GN (8.2%), and mesangiocapillary GN (4.8%). Our results indicate that FSGS is the predominant lesion in children with SRNS, followed by MCD and IgMN.

Clinicopathologic characteristics and steroid response of IgM nephropathy in children presenting with idiopathic nephrotic syndrome.

There is no detailed information on clinical and immunopathologic features of immunoglobulin M nephropathy (IgMN) in children with idiopathic nephrotic syndrome (INS) in Pakistan. We reviewed our native renal biopsies over 15 years (July 1995-July 2010) and identified 135 cases of IgMN in nephrotic children (≤17 years). Their demographic, clinical and immunopathologic data were retrieved from biopsy reports and case notes. Mean age of this cohort was 7.6 ± 4.2 years. Males were 92 (68.1%) and females were 43 (31.9%). Steroid-dependent NS was seen in 88 (65.2%) cases and steroid-resistant NS in 47 (34.2%). Hematuria was found in 42 cases (31.2%) and hypertension in 27 (19.5%). The most common morphologic change was glomerular mesangial proliferation, found in 89 (65.9%) biopsies. Minor changes were seen in 46 (34.1%) cases and focal segmental glomerulosclerosis (FSGS) in 37 (27.4%). Immunofluorescence microscopy showed diffuse mesangial positivity of IgM in all cases. C3 and C1q were found in 72 (53.3%) and 40 (29.7%) cases, respectively. Our results show that IgMN is a fairly common cause of INS in children in Pakistan. It shows a spectrum of morphologic changes ranging from minor changes to FSGS.