Deep learning-based classification of kidney transplant pathology: a retrospective, multicentre, proof-of-concept study.

BACKGROUND: Histopathological assessment of transplant biopsies is currently the standard method to diagnose allograft rejection and can help guide patient management, but it is one of the most challenging areas of pathology, requiring considerable expertise, time, and effort. We aimed to analyse the utility of deep learning to preclassify histology of kidney allograft biopsies into three main broad categories (ie, normal, rejection, and other diseases) as a potential biopsy triage system focusing on transplant rejection. METHODS: We performed a retrospective, multicentre, proof-of-concept study using 5844 digital whole slide images of kidney allograft biopsies from 1948 patients. Kidney allograft biopsy samples were identified by a database search in the Departments of Pathology of the Amsterdam UMC, Amsterdam, Netherlands (1130 patients) and the University Medical Center Utrecht, Utrecht, Netherlands (717 patients). 101 consecutive kidney transplant biopsies were identified in the archive of the Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany. Convolutional neural networks (CNNs) were trained to classify allograft biopsies as normal, rejection, or other diseases. Three times cross-validation (1847 patients) and deployment on an external real-world cohort (101 patients) were used for validation. Area under the receiver operating characteristic curve (AUROC) was used as the main performance metric (the primary endpoint to assess CNN performance). FINDINGS: Serial CNNs, first classifying kidney allograft biopsies as normal (AUROC 0·87 [ten times bootstrapped CI 0·85-0·88]) and disease (0·87 [0·86-0·88]), followed by a second CNN classifying biopsies classified as disease into rejection (0·75 [0·73-0·76]) and other diseases (0·75 [0·72-0·77]), showed similar AUROC in cross-validation and deployment on independent real-world data (first CNN normal AUROC 0·83 [0·80-0·85], disease 0·83 [0·73-0·91]; second CNN rejection 0·61 [0·51-0·70], other diseases 0·61 [0·50-0·74]). A single CNN classifying biopsies as normal, rejection, or other diseases showed similar performance in cross-validation (normal AUROC 0·80 [0·73-0·84], rejection 0·76 [0·66-0·80], other diseases 0·50 [0·36-0·57]) and generalised well for normal and rejection classes in the real-world data. Visualisation techniques highlighted rejection-relevant areas of biopsies in the tubulointerstitium. INTERPRETATION: This study showed that deep learning-based classification of transplant biopsies could support pathological diagnostics of kidney allograft rejection. FUNDING: European Research Council; German Research Foundation; German Federal Ministries of Education and Research, Health, and Economic Affairs and Energy; Dutch Kidney Foundation; Human(e) AI Research Priority Area of the University of Amsterdam; and Max-Eder Programme of German Cancer Aid.

Pharmacogenomics of mycophenolic acid in kidney transplantation: Contribution of immune response-related genes

Abstract Mycophenolic acid (MPA) inhibits IMPDH, involved in the guanosine nucleotides synthesis, and prevents DNA replication in immune cells. The repression of cell and humoral immunity by MPA induces allograft tolerance preventing acute rejection in solid organ transplantation. MPA is an effective and safe drug, but genetic and non-genetic factors have been implicated in the interindividual variability of drug response. Several studies have shown the impact of variants of pharmacokinetics or pharmacodynamics-related genes on MPA response in kidney transplantation. This review explored further the influence of genes involved in the immune response on clinical outcomes of kidney recipients on short- or long-term MPA treatment. Variants in genes related to T cell activation (CD28, CTL4, ICOS, PDPC1), pro-inflammatory cytokines (IL2, IL6, IL12A, IL12B, TNF, IFNG), immunomodulatory cytokines (IL4, IL10, TGFB1), and innate immune response (CD14, TLR2, TLR4) were shown to be associated with increased risk of acute rejection, graft function or survival, chronic graft nephropathy, viral infections or MPA-induced myelotoxicity. Some of the significant pharmacogenetic associations were confirmed by meta-analyses of kidney transplantation. These findings are suggestive that variants in immune response-related genes contribute to the variability of MPA response, and have potential application as biomarkers of acute rejection in kidney transplantation.

Matching Kidneys with Priority in Kidney Exchange Programs.

Kidney exchanges were developed to match kidney failure patients with willing but incompatible donors to other donor-patient pairs. Finding a match in a large candidate pool can be modeled as an integer program. However, these exchanges accumulate participants with characteristics that increase the difficulty of finding a match and, therefore, increase patients' waiting time. Therefore, we sought to fine-tune the formulation of the integer program by more accurately assigning priorities to patients based on their difficulty of matching. We provide a detailed formulation of prioritized kidney exchange and propose a novel prioritization algorithm. Our approach takes advantage of the global knowledge of the donor-patient compatibility within a pool of pairs and calculates an iterative, paired match power (iPMP) to represent the donor-patient pairs' abilities to match. Monte Carlo simulation shows that an algorithm using the iPMP reduces the waiting time more than using paired match power (PMP) for the difficult-to-match pairs with hazard ratios of 1.3480 and 1.1100, respectively. Thus, the iPMP may be a more accurate assessment of the difficulty of matching a pair in a pool than PMP is, and its use may improve matching algorithms being used to match donors and recipients.

Polimorfismos em genes envolvidos na farmacodinâmica de tacrolimo e everolimo e sua relação com a resposta ao tratamento imunossupressor, em receptores de transplante renal / Polymorphisms in pharmacodynamics-related genes of tacrolimus and everolimus and their relationship with the response to immunosuppressant treatment, in kidney transplant recipients

O monitoramento de imunossupressores, como os inibidores de calcineurina ou de mTOR, é essencial para evitar desfechos clínicos desfavoráveis, em receptores de transplante renal. Polimorfismos em genes envolvidos na farmacocinética têm sido associados com variabilidade na resposta a imunossupressores, porém o papel de polimorfismos em genes envolvidos na farmacodinâmica é pouco conhecido. O objetivo deste estudo foi investigar a influência de polimorfismos de MTOR, PPP3CA, FKBP1A, FKBP2 e FOXP3, genes envolvidos na farmacodinâmica de imunossupressores, sobre a resposta clínica a tacrolimo e everolimo, em receptores de transplante renal. Foram incluídos 269 pacientes do ensaio clínico original (NCT01354301), realizado no Hospital do Rim e Hipertensão da UNIFESP, e randomizados em três esquemas imunossupressores: tacrolimo 0,05 mg/kg/dia com everolimo 1,5 mg/dia (TAC5/EVR); tacrolimo 0,1 mg/kg/dia com everolimo 1,5 mg/dia (TAC10/EVR); e tacrolimo 0,1 mg/kg/dia com micofenolato de sódio (TAC10/MFS). Foram coletados dados clínicos e laboratoriais, tais como o monitoramento de imunossupressores e desfechos de eficácia de segurança. Os polimorfismos nos genes MTOR (c.4731G>A, c.1437T>C, c.2997C>T); PPP3CA (c.249G>A); FKBP1A (n.259+243936T>C); FBKP2 (c.-2110G>T) e FOXP3 (c.-23+2882A>C, c.-22-902A>G) foram analisados por PCR em tempo real. As frequências alélicas dos polimorfismos estudados foram similares às da população global do projeto 1000genomes. O tratamento com everolimo e tacrolimo em maior dose (TAC10/EVR) foi associado com menor taxa de filtração glomerular estimada (TFGe) e maior creatinina sérica. Enquanto que o tratamento com tacrolimo e micofenolato de sódio (TAC10/MFS) foi associado com maior número de episódios de infecção por citomegalovirus, no 1° ano pós-transplante. Com relação aos desfechos de eficácia, os portadores do genótipo CC de MTOR c.1437T>C e FOXP3 c-23+2882A>C apresentaram maiores concentrações de creatinina sérica, no 12° mês (p<0,05). O polimorfismo FOXP3 c.-23+2882A>C foi associado com maior probabilidade de creatinina sérica aumentada (OR=1,75; IC95%=1,07-2,86; p=0,025). Os resultados da análise de regressão logística mostraram que o alelo MTOR c.4731G (genótipos AG+GG) foi associado com maior risco de rejeição aguda (OR=3,37; IC95%=1,10-10,30; p=0,033). Os portadores do alelo c.4731G apresentaram maior incidência cumulativa de episódios de rejeição, no 1° ano pós-transplante. Com relação aos desfechos de segurança, a variante FKBP2 c.-2110G>T (genótipo GG) foi associada com maior risco de leucopenia (OR=7,10; IC95%=1,81-27,87; p=0,025). O polimorfismo FKBP1A n.259+24936T>C (alelo C) foi associado com maior risco de constipação (OR=2,52; IC95%=1,13 - 5,61; p=0,024), enquanto que os polimorfismos FOXP3 c.-22-902A>G (alelo A) e c.-23+2882A>C (alelo A) foram associados, respectivamente, com maior risco de epigastralgia (OR=2,15; IC95%=1,01-4,56; p=0,047) e náuseas e/ou vômitos (OR=2,38; IC95%=1,05-5,38; p=0,038). O risco de apresentar dislipidemia foi maior nos portadores dos genótipos FKBP2 c.-21110GG (OR=1,92; IC95%=1,01-3,69; p=0,049) e FOXP3 c.-22-902GG (OR=2,06; IC95%=1,08-3,92; p=0,028). Em conclusão, os polimorfismos de genes MTOR, FKBP1A, FKBP2 e FOXP3 influenciam na função renal do enxerto e estão associados com risco de rejeição aguda e de eventos adversos, em receptores de transplante renal

The monitoring of immunosuppressive drugs, such as calcineurin and mTOR inhibitors, is essential to avoid undesirable kidney transplant outcomes. Polymorphisms in pharmacokinetics-related genes have been associated with variability in the response to immunosuppressive drugs, but the role of polymorphisms in pharmacodynamics-related genes is little known. The aim of this work was to investigate the influence of polymorphisms in MTOR, PPP3CA, FKBP1A, FKBP2 and FOXP3, genes involved in the pharmacodynamics of immunosuppressive drugs, on the clinical response to tacrolimus and everolimus in kidney transplant recipients. Two-hundred seventy-five kidney transplant recipients were included in this study, among the enrolled in the original clinical trial (NCT01354301) carried out at the Hospital do Rim e Hipertensão/UNIFESP, and randomized in three immunosuppressive treatments: tacrolimus 0.05 mg/kg/day with everolimus 1.5 mg/day (TAC5/EVR); tacrolimus 0.1 mg/kg/day with everolimus 1.5 mg/day (TAC10/EVR); and tacrolimus 0.1 mg/kg/day with sodium mycophenolate (TAC10/MFS). Clinical and laboratory data, including immunosuppressive drug monitoring, efficacy and safety outcomes, were recorded. Polymorphisms on the MTOR (c.4731G>A, c.1437T>C, c.2997C>T); PPP3CA (c.249G>A); FKBP1A (n.259+243936T>C); FBKP2 (c.-2110G>T) and FOXP3 (c.-23+2882A>C, c.-22-902A>G) genes were analyzed by real-time PCR. Allelic frequencies of the studied polymorphisms were similar to those of the global population reported by the 1000genomes project. Treatment with everolimus and high-dose tacrolimus (TAC10/EVR) was associated with lower estimated glomerular filtration rate (eGFR) and higher serum creatinine. Meanwhile treatment with tacrolimus and sodium mycophenolate (TAC10/MFS) was associated with higher number of cytomegalovirus infections, at 1-year post-transplantation. With regard to the kidney efficacy outcomes, the carriers of the CC genotype of MTOR c.1437T>C and FOXP3 c.-23+2882A>C had higher serum creatinine, at month 12 (p<0.05). The FOXP3 c.-23+2882A>C polymorphism was associated with high likelihood of increased serum creatinine (OR=1.75, 95%IC=1.07-2.86, p=0.025). The results of the logistic regression analysis showed that the allele MTOR c.4731G (AG+GG genotypes) was associated with higher risk of acute rejection (OR=3.37, 95%IC=1.10-10.30, p=0.033). The carriers of the c.4731G allele showed higher cumulative incidence of acute rejection episodes at 1-year post-transplantation. With regard to kidney safety outcomes, the FKBP2 c.-2110G>T variant (GG genotype) was associated with higher risk of leucopenia (OR=7.10, 95%IC=1.81-27.87, p=0.025). The FKBP1A n.259+24936T>C (C allele) polymorphism was associated with higher risk of constipation (OR=2.52, 95%IC=1.13-5.61, p=0.024), whilst FOXP3 c.-22 902A>G (A allele) and c.-23+2882A>C (A allele) were associated, respectively, with higher risk of epigastric pain (OR=2.15, 95%IC=1.01-4.56, p=0.047) and nausea and/or vomiting (OR=2.38, 95%IC=1.05-5.38, p=0.038). The risk of developing dyslipidemia was higher in carriers of the genotypes FKBP2 c.-21110GG (OR=1.92, 95%CI=1.01-3.69, p=0.049) and FOXP3 c.-22-902GG (OR=2.06, 95%CI=1.08-3.92, p=0.028). In conclusion, the polymorphisms in the MTOR, FKBP1A, FKBP2 and FOXP3 genes influence renal graft function and are associated with risk of acute rejection and adverse events in renal transplant recipients

Study design in high-dimensional classification analysis.

Advances in high throughput technology have accelerated the use of hundreds to millions of biomarkers to construct classifiers that partition patients into different clinical conditions. Prior to classifier development in actual studies, a critical need is to determine the sample size required to reach a specified classification precision. We develop a systematic approach for sample size determination in high-dimensional (large [Formula: see text] small [Formula: see text]) classification analysis. Our method utilizes the probability of correct classification (PCC) as the optimization objective function and incorporates the higher criticism thresholding procedure for classifier development. Further, we derive the theoretical bound of maximal PCC gain from feature augmentation (e.g. when molecular and clinical predictors are combined in classifier development). Our methods are motivated and illustrated by a study using proteomics markers to classify post-kidney transplantation patients into stable and rejecting classes.

Integrating data from multiple sources for data completeness in a web-based registry for pediatric renal transplantation--the CERTAIN Registry.

Patient registries are a useful tool to measure outcomes and compare the effectiveness of therapies in a specific patient population. High data quality and completeness are therefore advantageous for registry analysis. Data integration from multiple sources may increase completeness of the data. The pediatric renal transplantation registry CERTAIN identified Eurotransplant (ET) and the Collaborative Transplant Study (CTS) as possible partners for data exchange. Import and export interfaces with CTS and ET were implemented. All parties reached their projected goals and benefit from the exchange.

En bloc kidneys transplanted from infant donors less than 5 kg into pediatric recipients.

BACKGROUND: Given the shortage of donor kidneys, the use of grafts from deceased infant donors is a potential approach to expand the donor pool. Four infant en bloc kidney transplants in pediatric recipients were reported, performed between 2012 and 2013 in the center. METHODS: The en bloc graft was implanted extraperitoneally in the right iliac fossa. The distal end of the donor aorta was anastomosed end-to-end to the internal iliac artery, while the donor vena cava was anastomosed (end-to-side) to the external iliac vein. Both ureters were anastomosed individually to the bladder, with the exception of one case in which a donor bladder patch was anastomosed to the bladder. After the operation, the recipients received basiliximab as induction therapy followed by tacrolimus and mycophenolic acid for immunosuppression. Prophylactic anticoagulation was used postoperatively. RESULTS: Recipients included two girls and two boys with age ranging from 4.6 to 11.6 years. Donor age ranged from 33 to 56 days with weight ranging from 2.5 to 5.0 kg. After a follow-up of 2 to 14 months, patient and graft survivals were 100% and 75%, respectively. Complications included delayed graft function in one patient, urine leak in one, and anticoagulation-related hemorrhage in one. One graft was lost early from vascular thrombosis. The remaining three recipients had excellent graft function with median serum creatinine of 1.1 mg/dL (range, 0.8-1.3 mg/dL) at last follow-up. CONCLUSIONS: Promising outcomes can be obtained from en bloc transplantation from infant donors. The use of this donor population for pediatric recipients should be encouraged.

[Diagnosis-related groups for kidney transplantation]. / DRG für die Nierentransplantation.

Renal transplantation is a cost-effective form of renal replacement therapy which prolongs life and improves the quality of life. The representation in the German DRG system is, however, not cost-covering in all cases. Cost-effectiveness must also be considered in view of long-term transplant survival which relates to overall costs to the health care system and goes beyond hospital costs.

Comparison of long-term outcomes between spousal transplants and other living unrelated donor transplants: single-center experience.

BACKGROUND/AIMS: The greater use of living unrelated donors (LUDs) as kidney donors is a worldwide trend in the current era of organ shortage, and spouses are an important source of LUDs. This study was to compare the long-term outcomes of spousal donor grafts with other LUD grafts. METHODS: Among 445 LUD grafts, 77 were spouses and 368 were other LUDs. The clinical characteristics and long-term survival rates for spousal transplants were compared with those for other LUD transplants, and risk factors affecting graft survival were assessed. RESULTS: Spousal donors had a significantly higher average number of human leukocyte antigen (HLA) mismatches (4.2 vs. 3.4, p < 0.001) and were older (41 vs. 33 years, p < 0.001) than LUDs. The 10-year survival rates for spousal donor grafts were 60.6%, similar to those for LUD grafts (58.5%, p = 0.61). The 10-year biopsy-proven acute rejection-free survival rates (85.5 vs. 89.6%, p = 0.45) and patient survival rates were also similar (84.3 vs. 79.6%, p = 0.35). The degree of HLA mismatching, the spousal donor type or donor age did not affect the graft survival. CONCLUSION: Renal transplants from spousal donors show similar long-term outcomes to those from better HLA-matched and younger LUDs.

Renal allografts with IF/TA display distinct expression profiles of metzincins and related genes.

Chronic renal allograft injury is often reflected by interstitial fibrosis (IF) and tubular atrophy (TA) without evidence of specific etiology. In most instances, IF/TA remains an irreversible disorder, representing a major cause of long-term allograft loss. As members of the protease family metzincins and functionally related genes are involved in fibrotic and sclerotic processes of the extracellular matrix (ECM), we hypothesized their deregulation in IF/TA. Gene expression and protein level analyses using allograft biopsies with and without Banff'05 classified IF/TA illustrated their deregulation. Expression profiles of these genes differentiated IF/TA from Banff'05 classified Normal biopsies in three independent microarray studies and demonstrated histological progression of IF/TA I to III. Significant upregulation of matrix metalloprotease-7 (MMP-7) and thrombospondin-2 (THBS-2) in IF/TA biopsies and sera was revealed in two independent patient sets. Furthermore, elevated THBS-2, osteopontin (SPP1) and beta-catenin may play regulatory roles on MMP. Our findings further suggest that deregulated ECM remodeling and possibly epithelial to mesenchymal transition (EMT) are implicated in IF/TA of kidney transplants, and that metzincins and related genes play an important role in these processes. Profiling of these genes may be used to complement IF/TA diagnosis and to disclose IF/TA progression in kidney transplant recipients.

Microarray analysis of rejection in human kidney transplants using pathogenesis-based transcript sets.

Microarrays offer potential for objective diagnosis and insights into pathogenesis of allograft rejection. We used mouse transplants to annotate pathogenesis-based transcript sets (PBTs) that reflect major biologic events in allograft rejection-cytotoxic T-cell infiltration, interferon-gamma effects and parenchymal deterioration. We examined the relationship between PBT expression, histopathologic lesions and clinical diagnoses in 143 consecutive human kidney transplant biopsies for cause. PBTs correlated strongly with one another, indicating that transcriptome disturbances in renal transplants have a stereotyped internal structure. This disturbance was continuous, not dichotomous, across rejection and nonrejection. PBTs correlated with histopathologic lesions and were the highest in biopsies with clinically apparent rejection episodes. Surprisingly, antibody-mediated rejection had changes similar to T-cell mediated rejection. Biopsies lacking PBT disturbances did not have rejection. PBTs suggested that some current Banff histopathology criteria are unreliable, particularly at the cut-off between borderline and rejection. Results were validated in 51 additional biopsies. Thus many transcriptome changes previously described in rejection are features of a large-scale disturbance characteristic of rejection but occurring at lower levels in many forms of injury. PBTs represent a quantitative measure of the inflammatory disturbances in organ transplants, and a new window on the mechanisms of these changes.

Trends in kidney transplantation in Australia and New Zealand, 1993-2004.

BACKGROUND: We hypothesize that transplant outcome in Australia and New Zealand has improved despite more unfavorable transplant characteristics. Data from the Australia and New Zealand Dialysis and Transplant registry was used to examine this hypothesis. METHODS: All adult kidney-only transplants from January 1993 to December 2004 in Australia or New Zealand were followed-up until death or December 2005. Outcomes were adjusted for covariates in multivariate models, with transplant year modeled as a continuous variable. RESULTS: Altogether 6764 patients were included. There were proportionately more live donor and primary transplants, older donors and recipients, and higher recipient body mass index, waiting time, and human leukocyte antigen mismatch in recent cohorts. Death-censored graft loss decreased (adjusted hazard ratio: 0.92 [0.90-0.95] per year, P<0.001). This trend was seen at both 0-1 and 1-5 years posttransplant, and was mainly for immune-mediated graft losses. Patient survival improved only in New Zealand, and only for the first posttransplant year (adjusted odds ratio: 0.88 [0.82-0.95] per year, P=0.001). Cardiovascular deaths decreased while infection or cancer deaths were unchanged. Adjusted delayed graft function rates were unchanged. The acute rejection incidence at 6 months decreased (adjusted odds ratio: 0.88 [0.85-0.90] per year, P<0.001). One and 3-year graft function significantly improved, even after adjusting for rejection. All outcomes did not vary by expanded donor criteria status. CONCLUSIONS: Graft survival and function have improved in recent years, but long-term patient survival remains unchanged. With longer follow-up, the improvement in rejection rates and graft function may lead to further improvements in long-term graft survival and potentially better patient survival.

Clinical predictors of renal allograft histopathology: a comparative study of single-lesion histology versus a composite, quantitative scoring system.

BACKGROUND: Progressive injury that is refractory to conventional immunosuppression remains the major hurdle to indefinite survival of transplanted organs. Several clinical risk factors of chronic renal allograft rejection have been identified; although some (e.g., acute rejection) are direct manifestations of immunological injury, others (e.g., donor age) have been more difficult to conceptually link with graft dysfunction. METHODS: We conducted formal multivariate statistical analyses to reveal associations between established clinical risk factors and allograft histopathology. In a multicenter protocol biopsy-controlled study, 17 clinical risk factors were studied in relation to either the composite Chronic Allograft Damage Index (CADI) score or, to each of eight individual histological indices, using multiple linear regression with forward selection. RESULTS: Nine clinical risk factors were not significantly associated with any histopathological index. Four (donor age, acute rejection, recipient age, and cold ischemia time) were associated both with the total CADI score and, to varying extents, with the individual histopathological indices. In our analysis, clinical risk factors accounted for, at best, only about 60% of the interindividual variation in histopathological score. CONCLUSIONS: Our study reveals a missing link between specific clinical risk factors and early histopathological findings that are known to presage accelerated failure of clinically healthy grafts. Given the complex relationship between clinical risk factors, early histopathological changes, and graft outcome, we conclude that composite, quantitative histological indices are best suited to for evaluation of the histological status of the transplant.

[Quality of kidney procurement in Germany. Ten years experience and 486 renal allografts in a single centre]. / Qualität der Leichennierenentnahme in Deutschland. 10-Jahres-Erfahrungen mit 486 transplantierten Leichennieren an einem Zentrum.

BACKGROUND: Organ damage during organ procurement is believed to be an increasing problem among transplant centres. However, only very few published data are available. The purpose of our study was to examine the quality of kidney procurement in Germany. METHODS: We retrospectively analyzed all allograft renal transplants performed at our centre from 1996 to 2005. All kidneys were retrieved in Germany and allocated by Eurotransplant. RESULTS: From a total of 486 cadaveric kidneys, 103 (21.2%) were not correctly retrieved. Nevertheless, none of the organs had to be rejected. In 18 (3.7%), a technically insufficient organ retrieval was associated with a considerable extension of the surgical procedure or complications. CONCLUSIONS: Technically insufficient kidney procurement rarely results in clinical consequences. However, surgeons performing organ retrieval should be better trained. Whether adequate technical proficiency is achieved with ten supervised cases, as requested by the German Medical Association, remains to be determined. In our opinion, a further interdisciplinary course that trains surgeons in more refined techniques of organ procurement is desirable.

Living unrelated-commercial-kidney transplantation: when there is no chance to survive.

Transplantation is the best treatment of end-stage renal disease (ESRD); however, organ shortage is a reality. Deceased donor organ donation is inadequate; hence, the number of patients on the waiting lists is increasing progressively. Since many ESRD patients do not have living genetically related donors, living unrelated transplantation is considered. These transplantations offer excellent graft and patient survival rates if practiced in conventional situations, while the results are not so favorable or even poor in unconventional transplantations, which mostly take place in developing countries. Ethical aspects of living unrelated transplantation are more complicated than the medical side due to concern of commercialization. Making payment to the donors has been considered strictly as nonethical by many authors, while some others suggest reopening previous debates for kidney sales. The latter claim that if exploitation of donors is avoided, the reward (or payment) to the donor can be morally justified. Apart from these controversies, it is uniformly accepted that commercial transplantation is certainly unethical when brokers are involved or the aim is just profit for transplant physicians, because the main reason in favor of organ sales is improving the quality of life of the patients and the donors, not the brokers or the physicians. All these theoretical ethical arguments in the Western countries turn out to become vital concerns in developing countries, because transplantation is the cheapest renal replacement therapy. Recently, it has been suggested that organ shortage problems can partly be solved by establishing controlled donor compensation programs in these countries, which may also prevent exploitation of the donors. However, it is impossible to suggest a uniform solution for all countries because of deep differences in economical status as well as social and cultural values. Thus, every country should build its own ethical standards for commercial transplantation.