Background information about the field of interest
Since the first successful kidney transplantation the procedure has become a long lasting cure for patients with kidney failure. By replacing the failing organ by a new one a problem is solved, but new problems will arise again mainly created by the human immune system. Reactions against the graft can be acute, but there will almost always be a chronic reaction too. The short-term acute renal graft rejection can often be prevented, but the main problem lies now in long-term graft functioning and survival. It is still not fully understood what exactly causes damage to the kidney on a long-term basis, but an antibody mediated response (AMR) against the allograft seems to be one of the main problems in renal failure.3 Antibodies again the donor organ kidney can already be present in the host resulting in an acute AMR which cause acute graft rejection by severe inflammation of the endothelium in the graft.3 This is triggered by the complement system which recognizes the donor specific antibodies (DSAs) and stimulates inflammatory lymphocytes. As a by-product of complement activation Cd4 deposition occurs in the membrane of the endothelial of the peritubular capillaries which is still present long after complement activation. An accurate transplantation prognosis and HLA comparisons between the donor and host can prevent the acute AMR, but DSAs against HLA on the endothelium of the graft can still develop after the transplantation resulting in a chronic AMR.3 Chronic allograft nephropathy which causes damage to the kidney, is one of the major causes for graft loss and can be detected by interstitial fibrosis and tubular atrophy.1,2 Transplant Glomerulopathy (TG), detoriation of the glomeruli, is also one of the major causes for kidney failure.4 TG is most likely related to the chronic AMR response, because several studies have shown that Cd4 and anti-donor HLA antibodies were detected in a majority of cases concerning patients with TG (60 to 80 %).4 The presence of Cd4 deposition itself in the peritubular capillaries has also been detected in other disfunctioning renal graft (up to 50%), but research has always been done in very small selective patient groups.5 C4d staining in early biopsies could be a good prediction method to predict the failure of kidney allograft so that it can be taken into consideration when administrating medicine to the patient, but a lot more research needs to be done to confirm if this is true.5
Summary of the article
What did they do
Research has been done on patients who have had their renal allograft for over 10 years after transplantation. Biopsies have been taken from their kidneys and were thoroughly checked for inflammations and abnormalities like TG. The kidneys were stained for C4d to see if there were traces of an AMR. They checked the sera of the patients for DSAs and creatine levels as a measurement for the functioning of the kidney and compared their findings with additional information about the patients. What they were mainly looking for was a possible correlation between C4d deposition and the functioning and survival of the kidneys. They pooled their data to test if additional correlations could be found between C4d staining, TG, DSAs and several other factors.
Results and conclusions
From the 99 patients 25% of them where positive for C4d staining. Damage to the renal allograft was higher in these patients then in the C4d- patients and TG and acute cellular rejection was also seen more often in these patients. Of all patients TG had a prevalence of 20%. Of the 25 C4d+ patients 60% were positive for TG and 14% of the C4d- patients. From some patients early biopsies where available and were used for a retrospective view. 88% of the C4d+ patients where already positive in earlier biopsies and 19% of the C4- patients showed C4d positivity in early biopsies. C4d+ patients often had their transplantation at a younger age then the C4d- group (29 versus 37 years) and received their organs from living donors (65% Cd4+ versus 23% C4d-). DSAs were found in 83% of the C4d+ patients, 0% of the C4d- patients, but no correlation could be found between anti HLA I or HLA II antibodies and TG. Graft loss occurred in 45% of the C4d+ patients and in 16% of the C4d- group. Graft loss had a higher prevalence in patients with TG (68% TG+ versus 12% TG-) and TG was detected in all 10 patients who were CD4+ and had lost their graft. Therapy against an AMR and antibody-depleting therapy had no effect on patients with TG. To predict graft loss creatine levels in the serum (>2.3 g/dl), C4d+ staining and TG where the best risk factors. The writers developed a scoring system which predicts graft failure and resulted in a high chance (>80% ) of graft failure in 1 year for patients who qualified for all 3 predictor factors.
The writers concluded that many, but not all TG are antibody mediated. T-cell mediated events and drug toxicities could also contribute to TG development. C4d+ seemed correlated to a younger age and organs received from living donors. Graft loss was higher in the C4d+ group, but strongly correlated to TG and high creatine levels. They could not find a correlation between anti HLA I and HLA II antibodies and TG. They could also not find an explanation for the 7 patients which were C4d+ in early biopsies, but C4d- in the later ones without receiving specific treatment.
The articles contribution to the field
The scoring method they developed to predict graft survival in the presence of TG, Cd4 and high creatine levels in the serum this could be a useful tool for clinicians. When rapid graft failure can be predicted better medication could be given to the patients and preparations could be made. The findings are therefore of great importance for diagnostic causes, but also for scientific knowledge in graft rejection.
Discussion about the article
There are still a lot of questions unanswered concerning chronic graft rejection but some of the factors involved have already been identified like the antibody mediated response (AMR). What this article has been focusing on is the C4d protein which functions as a fingerprint for an AMR. Unlike other articles which also focus on C4d the writers of this article had a reasonable big pool of patients of which biopsies and additional data could be obtained. Some of the patients where also healthy patients which still had a working renal allograft after 10 years of the transplantation. Unfortunately their biopsies had to come from a database and had sometimes insufficient additional information about the patients. The researchers started with a big pool of data and started looking for several factors like C4d deposition and the presence of TG as independent patient groups at first and later looked at correlations between the two as well as other factors which in my opinion is the best way to deal with this data and to get impartial overview of correlations in a relative general population of transplant patients.
They need to find more controls though to support their finding about higher C4d+ in younger patients who received their organs from living donors. Patients should be found who received their organs from nonliving donors as well and on which C4d staining can be done on biopsies as a reference. Furthermore they could have looked at the medication the transplant patients have received during the years and if this had effected C4d deposition and TG development, because they already mentioned the possible influence of drugs toxicity. With the knowledge the scientists have obtained with their research a longer follow up project could be done in which patients will be followed for +/- 15 years from the start of their transplantations. Blood samples and renal biopsies could be taken on an annual basis to see how C4d deposition, TG and renal function will develop over time to get a more accurate overview of the correlations these scientists have found. They will also be able to obtain several data about the patients which could not be retrieved in the study which has been done.
This article has made a contribution to the understanding, but mostly to the predicting of graft failure in patient who have has their renal allografts for many years. The scoring method they developed could be a useful tool for diagnosis for clinicians and will alert other scientists about the importance of TG and C4d+ in renal failure. This article has not resulted in a new treatment therapy for patients with renal allografts, but does contribute to it's understanding. An interesting finding is the 7 patients which became C4d- after earlier C4d+ staining in early biopsies without further treatment. This calls for further research in what has happened in these patients and how their body dealt with it. Understanding of this mechanism could ultimately lead a cure for the results of the AMR and prevent TG development in kidney allografts.
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Hypertension 2008, 17:149-155.
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3) A. Àlvarez-Márquez et all. Donor-Specific Antibodies Against HLA, MICA, and GSTT1 in Patients with Allograft Rejection and C4d Deposition in Renal Biopsies. Transplantation 2009, Volume 87, Number 1, January 15: 94-99.
4) B. Sis et all. Transplant Glomerulopathy, Late Antibody-Mediated Rejection and the ABCD Tetrad in Kidney Allograft Biopsies for Cause. American Journal of Transplantation 2007. 7: 1743-1752.
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