The detection of renal allograft rejection by fine-needle intrarenal manometry

The causes of early renal allograft malfunction include rejection, acute tubular necrosis, cyclosporin nephrotoxicity and vascular complications. Fine-needle intrarenal manometry is a potential method of distinguishing rejection from the other causes of malfunction and has been used by Salaman and Griffin in patients' treated with cyclosporin. The technique involves inserting a fine-needle, which is connected to a specially designed manometer, into the substance of the transplant kidney. One hundred and six measurements of intrarenal pressure have been made in 28 patients immunosuppressed with either azathioprine and prednisolone or cyclosporin. Thirteen rejection episodes were identified and confirmed by biopsy. These were treated by pulse steroid (methylprednisolone) therapy. Seven episodes of cyclosporin toxicity were identified and there were fifteen episodes of acute tubular necrosis. The mean intrarenal pressure in the rejecting group was 52.8 mmHg compared with 22.3, 24.1 and 24.3 mmHg for the normal function, acute tubular necrosis and cyclosporin nephrotoxicity groups, respectively (P less than 0.01; Wilcoxon unpaired test). There were no differences within these groups related to the type of immunosuppression used. There were no clinical complications associated with the procedure. Thus in newly transplanted patients, fine-needle intrarenal manometry accurately identified rejection and distinguished it from normal function, acute tubular necrosis and cyclosporin nephrotoxicity in all the patients regardless of the immunosuppressants used.     

Intrarenal manometry in the diagnosis of acute rejection superimposed on acute tubular necrosis in renal transplantation

We used fine-needle intrarenal manometry as a guide for detection of acute rejection superimposed on protracted oliguric acute tubular necrosis occurring in the postoperative course of human renal transplantation. We followed intrarenal pressure (IRP) in 31 patients who received 32 renal transplants, 12 from living related donors and 20 from cadaveric donors. There were 19 rejection episodes and 10 episodes of transient cyclosporin A (CyA) nephrotoxicity. Nine patients had posttransplant acute renal failure. Levels of IRP (mmHg) in acute rejection were (mean +/- SD) 48.6 +/- 11.1, significantly higher (p less than 0.001) than the levels in CyA nephrotoxicity (28.2 +/- 5.21), acute tubular necrosis (24.5 +/- 5.5) and normal functioning grafts (26.4 +/- 6.63). Antirejection treatment was associated with return to normal of IRP after 10 days. Intrarenal manometry was performed routinely ever 2-3 days in patients who had postoperative acute renal failure. Increments in IRP were detected on the 7-10th postoperative day in 7 patients who had 10-25 days of post-transplant oliguria. Renal biopsy findings were compatible with acute rejection, and the patients responded to intravenous bolus of steroids. We suggest that fine-needle intrarenal manometry is a reliable test for the detection of acute rejection in circumstances when traditional parameters of altered renal function cannot be evaluated.     

Fine-needle Aspiration Cytology Monitoring of Elective Conversion from Cyclosporin to Azathioprine and Prednisolone

The elective conversion of renal allograft recipients from cyclosporin(CsA) to azathioprine and prednisolone has the advantage thatthe long-term risk of CsA nephrotoxicity is reduced, but itmay precipitate a rejection episode. We have monitored thisperiod by fine-needle aspiration cytology (FNAC) in 24 patientsundergoing conversion of immunosuppression 6 months after transplantation. As expected the serum creatinine and alkaline phosphatase weresignificantly reduced and the mean creatinine clearance wassignificantly increased after conversion. FNAC exhibited increasedmononuclear cellular infiltration in 13 of the 24 patients.In nine patients there was a transient infiltration of lymphocytesand monocytes without changes in the normal parameters of renalfunction. In four others ‘blast’ cell infiltrationwas evident in association with rejection episodes. All fourresponded to pulsed doses of methylprednisolone. However, twoother patients had late rejection episodes (2 and 6 months afterconversion) which were steroid resistant and required reintroductionof CsA. No grafts were lost (median follow-up 9 months). This study has shown that although overt rejection occurredin only 16.6% of patients, cellular infiltration was presentin over 50% during conversion of immunosuppression. FNAC failedto identify clearly the patients at risk of rejection duringconversion of therapy.     

肾移植患者血小板活化指标测定的临床研究

为探讨移植肾排斥反应与血小板活化指标的关系，应用抗人活化血小板ＧＭＰ－１４０（α－颗粒膜蛋白）特异单克隆抗体Ｓｚ－５１（苏州－５１），检测６８例肾移植患者外周血血小板表面及血浆ＧＭＰ－１４０含量；同时采用放射免疫法测定血浆ＴｘＢ２（血栓烷Ｂ２）含量。术后肾功能正常者ＧＭＰ－１４０及ＴｘＢ２略有升高；发生急慢性排斥反应时两者均显著升高（Ｐ＜０．００１），排斥逆转或移植肾切除后逐渐下降。发生环孢素中毒者其含量无明显变化（Ｐ＞０．０５）。提示移植肾排斥与体内血小板活化有关，活化指标ＧＭＰ－１４０、ＴｘＢ２检测对早期诊断肾移植后排斥反应及环孢素中毒具有一定的临床价值，是监测移植肾排斥反应的一个较灵敏的生物学指标。     

Triple therapy in cadaver renal transplantation

One hundred consecutive first (n = 72) and regrafted (n = 28) cadaver renal allograft recipients were immunosuppressed with cyclosporin, azathioprine and prednisolone (triple therapy) and followed for a median of 17.3 months (range, 7-26 months). Actuarial patient survival at 12 and 24 months was 97.7 per cent. Actuarial graft survival at 12 and 24 months was 79.5 per cent (first graft recipients 81.3 per cent and regrafted recipients 75 per cent). HLA-DR matching significantly improved graft survival which was 93 per cent at 1 year in patients given HLA-DR compatible kidneys, compared with 83 and 54 per cent, respectively, in patients who received kidneys mismatched for one or two HLA-DR antigens. There were 0.8 (s.d. = 0.7) episodes of acute rejection per patient during the first 3 months after transplantation. Triple therapy provides effective immunosuppression without evidence of over immunosuppression and reduces the incidence of cyclosporin side-effects. Although acute nephrotoxicity was uncommon, serum creatinine remained elevated 6 and 12 months after transplantation.     

The role of C-reactive protein in graft dysfunction after renal transplantation

PURPOSE: We investigated whether serial daily measurements of serum C-reactive protein could help differentiate episodes of transplant dysfunction due to rejection, infection, cyclosporin A nephrotoxicity or acute tubular necrosis in renal allograft recipients. MATERIALS AND METHODS: Morning serum was obtained daily from 134 patients during the first 30 days after renal transplantation. All episodes of graft dysfunction were recorded and compared to transplant biopsies. C-reactive protein concentrations were correlated with postoperative graft function and the various causes of graft dysfunction. RESULTS: All patients demonstrated an increase in C-reactive protein in response to surgery and a maximum level was reached on day 2 after transplantation. Mean C-reactive protein concentration was significantly increased for delayed (61.50 microg./ml.) compared to primary (mean 38.01) graft function (p = 0.001, Mann-Whitney U test). There were significant increases in C-reactive protein for bacterial infections other than asymptomatic bacteriuria (33.98 microg./ml), interstitial graft rejection (16.43) and acute tubular necrosis (30.50) compared to uneventful courses. C-reactive protein was unchanged for viral infections or cyclosporin A toxicity. CONCLUSIONS: Serial C-reactive protein measurements help to identify renal transplant dysfunction of different origins. However, rejection, infection and acute tubular necrosis show similar patterns of C-reactive protein increase. Thus, C-reactive protein is unable to discriminate the causes of renal graft dysfunction. Biopsy remains the gold standard for the differential diagnosis of renal allograft dysfunction.     

Immunohistological analysis of renal allograft biopsies from cyclosporin-treated patients: Induced HLA-class II antigen expression does not exclude a diagnosis of cyclosporin nephrotoxicity

Abstract. Differentiation of cyclosporin nephrotoxicity from renal allograft rejection is often difficult. Induction of tubular HLA-class II antigens and elevated levels of leucocyte infiltration are associated with allograft rejection but their association with cyclosporin nephrotoxicity is unclear. In order to determine these relationships, transplant biopsies ( n =32) from patients considered to have cyclosporin nephrotoxicity, allograft rejection or stable graft function were stained with monoclonal antibodies specific for HLA-class II antigens and infiltrating leucocytes. Leucocyte infiltration was elevated during rejection but not in cyclosporin nephrotoxicity or stable graft function. While HLA-class II antigen expression was induced in 71% of the biopsies obtained during clinical rejection, no increased expression was found in the other 29%. Induced antigens were detected in five of the nine biopsies obtained in the presence of cyclosporin nephrotoxicity 90 days after transplantation. In four of these, induction was attributed to prolongation of increased class II expression following previous rejection episodes. Thus, the presence of induced class II antigens in the renal allograft does not exclude a diagnosis of cyclosporin nephrotoxicity.     

Immunohistological analysis of renal allograft biopsies from cyclosporin-treated patients

Differentiation of cyclosporin nephrotoxicity from renal allograft rejection is often difficult. Induction of tubular HLA-class II antigens and elevated levels of leucocyte infiltration are associated with allograft rejection but their association with cyclosporin nephrotoxicity is unclear. In order to determine these relationships, transplant biopsies (n=32) from patients considered to have cyclosporin nephrotoxicity, allograft rejection or stable graft function were stained with monoclonal antibodies specific for HLA-class II antigens and infiltrating leucocytes. Leucocyte infiltration was elevated during rejection but not in cyclosporin nephrotoxicity or stable graft function. While HLA-class II antigen expression was induced in 71% of the biopsies obtained during clinical rejection, no increased expression was found in the other 29%. Induced antigens were detected in five of the nine biopsies obtained in the presence of cyclosporin nephrotoxicity 90 days after transplantation. In four of these, induction was attributed to prolongation of increased class II expression following previous rejection episodes. Thus, the presence of induced class II antigens in the renal allograft does not exclude a diagnosis of cyclosporin nephrotoxicity.     

Percutaneous biopsy of bladder-drained pancreas transplants.

Percutaneous biopsy is a valuable investigation in the management of allograft rejection for all solid organs. Pancreas transplants have not been biopsed percutaneously, though open and percystoscopic biopsies have proved useful. We have compared percutaneous needle core biopsy with fine-needle aspiration cytology for the diagnosis of rejection in 18 patients receiving combined kidney and pancreas transplants and in one who was transplanted with the pancreas alone. Percutaneous needle core biopsy was successful in 37 of 40 attempts (93%), while fine-needle aspiration yielded diagnostic material on 33 of 47 attempts (70%). Transient hyperamylasemia occurred in 29%, returning to baseline in three days. One patient twice developed transient macroscopic hematuria. There was agreement between needle core biopsy and fine-needle aspiration on the diagnosis of rejection on six occasions and for the absence of rejection on 16. There was an 8% false-positive rate for fine-needle aspiration. In 13 instances of histologically proved renal rejection, concurrent pancreas biopsy revealed rejection in 69%. Pancreas rejection was not, however, seen in the absence of renal rejection. In this pilot study, percutaneous biopsy of the bladder-drained pancreas allograft was shown to be a practicable and valuable investigation without major complications.     

Aspirate cellularity as a rapid indicator of renal allograft rejection

No rapid and unequivocal test exists to diagnose renal allograft rejection. Despite advances in immunosuppression over the last 20 years, rejection is still the major problem in clinical organ transplantation. Most transplant centres report a renal graft survival rate of about 60 per cent at 5 years and the majority of graft losses are due to rejection. An influx into the graft of various cell types has been implicated in the diagnosis of rejection but it takes up to 24 h to obtain such information histologically. We have carried out fine needle aspiration biopsy of the allografts and estimated the number of white cells in the aspirate using a fluorescence activated cell sorter. Studies were performed in 34 cases of normal allograft function, 8 of rejection, 8 of acute tubular necrosis and 8 of cyclosporin nephrotoxicity. There was a statistically significantly higher cell number in the group undergoing rejection (P less than 0.01; Wilcoxon unpaired test) when compared to each of the other three groups. We believe that this technique, which takes only a few minutes to perform, could yield much valuable information. It deserves further study.     

Fine-needle aspiration cytology and conventional histology in 200 renal allografts

The diagnoses in 200 parallel fine-needle and core biopsies taken in acute renal allograft dysfunction, reduced function in long-term allografts, or in well-functioning grafts were compared. Fine-needle aspiration biopsy (FNAB) was found to be a reliable diagnostic tool with both a high sensitivity and specificity in acute cellular rejection (81 and 92%, respectively) and in normal kidney grafts (78 and 82%). On the other hand, the method was less valuable in the diagnosis of vascular rejection or interstitial fibrosis. Further evaluation is needed regarding the diagnostic implications of isometric vacuolization of tubular cells in FNAB specimens as a marker for acute cyclosporine nephrotoxicity.     

Role of duplex imaging and fine needle aspiration cytology of renal allografts in monitoring response to anti-rejection therapy

The role of duplex imaging and fine-needle aspiration cytology (FNAC) in monitoring the response to anti-rejection therapy was investigated in 14 of the 22 rejection episodes which occurred in 30 renal allografts recipients. In 9 of these 14 episodes of rejection, with good resolution, both resistive (RI) and pulsatility (PI) indices decreased by significant proportions (p less than 0.05). The FNAC scores also fell significantly with anti-rejection therapy. In 5 other episodes of rejection where the graft continued to deteriorate there was no significant fall of RI and PI (p greater than or equal to 0.2). In a small group of patients, both FNAC and Doppler predicted rejection. In conclusion, both duplex imaging and FNAC have a role in selection and optimal modulation of drugs in the treatment of acute renal allograft rejection.     

Diagnostic techniques in the work-up of renal allograft dysfunction--an update

After renal transplantation, acute allograft dysfunction secondary to acute rejection occurs in around 30-40% of patients. Although in the majority of patients these episodes are reversible, acute rejection remains a major risk factor for the development of chronic rejection. Remarkably, prior episodes of acute allograft rejection are associated with decreased allograft survival. Histologic examination of the percutaneous core needle transplant biopsy remains the gold standard for the diagnosis of acute rejection. It does, however, have a number of shortcomings, and less invasive procedures that could diagnose incipient rejection and simultaneously provide mechanistic information on the rejection process (allowing delivery of more tailored therapy) are being sought. To address these problems a number of alternative diagnostic procedures have been suggested, including duplex Doppler ultrasound assessment, fine-needle aspiration biopsy, urine cytology, urine cytokine analysis, serum cytokine analysis, and cytokine analysis of biopsy material.     

Prospective evaluation of renal allograft dysfunction with 99mtechnetium-diethylenetriaminepentaacetic acid renal scans

A prospective, single-blinded study was done to determine the ability of serial 99mtechnetium-diethylenetriaminepentaacetic acid scans to diagnose renal allograft rejection. Among 28 transplant recipients 111 renal scans were obtained 1 day postoperatively and every 3 to 4 days thereafter for 3 weeks in all patients retaining an allograft. Computer-generated time-activity blood flow curves were analyzed semiquantitatively for the 1) interval between curve peaks of the allograft and iliac artery, 2) renal transit time and 3) renal washout of radionuclide. Excretory function was assessed by degree and interval to appearance of radionuclide in the calices and bladder. Deterioration of renal blood flow and excretion compared to the initial scan was considered rejection. Of 52 scans performed during clinical rejection 47 (90.4 per cent) were interpreted as showing rejection (sensitivity). Of 53 scans interpreted as showing rejection 47 (88.7 per cent) were positive for clinical rejection. The remaining 6 patients (initial false positive results) suffered clinical rejection within 24 to 72 hours. We conclude that 99mtechnetium-diethylenetriaminepentaacetic acid renal scans are useful in the differential diagnosis of renal allograft dysfunction.     

Cyclosporin nephrotoxicity

Nephrotoxicity must always be excluded as a cause of renal dysfunction in allograft recipients receiving cyclosporin. Prolonged nephrotoxicity will lead to permanent impairment of renal function. This is a consequence of the renal vasospasm and vascular pathology that leads to ischemia and atrophy of the glomeruli and renal tubules.     

The use of fine-needle intrarenal manometry in the management of renal transplant patients receiving cyclosporine

The pressure inside a renal transplant can be measured by means of a fine (25-G) needle passed into the kidney, and we have shown previously that a rise in pressure to more than 40 mmHg commonly occurs during rejection episodes. A rise was not observed in patients with cyclosporine nephrotoxicity or acute tubular necrosis, so we have now used this test prospectively as part of our management of 37 patients undergoing renal transplantation. Fine needle intrarenal pressure was recorded weekly during the first three weeks after transplantation, with more frequent measures taken in patients with deteriorating or absent renal function. Treatment was dictated by the result of these tests. Deteriorating function in a kidney registering a normal pressure was diagnosed as cyclosporine nephrotoxicity and the dose of cyclosporine was reduced appropriately. A pressure reading in excess of 40 mmHg was regarded as rejection--and, after obtaining a conventional needle biopsy of the kidney, antirejection treatment was commenced immediately. Nineteen episodes of nephrotoxicity were confirmed and there was only one false-positive result. Twenty-eight of twenty-nine rejection episodes (observed in twenty-three patients) were associated with a significant rise in intrarenal pressure and were treated appropriately. In six patients who were oliguric at the time, as a result of posttransplant acute tubular necrosis, this rise in pressure was the first indication of rejection. A high pressure was recorded on the first day that the creatinine rose in two-thirds of the cases. In the remainder the pressure was seen to rise more slowly, particularly when the rejection was of the chronic vascular type and was occurring two months or more after transplantation. Fine-needle intrarenal manometry accurately identified rejection episodes in newly transplanted patients--and, because the results were unaffected by cyclosporine nephrotoxicity and acute tubular necrosis, the test was of most value in monitoring patients with these conditions.     

Value of percutaneous core needle biopsy in the differential diagnosis of renal transplant dysfunction

The value of percutaneous core needle biopsy in the differentiation of rejection from other causes of renal allograft dysfunction, and its subsequent effect on patient management were assessed in 64 consecutive biopsies performed on 34 patients in whom the clinical diagnosis was was uncertain. A complete clinical, biochemical and radiographic assessment was made in each patient before biopsy. Only 1 biopsy (1.6 per cent) yielded tissue inadequate for evaluation, while another biopsy caused a renal artery pseudoaneurysm that ruptured and resulted in graft loss. In 27 of these 64 biopsies (42 per cent) the results differed from the pre-biopsy diagnosis and directly affected patient management, particularly the use of steroids. The remaining biopsy specimens were helpful to confirm uncertain clinical impressions, and allowed accurate counseling for patients and family. Biopsies were of special usefulness in separating acute rejection from complications, such as acute tubular necrosis, cytomegalovirus infections, recurrence of original disease, cyclosporin toxicity and acute superimposed-upon chronic rejection. Of 64 biopsies 22 (34.3 per cent) demonstrated the absence of rejection and 8 demonstrated chronic rejection (12.5 per cent), thereby averting the use of steroids in 46.8 per cent of the patients. All patients with evidence of severe small vessel disease and/or antibody-mediated rejection eventually lost the grafts, including 2 with cytomegalovirus glomerulopathy who also suffered such vascular changes. These data highlight the extreme usefulness of needle biopsy in the evaluation and management of renal allograft dysfunction.     

The effect of cyclosporine on mortality and renal function in living related pediatric kidney transplant recipients

The outcome, incidence of acute rejection episodes, complications and cyclosporine (CyA) induced nephrotoxicity were studied in 10 pediatric kidney transplant recipients who were grafted from one-haplotype indentical parent with immunosuppression of CyA and prednisolone (Pred). Excellent patient and graft survival could be achieved in this population with low incidences of acute rejection or serious complications as when compared with the results of azathioprine (AZ) treated pediatric patients. With a mean follow-up of 12.9 months (range 1 to 50 months), the patient survival rate was 100 per cent and the graft survival rate was 100, 84, 84 and 84 per cent at 1, 2, 3 and 4 years post transplantation, respectively. Serum creatinine levels in the group were 0.97, 1.17, 1.14 and 1.2 mg/dl at 3, 6, 12 and 24 months post transplantation, respectively. The incidence of treated acute rejection episodes was 20 per cent (2 out of 10) in the CyA-treated children, whereas it was 53 per cent (9 of 17) in the Az-treated children. Five children who had undergone transplant surgery before they were 11 years old displayed linear growth in height after their transplantation. There have been no opportunistic infections, aseptic necrosis or peptic ulcers in this group and cyclosporine nephrotoxicity has not been a serious problem in the pediatric recipients. Only 10 per cent (1 out of 10) of the recipients displayed acute nephrotoxicity and only one recipient has converted from CyA+Pred to CyA+AZ+Pred (Three drug therapy) due to persistent nephrotoxicity. Cyclosporine and prednisolone have therefore constituted a relatively safe, effective immunosuppressive regimen for pediatric renal allograft recipients. This paper was presented at the 7th international congress of pediatric nephrology.     

A comparison of duplex Doppler ultrasonography and intrarenal manometry in the diagnosis of acute renal transplant rejection

Renal transplant rejection is frequently difficult to differentiate from other causes of renal dysfunction. This study examined the use of duplex Doppler ultrasound and intrarenal manometry in a consecutive series of 73 patients who underwent renal transplantation. Altogether 327 duplex scans were analyzed and, for each, a resistive index (RI) was calculated. A raised RI predicted rejection in patients with grafts that functioned immediately, but not in those that had delayed function. A rise in intrarenal pressure ( greater than or equal to 40 mmHg) indicated the presence of rejection in both groups. However, neither test had a sensitivity of more than 71% and this was not improved by combining the results of the two tests for each patient. Although both tests have a place in transplantation, renal biopsies may still be required to confirm rejection.     

Effect of cyclosporin A on the development of posttransplantation hypertension in rat renal allograft recipients

Hypertension secondary to renal transplantation was studied in our experimental model in the rat. In this model an intravenous injection of donor strain blood into recipients of allogeneic donor kidneys prior to transplantation was used to prolong the allograft survival. A reduced renal function associated with the hypertension was suggestive of incomplete prevention of the rejection process. We studied the effect of cyclosporin A, either alone or as adjuvant immunosuppressive therapy, on renal function and systolic blood pressure. Either way, cyclosporin A resulted in normotensive allograft recipients and in a better function of the graft when compared with recipients pretreated with donor strain blood only.