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Objectives: Plasma cell-rich acute rejection is an aggressive form of acute rejection that occurs late after transplant and is usually resistant to standard antirejection therapy. This study reports the safety, efficacy, and outcomes of plasma cell-rich acute rejection after treatment with bortezomib, a proteasome inhibitor, in 10 patients after a first living-related renal transplant., Materials and Methods: Plasma cell-rich acute rejection was diagnosed using the 2007 Banff classification. The treatment protocol for plasma cell-rich acute rejection included methylprednisolone (500 mg/kg), 7 sessions of plasmapheresis, antithymocyte globulin (3-5 mg/kg/day for 10 days), rituximab (2 doses at 375 mg/m2), and bortezomib (1 cycle at 1.3 mg/m2)., Results: The mean age of recipients and donors was 23.70 ± 11.39 and 37.30 ± 12.82 years, respectively. The mean time to plasma cell-rich acute rejection was 3.1 ± 2.5 years. The mean serum creatinine level at rejection was 4.8 ± 2.7 mg/dL. After treatment, serum creatinine decreased to 3.3 ± 1.8 mg/dL. Serum creatinine levels at 1-year and 2-year follow-up were 3.0 ± 2.3 and 3.3 ± 0.9 mg/dL, respectively. There was 1 graft failure due to recurrence of glomerulonephritis/de novo glomerulonephritis. No significant adverse effects were noted in the patients. Bortezomib successfully reverted plasma cell-rich acute rejection and stabilized graft function, with patients showing 2-year graft survival after rejection of 90%., Conclusion: Bortezomib-based treatment was successful in reverting plasma cell-rich acute rejection and stabilizing graft function, with graft survival of 90% at 2 years. Further studies with large cohorts and randomized trials with or without bortezomib will help in better evaluation of its efficacy, safety, and outcomes.

Aim: Living donor kidney is the main source of donor organs in low to middle income countries. We aimed to develop a living donor risk model that predicts graft and patient survival in an emerging economy., Methods: We used data from the Sindh Institute of Urology and Transplantation (SIUT) database (n = 2283 recipients and n = 2283 living kidney donors, transplanted between 1993 and 2009) and conducted Cox proportional hazard analyses to develop a composite score that predicts graft and patient survivals., Results: Donor factors age, creatinine clearance, nephron dose (estimated by donor/recipient body weight ratio) and human leukocyte antigen (HLA) match were included in the living donor risk model. The adjusted hazard ratios (HRs) for graft failures among those who received a kidney with living donor scores (reference to donor score of zero) of 1, 2, 3 and 4 were 1.14 (95%CI: 0.94-1.39), 1.24 (95%CI:1.03-1.49), 1.25 (95%CI:1.03-1.51) and 1.36 (95%CI:1.08-1.72) (P-value for trend =0.05). Similar findings were observed for patient survival., Conclusions: Similar to findings in high income countries, our study suggests that donor characteristics such as age, nephron dose, creatinine clearance and HLA match are important factors that determine the long-term patient and graft survival in low income countries. However, other crucial but undefined factors may play a role in determining the overall risk of graft failure and mortality in living kidney donor transplant recipients., (© 2016 Asian Pacific Society of Nephrology.)

Objectives: Our aim was to analyze the immunohistopathologic features of plasma cell-rich acute rejection in a living-related renal transplant setting., Materials and Methods: Renal allograft biopsies of 50 cases of plasma cell-rich acute rejection were reviewed, and the main immunohistopathologic features were analyzed. The biopsies were studied using light microscopy, immunofluorescence, and immunohistochemistry and reported according to Banff classification. Biopsy findings were correlated with graft function and outcome., Results: From February 2012 to December 2013, 50/1630 (3%) dysfunctional renal allograft biopsies showed plasma cell-rich acute rejection. Among acute changes, interstitial inflammation was of moderate degree in 8 cases (16%) and severe in 42 cases (84%). Mild tubulitis was found in 4 cases (8%), moderate tubulitis in 8 cases (16%), and severe tubulitis in 38 cases (76%). Glomerulitis was found in 2 cases (4%). No presence of arteritis was found. All plasma cell-rich acute rejection cases were of tubulointerstitial type, and most were of type IB. The mean percent of plasma cells on light microscopy in all cases was 28.8 ± 11.7%, and the range was 10% to 60%, with 46 cases (92%) showing plasma cell percent of ≥ 20%. The mean plasma cell percent on immunohistochemistry for CD138 was 29.0 ± 12.4%. Microvascular inflammation was found in 34 cases (68%). C4d testing was done by immunofluorescence in 22 cases (44%) and was positive in 8 cases (36%). Interstitial fibrosis/tubular atrophy was mild in 18 (36%), moderate in 28 (56%), and severe in 4 cases (8%). Plasma cell enrichment did not correlate with a variety of clinical and pathologic features (all P > .05)., Conclusions: Plasma cell enrichment is not an independent prognostic morphologic feature and may represent either T-cell-mediated or antibody-mediated rejection or a mixture of these processes. Further investigations regarding its pathogenesis, accurate categorization, and treatment are needed.

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.

Kidney paired exchange is an established method of overcoming incompatibility in donor-recipient pairs and expanding the living-donor pool. It is infrequently performed in developing countries. We report the first kidney paired exchange in Pakistan, successfully performed at our center. One donor-recipient pair consisted of a 38-year-old female recipient (blood type, B positive) and her 40-year-old husband (A positive) as the potential donor. The second pair consisted of a 30-year-old male recipient (A positive) and his 30-year-old wife (B positive) as the potential donor. The donors were exchanged with the recipients, and both pairs were antigen matched for human leukocyte antigen A and human leukocyte antigen DR. Luminex antibody screening was negative, as were the crossmatches for T and B cells and for IgG and IgM. The transplant procedures and recoveries proceeded uneventfully. The recipients are maintaining serum creatinine levels around 0.78 mg/dL and 0.90 mg/dL, 1 year after transplant. Kidney paired exchange is a relatively low-cost option for overcoming the barrier of incompatibility in a resource-constrained setting.

Background: Long-term follow-up and management of donors was undertaken in a specialist kidney transplant unit in Pakistan to identify risk and prevent adverse outcomes in living related kidney donors., Methods: In an observation cohort study between 1985 and 2012, 3748 donors were offered free medical follow-up and treatment 6 to 12 months after donation and annually thereafter. Each visit included history, physical examination, blood tests for renal, lipid, glucose profiles, and 24-hour urine for proteinuria and creatinine clearance. Preventive intervention was undertaken for new onset clinical conditions. Donor outcomes were compared with 90 nondonor healthy siblings matched for age, sex, and body mass index., Results: Of the 3748 donors, 2696 (72%) were in regular yearly follow-up for up to 27 years (median, 5.6; interquartile range, 7.9). Eleven (0.4%) died 4 to 22 years after donation with all-cause mortality of 4.0/10 000 person years. Six (0.2%) developed end-stage renal disease 5 to 17 years after donation, (2.7/10 000 person years). Proteinuria greater than 1000 mg/24 hours developed in 28 patients (1%), hypertension in 371 patients (13.7%), and diabetes in 95 patients (3.6%). Therapeutic intervention-controlled protein was less than 1000 mg/24 hours, blood pressure was below 140/90 mm Hg, and glycemic control in 85% up to 15 years after onset. Creatinine clearance fell from 109.8 ± 22.3 mL/min per 1.73 m predonation to 78 ± 17 at 1 year, 84 ± 19 at 5 years, and 70 ± 20 at 25 years. Comparison of 90 nondonor sibling and donor pairs showed significantly higher fasting glucose and hypertension in nondonors., Conclusions: Long-term follow-up of donors has demonstrated end-stage renal disease in 0.6% at 25 years. Regular follow-up identified new onset of disease and allowed interventions that may have prevented adverse outcomes.

Background: Acute rejections (ARs) with plasma cell-rich infiltrates (PCARs) are associated with poor outcomes., Patients and Methods: Between February 2012 and December 2013, 1630 dysfunctional renal graft biopsies were performed. Of these, 50 (3%) showed PCAR. ARs with >10% plasma cells were defined as PCAR. Human leukocyte antigen (HLA) antibodies were tested in historic sera and at the time of PCAR. Treatment for PCAR comprised methylprednisolone, antithymocyte globulin, plasmapheresis, and anti-CD20 antibody., Results: Of the 1630 dysfunctional biopsies, 50 (3%) had PCAR which occurred 3.1 ± 2.55 yr after transplant. The percentage of plasma cells was 28.8 ± 11.7, and CD138, 29.0 ± 12.4. Donor-specific antibodies (DSAs) were found in 32 (64%) overall, Class I in 15% and Class II in 65%. Post-treatment serum creatinine improved from 3.80 ± 2.59 to 2.66 ± 1.59 mg/dL in DSA positive (p < 0.003) and from 2.59 ± 1.09 to 2.08 ± 0.86 mg/dL in DSA negative (p < 0.008). One- and two-yr graft survival after PCAR was 72%, 42% in the DSA-positive vs. 89%, 82% in the DSA-negative group, respectively (p = 0.071)., Conclusions: Our results show that PCAR occurs late after transplant and in many cases is associated with DSAs. Graft outcome was poor when PCAR was associated with DSAs., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To determine Serum Cystatin C (S.CysC) levels in healthy potential kidney donors and its correlation with Serum Creatinine (S.Cr), Glomerular filtration rate (GFR) by 24 hour urinary Creatinine clearance (CCL) and GFR by formulae of Cockcroft Gault (CCG) and Modification of diet in Renal Disease (MDRD)., Methods: A Cross sectional study was conducted at Sindh Institute of Urology and Transplantation (SIUT), Karachi, between June and December 2012. One hundred and three potential healthy kidney donors were enrolled in the study to measure their S.CysC and correlate it with S.Cr, CCL and GFR by CCG and MDRD. Statistical analysis was done by SPSS 17., Results: The mean age of the healthy kidney donors was 32.19 + 8.27 years with a M:F ratio of 1.86:1. The mean Serum Creatinine (S.Cr) was 0.86 + 0.18 mg/dl and mean S.CysC was 0.88 + 0.12 mg/dl. S.CysC showed significant correlation with S.Cr (r = 0.78, p < 0.001), CCL (r = 0.67, p < 0.001), GFR CCG (r = 0.54, p < 0.001) and GFR MDRD (r = 0.67, p < 0.001). Correlation of S.CysC was better than S.Cr for CCL, S.Cr (0.60) vs S.CysC (0.67) and GFR CCG, S.Cr (0.41) vs S.CysC (0.54). Correlation was comparable for MDRD, S.Cr (0.67) vs S.Cys (0.67)., Conclusion: S.CysC is better marker of kidney function in potential healthy kidney donors. It is a reliable, convenient and economical marker that can be used especially in routine clinical practice.

Aims: To describe the dynamic of a model of public government partnership for dialysis and transplantation in developing countries., Materials: A model was established on the philosophy of public-government partnership to provide an integrated dialysis and transplant service "Free with dignity" with lifelong follow-up care and medications. The government provided 50% of funds and the public was motivated to donate the rest. This included affluent individuals, corporations, business houses and the general public., Results: This model has been sustained for the last two decades. In 2008, 655,000 patients were treated at SIUT. Over 600 patients are dialyzed each day with a total of 165,411 dialysis sessions/year. Thus far 2,249 transplants have been performed, 431 in 2008. One- and 5-year graft survival rates were 92% and 85%, respectively. The laboratory performed 4.1 million tests and radiological investigations numbered 164,217. Over $ 6 million were spent on medications. Free services offered by the model have motivated the government to increase its funding from $ 2.1 million in 1998 to $ 10 million in 2008 and the public has matched these figures with total donations exceeding $ 20 million., Conclusions: For transplantation to be successful in developing countries, it has to be made available to the common people who constitute 90% of the population. Our model of public-government partnership has made dialysis and transplantation available to the disenfranchised with lifelong follow-up and medications. Transplantation has become relevant to them, resulting in societal acceptance of transplantation as a preferred mode of therapy. This has motivated society to support both living related and deceased donor programs.

Donor shortage and absence of transplant law lead to unrelated commercial transplants in Pakistan. We report the socio-economic and outcome parameters of 126 local recipients of unrelated kidney vendor transplants presenting to our institute between 1997 and 2007. Their outcome was compared with 180 recipients of living-related donor transplants matched for age, gender and transplant duration as controls. Age of commercial recipients was 35.63 +/- 11.57 years with an M:F ratio of 2.4:1. Majority (92%) were transplanted in northern Pakistan paying US$7271 +/- 2198. All were educated with 50% being graduates or above and rich earning a monthly salary of US$517 +/- 518 with 44% earning >US$500. Comparison of commercial recipients with controls showed high comorbidities 35 (28%) vs. 14 (8%) (P = 0.0001) with diabetes, hepatitis-C and cardiovascular diseases. Donor age was 29.97 +/- 6.16 vs. 32.63 +/- 9.3 years (P = 0.035). Biologic agents induction in 101 (80%) vs. 14 (8%) (P = 0.0001), acute rejections in 42 (33%) vs. 31 (17%) (P = 0.005), 1-year creatinine 1.84 +/- 1.28 vs. 1.27 +/- 0.4 mg/dl (P = 0.0001), surgical complications 28 (22%) vs. 14 (8%) (P = 0.001), tuberculosis 14 (11%) vs. 6 (6%) (P = 0.007), acute hepatitis 20 (16%) vs. 3 (2%) (P = 0.0001), cytomegalovirus 33 (26%) vs. 21 (11%) (P = 0.001) and recurrent urinary tract infection 35 (28%) vs. 30 (16%) (P = 0.034). Overall 1- and 5-year graft survival was 86% and 45% vs. 94% and 80%, respectively (P = 0.00001). Total deaths were 34 (27%) vs. 12 (6.0%) (P = 0.001). In conclusion, recipients of the vended kidneys are poor candidates, educated, rich and often self-selecting. Their outcome is poor, which will leave them poorer still and back to dialysis if not death.

Unrelated kidney transplants have lead to commerce and kidney vending in Pakistan. This study on 104 vendors reports demographics, history, physical and systemic examination, ultrasound findings, renal and liver function and GFR by Cockcroft-Gault. Results were compared with 184 age, sex and nephrectomy duration matched living-related donors controls. Comparison of vendors versus controls showed mean age of 30.55 +/- 8.1 versus 30.65 +/- 7.85 (p = 0.91) years, M:F of 4.5:1 versus 4.2:1 and nephrectomy period of 33.89 +/- 30 versus 32.01 +/- 29.71 (p = 0.60) months respectively. Of the vendors 67% were bonded laborers earning <50 $/month as compared to controls where 68% were skilled laborers and self-employed earning >100 $/month. History of vendors revealed jaundice in 8%, stone disease in 2% and urinary tract symptoms in 4.8%. Postnephrectomy findings between vendors versus donors showed BMI of 21.02 +/- 2.8 versus 23.02 +/- 4.2 (p = 0.0001), hypertension in 17% versus 9.2% (p = 0.04), serum creatinine (mg/dL) of 1.17+/-0.21 versus 1.02 +/- 0.27 (p = 0.0001), GFR (mL/min) of 70.94 +/- 14.2 versus 95.4 +/- 20.44 (p = 0.0001), urine protein/creatinine of 0.150 +/- 0.109 versus 0.10 +/- 0.10 (p = 0.0001), hepatitis C positivity in 27% versus 1.0% (p = 0.0001) and hepatitis B positive 5.7% versus 0.5% (p = 0.04), respectively. In conclusion, vendors had compromised renal function suggesting inferior selection and high risk for developing chronic kidney disease in long term.

In recent years, Pakistan has emerged as one of the largest centres for commerce and tourism in renal transplantation. Kidney vendors belong to Punjab in eastern Pakistan, the agricultural heartland, where 34% people live below poverty line. We report results of a socioeconomic and health survey of 239 kidney vendors. The mean age was 33.6 +/- 7.2 years (M:F 3.5:1). Mean nephrectomy period was 4.8 +/- 2.3 years. Ninety per cent of the vendors were illiterate. Sixty-nine per cent were bonded labourers who were virtual slaves to landlords, labourers 12%, housewives 8.5% and unemployed 11%. Monthly income was $US15.4 +/- 8.9 with 2-11 dependents per family. Majority (93%), vended for debt repayment with mean debt of $1311.4 +/- 819. The mean agreed sale price was $1737 +/- 262. However, they received $1377 +/- 196 after deduction for hospital and travel expenses. Postvending 88% had no economic improvement in their lives and 98% reported deterioration in general health status. Future vending was encouraged by 35% to pay off debts and freedom from bondage. This study gives a snapshot of kidney vendors from Pakistan. These impoverished people, many in bondage, are examples of modern day slavery. They will remain exploited until law against bondage is implemented and new laws are introduced to ban commerce and transplant tourism in Pakistan.

Organ transplantation started with organs donated by living subjects. Increasing demands brought cadaveric organ donation. The brain-death law, mandatory for this procedure, is prevalent in all countries involved in organ transplantation except Pakistan. Spain is the leading country in cadaveric organ donation (32.5 pmp). Despite the sources of living and cadaveric organs, both heart-beating and non-heart-beating, the gap between the demand and supply has widened. An example is the United States, where the numbers of patients on the waiting list for kidney transplantation have risen from 30,000 in 1988 to more than 116,000 in 2001. This has caused a resurgence in living donors all over the world. These can be related, unrelated, spousal, marginal, or ABO-incompatible donors. Family apprehensions, medical care costs, and nonexistent social security can be barriers to this form of organ donation. Unrelated organ donation can open the doors to commercialism. To make this process more successful, transplantation should be made reachable by all sectors of the population. This is possible when transplantation is taken to the public sector institutions and financed jointly by the government and community. To increase living organ donation especially in Asian countries, which face barriers of low literacy rates, ignorance, and cultural and religious beliefs, more efforts are needed. Public awareness and education play an important role. Appreciation and supporting the donors is necessary and justified. It is a noble act and should be recognized by offering job security, health insurance, and free education for the donor's children.

DNA methods have resulted in improved renal allograft survival rates in cadaveric renal transplantation. This paper describes the impact of DNA typing by PCRSSP on a living related renal transplant (LRRT) programme. It evaluates error rates in serology, acute rejections, graft function and survival rates between the two typing methods. Serological typing was done on CTS 120 antisera Class 1 and 60 antisera Class 2 and 72 antisera Terasaki Class1 and 72 antisera Class2 Antigens. Low resolution PCR-SSP typing was done by 24 primers for HLA A , 48 for HLA B and 24 for HLA DR. Of the 585 transplants, 159 (Group I) were serology based, 172 serology and PCR-SSP for HLA DR (Group II) and 254 on serology and PCR-SSP for HLA A and B and only PCR-SSP for HLA DR (Group III). Error rates in serology as compared to PCR-SSP were 24% for HLA A, 16% for HLA B and 35% for HLA DR. Acute rejection in Group I were 39% Group II 30% and Group III 26% (p 0.02). Graft function of serum creatinine<1.5 mg/dl at 1 year was found in 26% of Group I patients as compared to 48% of Group III (p<0.0001). One and three year graft survival was 93% and 87% for Group II as compared to 81% and 69% for Group I respectively (p 0.0001). Matching by this combination of serology and PCR-SSP is not only economical for a developing country but also improves graft survival by 12% at 1 and 18% at 3 years.