Could living unrelated renal transplantation ameliorate the actual shortage of organs in the Balkan region?

BACKGROUND: Despite the efforts for more transplants performed with organs from deceased donors, the living renal transplantation is still the predominant transplant activity in the Balkan region. In order to adress the severe organ shortage, we started accepting unrelated (emotionally related) living donors (LURD). Here we present our 10-year experience with living unrelated renal transplantation (LURT). METHODS: Twenty four LURT were performed in our center in the last 10 years. The mean recipients and donors age was 41.7 and 47.2 years, respectively. As LURD spouses (n=17) and extended family members (n=7) were accepted predominantly. All donors went through careful psychological evaluation in order to confirm emotional relationship. The final decision was taken after both the recipient and the donor signed a consent in front of a judge. A quadruple sequential immunosuppressive protocol was used in all recipients. The 5-year Kaplan Meier graft survival rate, HLA mismatch, rejection episodes, delayed graft function, serum creatinine and Glomerular filtration rate-Modification of the diet in renal disease (GFR-MDRD) were analyzed. The results were compared with 30 living related renal transplants (LRT) performed during the same time with mean recipients and donors age of 35.9 and 58.5 years, respectively. RESULTS: The mean follow up for LURT and LRT recipients were 81.4 and 79.6 months, respectively. There was a significant difference regarding recipients and donors age, HLA mismatch (5.07 and 2.9) and rejection episodes (16% vs. 11%) in LURT and LRT recipients. The 5 years graft survival rate was excellent in both groups (83 and 81%, respectively). There was no significant difference in 5 years serum creatinine (129.3 vs 121.1 µmol/lit) and 5 years GFR-MDRD (56.6 and 58.6 ml/min). CONCLUSION: The authors present an excellent 5-year graft survival rate in both LURT and LRT recipients. Therefore, LURT could ameliorate the severe organ shortage in the region and could be recommended as a valuable source of organs in the countries with developed and underdeveloped deceased donor donation.

Biopsy of the transplanted kidney--role of protocol biopsies.

Traditionally, renal allograft biopsies were performed mainly in the setting of acute graft dysfunction. Recently, there has been a change of paradigms. Several reports suggested that acute rejection of the graft and chronic allograft nephropathy are often subclinical without any deterioration in the graft function. This raises the issue of biopsies in functionally stable allografts (e.g. protocol biopsies) and the clinically useful information they provide. Namely, recent reports provide evidence in favour of treating biopsy-proven subclinical rejections. Moreover, by early identification of chronic histological lesions, protocol biopsies give an opportunity for individualized immunosuppressive regimen and use of targeted therapeutic strategies, in order to prevent chronic allograft dysfunction and improve long-term graft outcome. In this review, diagnostic, therapeutic and research benefit information on protocol biopsies performed in stable kidney recipients are described.

Achievements in CKD-MBD guidelines targets: is there a progress in the implementation practice?

BACKGROUND: Guidelines should help the practicing nephrologists to reduce the variability in diagnostic and treatment strategies, and achieve the best possible patients' outcomes. The aim of our study was to look at the treatment strategies and the shortcomings in the implementation of the chronic kidney disease mineral and bone disorder (CKD-MBD) KDOQI guidelines in dialysis units across the Republic of Macedonia in 2009, and to analyze trends with regard to our previous analysis from 2005. METHODS: A questionnaire was sent in 2009 to all dialysis units in our country for data concerning CKD-MBD in dialysis patients. This study included 742 patients, comparable with the reply we got on the same our 2005 survey, with a total of 588 patients. We collected the last 6 months mean values of biochemical parameters [calcium (Ca), phosphate (P), and intact parathyroid hormone (iPTH)], as well as treatment data including dialysate Ca concentration, phosphate binding agents, and vitamin D doses. RESULTS: The majority of patients in both surveys had values within the target ranges for all parameters, except for iPTH, which was <150 pg/ml in most patients, in both reports. Compared to the 2005 study, in 2009 we found a significantly improved control of all four biochemical parameters, but a greater proportion of patients within guidelines targets was found only for serum Ca (79 vs. 67.4%, P<0.05). Treatment with low Ca dialysate concentration of 1.25 mmol/L continued to be an underused option (3.7 vs. 6.1%), while the 1.75 mmol/L was still the standard dialysate in the majority of patients (57.7 vs. 64.2%). The dose of calcium carbonate was significantly reduced (2.77±1.71 vs. 3.06±1.54, P<0.01) in 2009 compared to 2005. The mean of the achieved targets increased significantly in 2009 (2.33±1.05 vs. 2.13±1.03, P<0.01). CONCLUSION: There was an improved control of all bone and mineral parameters in our dialysis units, following the publication of the CKD-MBD KDOQI guidelines. In order to improve the iPTH values, a more frequent use of low Ca dialysate (1.25 mmol/L) and of non-calcium-based phosphate binders in this small subset of patients should be implemented, as recommended by the guidelines. Individualization of the CKD-MBD management may be successful, even when newer treatment options are not available. Finally, the guidelines implementation process should be a continuous and self-monitored process, with the help of periodic surveys.

Do we have to treat subclinical rejections in early protocol renal allograft biopsies?

The aim of the present study was to evaluate whether treatment of subclinical, borderline rejections (SR/BR) or histological findings of chronic allograft nephropathy (CAN) in protocol biopsies in the first month posttransplantation after living related kidney transplantation has a beneficial effect on graft histology and renal function at 6 months. Among the 40 paired biopsies, only 6/80 showed no histological lesions. BR was found in 13/40 and 12/40, and SR in 15/40 and 21/40 of patients on the 1- and 6-month biopsies, respectively. The mean histological index/total sum of scores for acute and chronic changes (HI) increased at 6-month biopsy: 5.3 +/- 2.9 vs 7.8 +/- 3.6 (P < .001). Similarly, the mean sum of histological markers for chronicity (CAN score) of 2.1 +/- 1.5 increased to 4.6 +/- 2.3 (P < .001) on the 6-month biopsy. When divided according to whether there was treatment of BR and SR, the treated BR/SR group on 1-month biopsy had a mean HI score of 7.11 +/- 1.9, which remained almost the same (7.11 +/- 2.32) at 6 months. Among the untreated BR/SR group it increased from 4.95 +/- 1.99 to 8.16 +/- 4.30. However, there was no difference in graft function between the groups from 1 to 6 months. In conclusion, a protocol 1-month biopsy may be valuable to establish the prevalence of BR/SR in stable allografts. The presence of an untreated BR/SR upon a 1-month biopsy showed greater susceptibility for histological deterioration on the 6-month biopsy due to an accelerated CAN process.

The evolution of untreated borderline and subclinical rejections at first month kidney allograft biopsy in comparison with histological changes at 6 months protocol biopsies.

Our study sought to identify the possible implications of histological findings of borderline and subclinical rejections as well as histological markers of chronic allograft nephropathy (CAN) in protocol biopsies at 1 and 6 months after living-related kidney transplantation. Twenty-eight paired allograft biopsies were blindly reviewed using Banff '97 criteria, among which only 10.7% (6/56) showed no histopathological lesions. BR was found in 9/28 (32.1%) and 6/28 (21.4%), and SR in 3/28 (10.7%) and 10/28 (35.7%) of the patients, in the 1 and 6 month biopsies, respectively. The mean CAN score (sum of histological markers for chronicity) increased significantly at 6 months biopsy, 1.57 +/- 1.36 vs. 4.36 +/- 2.32 (p < 0.01). When compared according to chronicity index (CI < 5 >), the high CI group had a mean CAN score of 2.36 +/- 1.15 at 1 month, which increased to 5.14 +/- 1.99 at 6 months biopsy (188.9%). The proportion of these changes in low CI group were also increased from 0.79 +/- 1.12 to 3.57 +/- 2.38 (451.9%). In conclusion, a protocol 1 month biopsy may uncover a high prevalence of BR or SR in stable allografts. The presence of an untreated BR or SR in biopsies with low chronicity index showed greater susceptibility to histological deterioration on the 6 month biopsy, associated with rapid impairment of graft function and chronic allograft nephropathy.

Protocol biopsies in kidney transplant recipients: histologic findings as prognostic markers for graft function and outcome.

The aim of the present study was to identify subclinical and borderline rejections as well as histological markers of chronic allograft nephropathy (CAN) among protocol biopsies performed at 1 and 6 months after living related kidney transplantation to assess their possible implications for graft function. Twenty paired allograft biopsies performed at 1 and 6 months were reviewed according to the Banff scoring scheme. The mean ages of donors and recipients were 59.6 +/- 13.8 and 34.4 +/- 8.7 years, respectively. Among all biopsies only 10% (4/40) showed no histopathological lesions. At the first month borderline rejection was shown in 35% and subclinical rejection in 10% of patients. At 6 months the proportion of findings was even higher, namely, 40% and 30%, respectively. When divided according to donor age, donors above 55 years showed a mean CAN score of 2.33 +/- 1.56 which increased to 5.0 +/- 2.26 on the 6 month biopsy (214.3%). Unexpectedly, the proportion of these changes in the younger donor group also increased by 173.3%, which might have been explained by the greater number of borderline and subclinical rejections in the younger donor group at the 1 month biopsy. In conclusion, 1 month biopsy may be valuable to determine borderline and subclinical rejection and to prognosticate the outcome of renal allograft function. Our findings suggest a greater susceptibility of histological deterioration among the older donor population. However, the presence of an untreated rejection in the younger donor pool leads to a rapid impairment of the graft function accelerating the process of chronic allograft nephropathy.

Recurrent glomerulonephritis in living kidney transplantation.

Glomerulonephritis (GN) is one of the most frequent causes of end-stage renal disease. Recurrent GN can occur very early after transplantation in up to 20% of renal-allograft recipients and should be considered with late graft dysfunction in 2-5%. Importantly, diagnosis of a clinically silent recurrence of the disease will pass undetected unless transplant centers have a policy of protocol biopsies. In addition, the classification of the type of recurrent GN should be done with data on electron microscopy and immunofluorescence, in order to promote prompt treatment and a strategy for long-term graft survival. The aim of our paper was to present a few typical cases of recurrent GN, showing the actuality of the problem in living related kidney transplant recipients and to ascertain the importance of precise and timely diagnosis by protocol biopsy. Recurrent focal segmental glomerular sclerosis (FSGS) in childhood is associated with the highest number of graft loss. The treatment of recurrent FSGN is difficult, so prophylactic plasmapheresis prior to transplantation appeared to be more effective in preventing recurrence than plasmapheresis after transplantation, especially in population of children. Mesangio proliferative GN type II is the second most frequent recurrent GN, followed by type I. Here, it is of paramount importance to classify the type of the disease. The family of the patient at risk for recurrent GN, a candidate for living related kidney transplantation, should be informed for the expected outcome and their voluntary decision whether to proceed with transplantation should be awaited.

Chronic allograft nephropathy (CAN) in early renal protocol biopsies: does treatment of borderline and subclinical acute rejections prevent development and progression of CAN?

Histological markers of chronic allograft nephropathy (CAN) in early protocol biopsies may ultimately result in deterioration of graft function. The aim of our study was to evaluate risk factors of early CAN histology and to determine whether treatment of borderline and subclinical acute rejections (BR/SAR) at 1-month posttransplant, prevents development and/or progression of CAN at 6-month biopsy. Thirty-five paired kidney allograft biopsies at 1 and 6 months after transplantation were blindly reviewed using Banff'97 criteria. The mean CAN score (sum of histological markers for chronicity) increased significantly at 6-month biopsy (1.83 +/- 1.46 vs 4.66 +/- 2.35; p < 0.01). No CAN was present in 27/70 biopsies (38.6%), 71.4% showed progression and 28.6% were with stable CAN at 6-month biopsy. When compared according to the progression, mean histological index (HI) score (sum of acute/chronic changes) in progressed CAN group (pCAN) increased significantly at 6-month biopsy (5.0 +/- 3.0 vs 9.5 +/- 2.8; p < 0.001). At 1-month biopsy, BR/SAR were found in 68% and 70%, in the pCAN and stable (sCAN) groups, respectively. The percentage of treated BR/SAR in sCAN group was significantly higher (57.1 vs 23.5%; p < 0.05), and the score of acute histological lesions lower (1.08 +/- 0.95 vs 0.35 +/- 0.66; p < 0.01) at 6-month biopsy. In conclusion, 1-month protocol biopsy may be valuable to uncover BR/SAR and the presence of early CAN in stable renal allografts. Progression of CAN at 6-month biopsy in our study was found to be associated with a greater number of untreated BR/SAR at 1-month biopsy. This observation may have important implications in the design of clinical trials aimed to prevent the progression of CAN.