Pathogenesis of chronic renal allograft dysfunction

The pathogenesis of chronic renal allograft dysfunction was reviewed. Chronic rejection/chronic renal allograft nephropathy is the most prevalent cause of renal graft loss after the first year post-transplant. Both immunologic and non-immunologic factors play key roles in the pathogenesis of chronic allograft nephropathy. Acute rejection episodes are the most prevalent risk factor for chronic rejection. Many risk factors for chronic allograft nephropathy have been identified, such as glomerular hyper-filtration, delayed graft function, repeated acute rejection, systemic hypertension and hyperlipidemia. However, the precise pathogenesis of chronic allograft nephropathy remains obscure. The differential diagnosis of immunologically mediated chronic rejection and chronic allograft dysfunction caused by non-immunologic factors is usually impossible using clinical parameters. The histopathologic findings of chronic allograft nephropathy are progressive interstitial fibrosis with tubular atrophy and thickening of vascular intima, and these findings are non-specific. Therefore, the term chronic allograft nephropathy may be clinically preferable to chronic rejection to describe the gradual decline in graft function. The most effective way to prevent chronic allograft dysfunction is to avoid any kind of graft damage via immunologic or non-immunologic pathway.     

Salvaging kidneys with renal allograft compartment syndrome

Renal allograft compartment syndrome is an under recognized cause of early allograft dysfunction which can be reversed by early intervention. It occurs early after renal transplantation where closure of the anterior abdominal wall seems to compress the transplant in the limited retroperitoneal space. The literature about this syndrome in renal transplantation is sparse. Our report describes the diagnostic criteria and the management of two renal transplant recipients with this syndrome. Its diagnosis depends upon duplex vascular scan findings of reversed or absent diastolic flow in the renal vasculature in the absence of any perigraft collection or severe acute tubular necrosis. In our hands emergency laparotomy, decompression of the transplant and closure with interposition mesh salvaged these kidneys.     

移植肾的病理类型与肾功能及预后的关系——单中心十年经验回顾分析

目的 分析肾移植受者移植肾的病理类型和特征,及其与肾功能和预后的关系.方法 肾移植术后230例受者接受了移植肾穿刺病理活检,分析其病理表现类型和特征,比较不同病理类型和特征受者移植肾穿刺活检时的血肌酐(SCr)水平,随访受者穿刺活检后1年的移植肾功能情况,评价不同病理特征受者的预后.结果 移植术后3个月时接受了程序性肾活检的10例受者中,9例为正常肾组织,1例为移植后IgA肾病.有肾功能损害临床表现的220例受者中,病理表现为交界性改变33例,急性排斥反应(AR)45例,慢性排斥反应(CR)24例,慢性移植肾肾病(CAN)26例,移植后肾炎(PTGN)39例,以上共167例;另外,28例同时有前面两种或两种以上的病理类型表现,还有CNI肾毒性反应8例,BK病毒肾病7例,急性肾小管坏死5例.有5例受者因采集的移植肾组织过少而不能明确诊断.病理诊断为交界性改变、AR、CR、CAN和PTGN的受者,其穿刺活检时的SCr水平分别为(171±17)、(259±25)、(343±33)、(406±67)和(207±26)μmol/L,不同病理类型者的SCr水平两两比较,差异均有统计学意义(P＜0.01).穿刺活检后1年,随访到上述5种病理类型167例受者中的134例(80.2%),其中交界性改变23例、AR 36例、CR 20例、CAN 18例及PTGN37例,分别有1例(3.1%)、8例(18.2%)、8例(22.2%)、6例(33.3%)、5例(13.5%)发生移植肾功能丧失.穿刺活检后1年,上述5种病理类型移植肾功能异常受者的SCr水平与穿刺时SCr水平的差值(△SCr)分别为(-47±20.7)、(-37.3±36.9)、(25.5±24.3)、(13.5±27.7)和(25.2±17.1)μmol/L.结论 移植肾的病理改变复杂多样,结合移植肾穿刺病理活检结果和临床分析进行准确诊断,可以帮助临床选择合适的治疗方案,促进移植肾的长期存活.     

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.     

Mechanisms and amelioration of acute renal allograft failure in the cyclosporine era.

The fairly wide-ranging spectrum of tactics under investigation for ameliorating acute renal allograft dysfunction caused by harvest/preservation-related ischemia, acute CsA nephrotoxicity, and acute immunologic crises reflect the fact that no single approach has emerged as universally useful for mitigating the vasomotor nephropathy produced by the combined effects of each of these vectors of vasomotor renal allograft injury. Given the clinical heterogeneity of patients and allografts, it is the author's bias that, in addition to careful donor and recipient hemodynamic management, induction immunosuppressive regimens should be individualized on the basis of allograft function in the immediate postreperfusion period (judged by rate of diuresis, intraoperative parenchymal tone, renal scan profiles, and rate of decline of serum creatinine concentration) as well as patient-specific immunologic and general medical risk factors. Promising laboratory and clinical investigations of such agents as calcium channel blockers, substances promoting intrarenal vasodilator vs. vasoconstrictor prostaglandin formation, and atriopeptins have the potential to provide clinically helpful options with regard to adjunctive therapy for ameliorating acute renal allograft dysfunction associated with INF and ACR.     

Histopathology of chronic renal allograft dysfunction

The rate of late allograft loss remains relatively constant, despite greatly improved success in the early management of renal transplants. The pathological changes encountered in kidneys undergoing late allograft dysfunction are the result of a variety of processes, both immune and nonimmune. The gradual appearance of interstitial fibrosis and tubular atrophy is a nonspecific finding, which characterizes late allograft dysfunction. Features that indicate chronic rejection include transplant glomerulopathy, vascular intimal hyperplasia, particularly in association with intimal lymphocytic infiltration. Both of these changes may be related to humoral rejection. Animal models provide important insights into the mechanism of chronic rejection. In a commonly used model, the Fisher to Lewis rat model, antidonor antibodies against matrix proteins are associated with the development of transplant glomerulopathy, and the appearance of antitubular antibodies and a granulomatous interstitial nephritis may indicate graft-host differences in tubular basement membrane structure.     

Cholesterol crystal embolic disease in renal allografts

Cholesterol embolic disease in the renal allograft is not recognized as an important cause of graft dysfunction. We describe here two renal transplant patients with cholesterol embolization in their allograft biopsies. The first, a 48-year-old patient, received a renal transplant from a 62-year-old donor with a history of hypertension and tobacco use. On account of initial non-function, a renal biopsy was taken, which showed acute tubular necrosis and cholesterol emboli. The second, a 55-year-old man, presented chronic allograft failure six years after transplantation; ultrasonography showed a solid renal mass. Nephrectomy specimens revealed renal carcinoma and a combination of chronic rejection and multiple cholesterol emboli. Cholesterol embolic disease is probably an under-reported cause of renal graft dysfunction. The source of the emboli may be either the donor or the recipient's vessels. Since the current tendency is to accept older donors and recipients with more advanced atherosclerotic disease, this condition is likely to become more frequent in the future. Particular care must be taken at the time of organ procurement and during the evaluation of organ donors, in order to reduce the risk of embolization.     

Evaluation of renal allograft function by Doppler spectrum analysis

A decreased renal function is rather common after renal transplantation. The causes of this decreased function are diverse and difficult to differentiate. Yet, duplex examination, and especially quantitative Doppler spectrum analysis of the blood velocities in the renal artery, may be an effective method for differentiating between some of these causes. Forty-five renal transplant recipients were included in this preliminary study. Doppler spectra were recorded from the renal artery to the allograft. Parameters were derived from every Doppler spectrum in order to characterize each spectrum. Renal allograft function was evaluated on the basis of a number of clinical parameters. A significant correlation was found between the clinical parameters and the Doppler spectrum parameters indicative for changes in the peripheral resistance. Patients with a normal renal allograft function showed Doppler spectra with a high diastolic flow, typical of a vascular bed with a low peripheral resistance. Patients with a decreased renal allograft function caused by a stenosis in the renal artery could be distinguished by a low peak velocity and a low pulsatility index. A decreased allograft function caused by allograft rejection or cyclosporin nephrotoxicity also led to characteristic arterial flow disturbances. In these cases, the peripheral resistance was increased, and this was primarily reflected in a decrease in the diastolic blood velocity. We conclude that quantitative analysis of the blood velocities in the renal artery by Doppler spectrum analysis seems to be a useful, noninvasive diagnostic tool that discriminates between some of the causes of a decreased renal allograft function.     

Polyomavirus nephropathy after renal transplantation: a single centre experience

BACKGROUND: Polyomavirus associated nephropathy (PVN) in renal transplant recipients has been observed with increasing frequency recently and has emerged as a cause of allograft failure linked to highly potent new immunosuppressive regimens containing tacrolimus or mycophenolate mofetil (MMF). METHODS: Polyomavirus associated nephropathy was identified in nine out of 182 patients who received renal transplantation between October 1998 and July 2003. PVN was confirmed by allograft biopsy. The clinical records of these nine patients were reviewed, as were all of the allograft biopsies. Electron microscopy was performed in all nine cases. After the diagnosis of PVN, maintenance immunosuppression was reduced. The clinical course and outcome of the PVN patients were reviewed in relation to manipulation of immunosuppressive agents. RESULTS: There were nine cases of PVN in renal transplant recipients and the incidence of PVN was 4.9%. All patients with PVN were under triple immunosuppression comprising tacrolimus and MMF. The mean time to a diagnosis of PVN was 7.8 months after transplantation. Three of the nine patients received antirejection therapy prior to PVN. Seven out of nine PVN patients presenting acute allograft dysfunction were initially treated with high-dose intravenous steroid pulse or OKT3 before reduction of the immunosuppression. After reduction of the immunosuppression, seven patients stabilized their renal function. Two (22%) lost their grafts due to persistent PVN and chronic rejection. Two (22%) patients later developed acute rejection after reduction of the immunosuppression. CONCLUSION: PVN can cause allograft dysfunction and graft loss. Renal allograft recipients who are at risk of PVN should be routinely screened with urine cytology and quantitative measurements of viral load in the blood, particularly patients who had graft dysfunction. Early diagnosis and judicious alteration of immunosuppressive agents might permit a superior prognosis and reduce the graft loss from PVN in renal transplant recipients.     

Analysis of allograft biopsy specimens from long-term surviving patients with stable renal function: predictive value of long-term graft prognosis

Abstract: Chronic allograft dysfunction is multi-factorial, and histology of long-term renal allograft shows variable findings. It is important to characterize the pathological features of graft kidneys with normal function to understand the natural course of transplants, which in turn would contribute to elucidate the causes of chronic allograft nephropathy (CAN). To address this issue, we performed 'non-episode' biopsies on well-functioning renal allografts, and evaluated the correlation between clinical outcome and histopathological findings. Patients who underwent a non-episode biopsy had a serum creatinine concentration less than 2.0 mg/dL, urinary protein of less than 500 mg/day and a stable clinical course. In total, 90 such biopsies were performed. Mean follow-up period after biopsy was 29 ± 16 months. We evaluated the histopathological findings and clinical outcome on each finding. Moreover, we compared the findings in the patients on tacrolimus with those of patients taking cyclosporin. Twenty-three biopsy specimens were essentially normal. Graft dysfunction during the follow-up period was recognized more frequently in patients showing more than one pathological process than in those with isolated findings. Graft outcome was not associated with drug-induced nephropathy, but with acute rejection ( P  = 0.0193) and CAN ( P  = 0.0032). Patients found to have CAN-b had a worse outcome than those with CAN-a. CAN-b was less common in the tacrolimus group than in the cyclosporin group. Non-episode biopsy has a predictive value of the long-term outcome of a renal allograft. CAN is associated with graft dysfunction; neither is drug-induced nephropathy. Patients treated with tacrolimus had lower rates of CAN-b than did cyclosporin-treated subjects.     

Late recurrent urinary tract infections may produce renal allograft scarring even in the absence of symptoms or vesicoureteric reflux

BACKGROUND: The significance of late urinary tract infections (UTIs) after renal transplantation and their association with scarring and graft dysfunction remains controversial. We sought to define the prevalence of renal scarring in allograft recipients with a history of late recurrent UTIs, to determine whether the presence of vesicoureteric reflux (VUR) confers an increased risk of scarring and to establish whether scarring correlates with graft dysfunction. METHODS: Among 307 renal allograft recipients, we identified 56 (18%) with late recurrent UTIs (> or =3/year). A total of 32 patients had undergone further investigation by both 2,3 dimercapto-succinic acid single-photon emission computed tomography (99mTc-DMSA SPECT) scan and micturating cystourethrogram (MCUG). RESULTS: Of the 32 patients, 24 (75%) had scars on 99mTc-DMSA SPECT and 15 (47%) had reflux on MCUG. Thirteen of these 15 patients with reflux (87%) had scars, although there was no significant correlation between number of scars and degree of reflux. Eleven of 17 patients (65%) with UTIs but without VUR had scars, as did 12 of 14 (86%) with previous graft pyelonephritis. The pattern of scarring (typically multiple focal cortical defects) suggested infection as the cause. This pattern was not seen in a contemporary cohort with vascular occlusions and was rarely seen in patients with chronic allograft nephropathy. Scarring was not associated with inferior graft survival (median follow-up, 15 years). CONCLUSIONS: In patients with late UTIs, renal scarring is a frequent finding. Scarring may occur even in asymptomatic patients without VUR. The lack of an effect on graft survival may reflect successful intervention with prophylactic antibiotics and surveillance urine cultures. Late recurrent UTIs may be damaging to renal allografts, even in the absence of reflux.     

Treatment of Refractory BK Virus-Associated Nephropathy With Cidofovir

BK virus-associated nephropathy (BKVN) has become recognized as an important cause of allograft dysfunction in renal transplant recipients and despite reduction in immunosuppression, 30-40% of recipients ultimately progress to allograft loss. Cidofovir is an antiviral agent that demonstrates in vitro activity against murine polyomavirus and has been proposed for treatment of BKVN in renal allograft recipients. We describe the clinical course, renal function, serial renal histology and urine and blood viral load measurements in two consecutive patients with refractory BKVN who were treated with low-dose cidofovir (0.25 mg/kg IV). In each case, renal dysfunction and BK viral load progressed despite reduced immunosuppression, and persistent BK virus infection was documented in serial renal allograft biopsy specimens. Administration of low-dose cidofovir was associated with clearance of BK virus DNA from blood and allograft, and stabilization of renal function in both patients, without significant toxicity. These preliminary data suggest that low-dose cidofovir may be tolerated, even among renal transplant recipients with significant renal dysfunction due to BKVN. Prospective, controlled trials are warranted to further define the optimal dose, toxicity and potential role of cidofovir in renal transplant recipients with BK virus nephropathy.     

Page kidney following renal allograft biopsy - early recognition and treatment

Ultrasound- guided percutaneous allograft renal biopsy is commonly done to evaluate graft dysfunction. Complications of renal biopsy are usually minor, and major complications occur only in less than 1% cases. We report a case of allograft renal biopsy which caused a subcapsular hematoma, Page kidney and deterioration of graft function. This was diagnosed by computed tomography (CT) scan, and early surgical intervention led to complete recovery.     

Reversible acute renal allograft dysfunction due to gabapentin

BACKGROUND: The use of gabapentin as an effective analgesic agent for neuropathic pain has expanded considerably. Its lack of both anticholinergic side effects and interference with the metabolism of drugs via the cytochrome P450 pathway make it especially useful for transplant recipients. METHODS AND RESULTS: We describe the case of a renal transplant recipient with a long-term stable functioning allograft who developed reversible acute renal dysfunction after beginning gabapentin therapy for chronic pain due to diabetic neuropathy. CONCLUSIONS: We suggest that gabapentin may cause acute renal dysfunction by a mechanism involving renal afferent vasoconstriction. Caution should be employed when considering the use of gabapentin in transplant recipients, especially when combined with other agents that may potentiate renal vasoconstriction.     

Workshop on Late Renal Allograft Dysfunction

Despite continued improvement in incidence of acute immune injury and short-term graft survival, late allograft dysfunction remains a significant problem in the renal transplant population. Recent reports suggest that rates of renal function decline are quite varied in the overall recipient population, and that individual rates for many recipients may not change substantially over time. Moreover, analyses also reveal distinct predictive factors for both early and late functional decline. Long-term outcome studies for renal transplantation, however, might be significantly limited by incomplete data sets for assessing clinical endpoints. In view of the heterogeneous factors that may cause progressive allograft injury, more routine biopsy sampling would allow a more complete characterization of induced injuries. Elucidating mechanisms of renal fibrosis in response to injury, in experimental systems and humans, is also an important goal in better understanding chronic allograft damage. Regulation of cell senescence genes and epithelial to mesenchymal transition, studied in other models of renal fibrosis, are likely relevant to studies of renal allograft dysfunction. Recent technical advances in analyzing biological samples may play a pivotal role in identifying and validating surrogate markers of allograft function for future interventional trials in transplantation.     

Ultrasound-guided percutaneous ablation of a renal mass in a renal allograft

A 50-year-old man underwent magnetic resonance imaging and was found to have an incidental 3.2-cm mass in a renal allograft. Because of the multiple comorbidities associated with renal allograft patients, a minimally invasive option such as percutaneous ablation should be considered. The patient underwent percutaneous ultrasound-guided cryoablation. The final histopathologic examination of the needle biopsy was consistent with an oncocytic neoplasm. The 9-month follow-up contrast-enhanced magnetic resonance imaging scan showed no residual tumor. Long-term follow-up and greater clinical experience are still necessary to confirm the efficacy of cryoablation for allograft lesions.     

Successful treatment of Nocardia pneumonia with cytomegalovirus retinitis coinfection in a renal transplant recipient

Nocardiosis is a rare opportunistic infection, especially seen in immunocompromised patients, including renal allograft recipients. Primary pulmonary infection is the most common clinical pattern and can easily result in disseminated Nocardia infection if treatment therapy is not adequate at the beginning. We report a case of pulmonary nocardiosis associated with cytomegalovirus retinitis in a renal transplant recipient, followed by chronic allograft dysfunction. Our patient was a 50-year-old male renal allograft recipient, with diabetes mellitus and hypertension, who was diagnosed with pneumonia and cytomegalovirus retinitis. High-resolution computed tomography scan of the thorax and bronchoscopy revealed nocardial pneumonia. The patient responded well to ceftriaxone and was later switched to oral minocycline. To our knowledge, this is the first report of a successful treatment of co-infection with Nocardia pneumonia and cytomegalovirus retinitis in a renal transplant patient, with early diagnosis and prompt treatment.     

Combination fine-needle aspiration cytology and intrarenal manometry at the onset of renal dysfunction

Twenty-three consecutive cadaveric renal allograft recipients immunosuppressed with cyclosporin have been monitored three times a week by fine-needle aspiration cytology and intrarenal manometry until discharge from hospital or until 30 days post-transplant. Standard criteria were used to determine the cause of allograft dysfunction. The onset of allograft rejection was marked by an elevation of the total corrected increment score by fine-needle aspiration cytology in 80 per cent of rejection episodes whereas intrarenal pressure was raised in only 46.6 per cent. However, intrarenal pressure was greater than 40 mmHg on a single occasion in 16 measurements performed on allografts showing evidence of cyclosporin nephrotoxicity. By combining fine-needle aspiration cytology and intrarenal manometry the sensitivity of these tests for allograft rejection was increased to 93.3 per cent at the onset of renal dysfunction. Our results demonstrate that fine-needle aspiration cytology is more sensitive than intrarenal manometry as a single investigation. However, the combined test may have an important role in the differentiation of allograft rejection and cyclosporin nephrotoxicity in the early management of renal allograft recipients.     

Delayed renal allograft dysfunction and cystitis associated with human polyomavirus (BK) infection in a renal transplant recipient: a case report and review of literature

Human polyomavirus type BK (BKV) associated nephritis (BKVAN) has recently emerged as an important cause of renal allograft dysfunction and failure. Early recognition of this entity as a cause of allograft dysfunction is extremely important since misdiagnosis can accelerate graft loss. We report a case of BKVAN that presented with symptoms related to cystitis, and review the risk factors, the diagnostic tools and the approach to treatment of BK virus associated allograft nephropathy.     

Myoglobinuria masquerading as acute rejection in a renal allograft recipient with recurrent post transplant diabetic nephropathy

Rhabdomyolysis contributes to 7–10% of total AKI cases. Myoglobinuria as a cause of acute renal allograft dysfunction is extremely uncommon. Renal allograft recipient on cyclosporine or tacrolimus can develop myoglobinuria in presence of other precipitating factors. Present case describes an interesting report of myoglobinuria in a patient with post transplant diabetic nephropathy mimicking acute graft rejection. Clinically myoglobinuria presenting as renal allograft dysfunction is diagnosis of exclusion and renal biopsy is extremely important in making a correct diagnosis and planning optimal management in such cases.