a United States Army Medical Department Continuing education program diagnosis of rejection with john D. Welcome Lieutenant Colonel U.S. Air Force Medical Corps Chief transplant unit Wilford Hall U.S. Air Force Medical Center. Lackland Air Force base. Despite almost 20 years of experience in renal transplantation. Now the early diagnoses of graft rejection prior to significant insult to the graft remains one of the most difficult and complex ng problems in clinical transplantation. Can we have the first slide please from one thinks of rejection. He thinks of it in a path a physiological consequences. These consequences can divided into three areas, can be divided into three areas The immunological nature of rejection, the path of physiological alterations and the pathological sequence. The ecological nature has been discussed earlier this morning and experts in the field will also discuss the pathological sequence. So we will devote our remarks towards the path of physiological alterations. These in my mind are extremely important because frequently this is the only information the clinician may have to make the diagnosis of rejection. The path of physiological alterations can be classified as chemo, dynamic, glamorous, tabular and urinary as stated before. A knowledge of this data is very important as it is upon this data that the physician must depend to make his diagnoses very frequently. It may be the only data that he has. The classification of rejection in general use today is divided into hyper cute, acute and chronic hyper acute rejection is a rapidly progressive destructive process that usually occurs within minutes to hours following the transplant today, we really have no successful method of dealing with this type of rejection. Therefore, I'm not going to discuss it any further is usually not a dubious problem that you're dealing with. When this occurs, acute rejection is a process that occurs between days and even two up two years. Post transplant, it has been discussed in some detail today. The sailor changes etcetera. Since this is a reversible lesion and the one that we usually have the most success with this will probably this will be the topic of my discussion. Chronic rejection is a rather insidious process is characterized by slow deterioration and final loss of graph graph function at the present state of the art. We really aren't able to control this and have no successful means of treating it over a prolonged period of time. The earliest alteration in acute rejection, there's a disturbance in the hemo dynamics. These changes are present prior to the clinical evidence of deterioration in renal function and is initially results of the shunning of blood away from the cortex to the medulla with a corresponding decline in gomorrah and tabular function. The shunning that we see is probably due to vessel spasm and associated a demon that results from immunological reaction. As the process continues. The cortical blood flow further decreases, resulting in decreased camera function, which results in a decreased sodium delivery to the distal tubules. T bills is reflected in a loss or decrease of sodium excretion as the process continues the total blood flow to the graph deteriorates in the face of an increasing resistance from vessel spasm vessel and epithelial swelling micro thrown by an increasing interstitial edema resulting from the gemological vascular injury and adama. Unfortunately, these changes lead to further damage, creating a rather vicious cycle that will ultimately result in death of the graph unless they are altered. The decrease in gomorrah filtration and tubular function can initially be detected by a decrease in heparin clearance. This is followed in 24 hours by detectable decrease in the creatinine clearance and in 24-48 hours by rising serum creatinine. This chemical and immunological damage in the primarily membrane results in an increased permeability of that membrane. This is characterized by a loss of excessive amounts of protein in the field. Trade as a damage to the membrane increases during the rejection and ischemic episodes larger and larger molecular eight membranes become present in the urine. A variety of tubular d arrangements in the handling of sodium bicarbonate, phosphate, chloride and hydrogen irons are seen during rejection. Renal tubular acidosis, hyper chlorine, mia, glucose, urea amino acid urea and foss materia may occur several days prior to the clinical evidence of rejection, such as arising Bunn correct name due to the ischemic changes in the tubular cells, there is a compensatory shift from anaerobic too, from aerobic to anaerobic metabolism and enzymes such as likely D hydrogenated alkaline phosphates and listen, enzymes may appear in the urine urinary firebrand split products and increased numbers of Lucas sites, neutrophils and red blood cells may also appear fever, malaise anorexia and a general feeling of poor health are frequently associated with the early stages of rejection. Unfortunately, many of these changes also occur in other conditions such as infection, making the diagnosis somewhat difficult. In an attempt to define the criteria that would aid us in uh recognizing and initiating treatment of rejection episodes. Early in their course, we attempted to establish a protocol or at least a list of signs that we could depend on. To do this. We set a criteria major and minor signs. In order to make the diagnosis of rejection. We have chosen to use two majors. One major or one or two miners are four minors as the diagnostic criteria in which we would start our immunosuppressive protocols. The blood studies that we have utilized are those probably utilized in most centers, although not always consistently are standardized, are rising creatinine depending upon the degree of rise, whether whether it be a major and minor sign the same for the Buon chloride and the white blood cell count. The urine studies that we depend upon our volume threatening clearance, sodium excretion, the presence of lymphocyte in the urine and protein. The physical findings that we have found useful are gaining weight, swelling of the kidney. Our graph characteristics on physical exam, hypertension and fever. To augment these particular criteria. We have also utilized serial renal scans. These scans. We first began 24 hours after the transplant and then performed the follow up scans every 2-3 days. A typical example of the case of a case in which this has been most beneficial was this young lady who received a transplant on 18 September at this point in time, she had a normal technique, easy um flow study which is depicted on this slide. Her following studies were normal in her clinical clinical condition appeared very stable. And on 10 October a scan revealed at a 12-16 2nd flow 12-16 seconds into a flow study. Some deterioration of the flow, the technician flow at this point in time. All of our parameters that we normally measure for rejection were normal. On the 11th the following day after this scan, her her creatinine clearance began to decrease and she became febrile On 12 October. Her scan showed further deterioration in the flow and uh immunosuppressive. I mean rejection therapy was instigated on 15 October. There shows there was a slight improvement in the flow and her clinical course followed rapidly behind this improvement in scan with a dropping of her sim card and an improvement in her creatinine clearance and clearing of her fever. The hip Iran aspect of the scam. We also utilized to determine what is happening on the scam. This is the hip Iran study. This young lady had on the 10th of october, which unfortunately I do not have the slide for the 18th showed slight deterioration in her handling of hippie ran her up taking clearance On 12 October. There was even further deterioration again uh strengthening our feeling that we were dealing with the rejection on the 10th and clinically dealing with rejection. On the 11th, on the 15th of october. After four days of him of uh increased doses of selenium Pedro, she had improvement in her hip here and study the following reno grams. Further substantiate the findings Showing on 18 September a very nice renal flow rate, a good bladder uh concentration On the 10th, there was some flattening of the renal flow study with some decrease in the accumulation of a die in the bladder on the 12th. Further deterioration and on the 15th some improvement thus far in our in our series of patients, we have not had to utilize our terry ah graffiti to diagnose rejection. We have utilized it in certain instances where we have experienced acute rejection that is not that does not appear to respond to our uh to our rejection therapy in an attempt to decide if a graft is salvageable or not, to get an idea of the radiological changes. This is a normal arteriogram that's performed in a young man who experienced uh no urine output shortly after surgery. And uh we felt that he could possibly have occlusion of his artery. Therefore, an arteriogram was performed fortunately. It was only a acute tubular necrosis which rapidly cleared here. You can see that the outline of the kidney is very nicely depicted. The small temporary cortical vessels are filling. There's no spasm of the vessels of the vessels, there's no beating. In the same series of studies. We thought we see a very nice Neffa graham. And another side benefit is that you can see the renal veins. This was what we would have to clear. This is what the radiological libertarian. We also call a normal arteriogram and a transplant patient. The following slide is that of a young 23 year old male who received a living related draft and experienced an acute the an old set of acute rejection approximately two weeks following the transplant prior to that time. His function had been quite adequate. Despite rather intensive anti rejection therapy, his function did not improve approximately a week and a half, a week and a half into his acute rejection course. His urine output was very low and his crafting and be um, are continuing to climb to determine if increasing our our continuing the the rejection therapy was indicated. We felt that an arteriogram might give us some information. As you see on this arteriogram, there is some stretching of the vessels. There is loss of that nice cortical outline that we saw in the normal study by loss of flow into the Treasury temporary vessels from the results of this arteriogram, we thought that we still had a salvageable graft. But unfortunately, that did not prove to be the case. And the young man lost his kidney several weeks later. The next arteriogram is that of a young 19 year old male who received a one energy match cadaver kidney, who experienced a rather acute on a rather acute rejection episode approximately one week following the transplant, that was reversed by increasing his steroid therapy. Following a tapering of the drugs he immediately rejected again. And at that point in time we instigated, we instituted uh again, repeat increased steroid uh therapy and he failed to respond to this again, we utilized our terry og ra fee to see if we had a graph that was worth continuing continuing the rejection therapy this young man shows. And fair, I think you can see this beating of the secondary vessels of his graft, pruning of the vessels, but no particular arterial spasm. Again, we felt that this kidney might be salvageable. But unfortunately, he too went on to reject his kidney when it became apparent that our immune suppressive therapy was inadequate. And we ceased it. The following slide is an arteriogram of a 34 year old female who received a two energy match cadaver graft, who experienced a rather marked onset of acute rejection going from apparently normal function to complete allegory Yuria. In two days accompanied by high spiking fevers. An arteriogram was likewise performed on her when our immune suppressive therapy appeared not to have any effect and she was returned to dialysis. In this particular study, you can see mark spasm of the arenal artery going into the arena to the bifurcation of the arenal main renal artery into its branches. This may be a very ominous sign because this young lady rapidly lost her graph despite our efforts of trying to save it. An intravenous polygram can on occasions also be very helpful in diagnosing early rejection. Fortunately, we had a nice situation in which to see. This is something that is not usually seen. This is an ivp from a 21 year old male who received a two engine match, living-related kidney. As standard in our program, we obtain an IVP on the fifth post update, hoping to get a good study of the your it'll anatomy or the collecting system before rejection occurs so that we can at least rule out or uh have some security in the fact that we don't have a severe anatomical problem in this particular situation. This particular patient, he had a functional obstruction of the ureter mile but probably secondary to your eternal edema at the systematic site resulting in a mouth hydro Euro. To the striking thing is that all of the pelvis and the Euro to dilated. There's no dilatation of the calluses, which one normally would expect to see. But you can if I think you can pick it out on this, there is marked edema of the remote capella which at the time we weren't sure what this meant. But two days later we were quite certain what it meant is he developed a rising B. One and creatinine where they fall in. His creatinine clearance slides off. Please. Despite all of these manipulations methods etcetera. Making the diagnosis of rejection, we're still depending upon rather severe changes in the graft uh as depicted by its function before we can make the diagnosis and institute therapy, there's no doubt that we're losing some some areas of the graph that we will probably never recover. Therefore it is imperative that we continue to search for better methods of detecting rejection. And there is some probable hope in the gemological studies that we mentioned earlier this morning diagnosis of rejection with john D. Well call Lieutenant Colonel U. S. Air Force Medical Corps Chief transplant unit, Wilford Hall U. S. Air Force Medical Center. Lackland Air Force Base was produced through the mobile facilities of the television division Academy of Health Sciences, United States Army Fort Sam Houston texas