Anke Schwarz

Safety and Adequacy of Renal Transplant Protocol Biopsies

The protocol biopsy strategy has been criticized because of risks and marginal utility. We tested the risk.

Early Calcification of Renal Allografts Detected by Protocol Biopsies: Causes and Clinical Implications

Interstitial calcification has been described in renal allografts, however, the etiology and significance of this finding for the graft are unclear. The aim of this study was to examine calcification in serial protocol biopsies, to test the hypothesis that calcification is related to parameters of calcium homeostasis in these patients and to analyze a possible relation between calcification and graft function at 1 year. We studied 213 patients with 586 protocol biopsies obtained 6 weeks, 3 and 6 months after transplantation. Calcifications increased over time, from 6.1% at 6 weeks to 17.8% at 6 months. Out of the 213 patients, 56 had calcification in one or more biopsies. Patients age and gender, underlying renal disease, dialysis mode and duration, previous transplantations, donor type, age and gender, HLA matches and ischemia time had no influence on calcification. Calcification was not related to rejection episodes, acute tubular lesions, calcineurin inhibitor toxicity or tubulointerstitial fibrosis and tubular atrophy. Patients with calcification had significantly higher serum parathormone and calcium levels. In patients with calcification, high PTH levels correlated with an inferior outcome of graft function at 1 year after transplantation (p < 0.05). Therefore, treatment of hyperparathyroidism should be considered earlier and more often in these patients.

Protocol biopsy of the stable renal transplant: a multicenter study of methods and complication rates.

Background. Clinical trials in renal transplantation must use surrogate markers of long-term graft survival if conclusions are to be drawn at acceptable speed and cost. Morphologic changes in transplant biopsies provide the earliest available evidence of damage, and “protocol” biopsies from stable grafts can be used to reduce the number of patients needed in clinical trials. This approach has been inhibited by concerns over safety, but the risk of biopsy of a stable kidney, with no active inflammation or acute functional impairment, has never been formally estimated. Methods. In accordance with a predefined set of questions, a retrospective audit of a sequential series of protocol biopsies was performed in four major transplant centers. Results. A total of 2,127 biopsy events were assessed for major complications, and 1,486 were assessed for minor ones. There were no deaths. One graft was lost, under circumstances indicating that the loss should have been prevented. Three episodes of hemorrhage required direct intervention. Three further patients required transfusion. There were two episodes of peritonitis, but one was arguably an unrelated event. All serious complications presented within 4 hr of biopsy. Conclusions. The incidence of clinically significant complications after protocol biopsy of a stable renal transplant is low. Direct benefits to the patients concerned (irrespective of the benefit that may accrue in clinical trials) were not formally assessed but seem likely to outweigh the risk of the procedure. We believe that it is ethically justifiable to ask renal transplant recipients to undergo protocol biopsies in clinical trials and routine care.

Incidence of C4d Stain in Protocol Biopsies from Renal Allografts: Results from a Multicenter Trial

C4d staining of renal allografts is regarded as an in situ marker of active humoral rejection. Few data are available about the incidence of C4d deposition in protocol biopsies compared to indication biopsies. To evaluate whether center‐specific factors influence the incidence of C4d detection, we performed a multicenter study. From three European centers, 551 protocol and 377 indication biopsies were reclassified according to the updated Banff criteria and stained for C4d. C4d results were recorded as diffuse or focal positive and statistically correlated to clinical parameters, morphology and graft survival. In the protocol biopsies, a diffuse C4d stain was found in 2.0%, and a focal stain in 2.4%. In indication biopsies, 12.2% were diffusely and 8.5% focally C4d positive (protocol:indication p < 0.0001). The incidence of C4d deposition varied significantly between centers, attributable to variable numbers of presensitized patients with more C4d positive indication and protocol biopsies. Diffuse and focal C4d stain correlated with morphology of humoral rejection in protocol as well as in indication biopsies. Protocol biopsies show a significantly lower incidence of C4d deposition than indication biopsies. Subclinical C4d detection in protocol biopsies had no significant impact on allograft survival in our series.

Detection of Acute Tubulointerstitial Rejection by Proteomic Analysis of Urinary Samples in Renal Transplant Recipients

This study investigates proteomic analysis of urinary samples as a non‐invasive method to detect acute rejection of renal allografts.

Renal Cell Carcinoma in Transplant Recipients with Acquired Cystic Kidney Disease

BACKGROUND Acquired cystic kidney disease (ACKD) is a widely known renal cell carcinoma risk factor. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS An ultrasound screening of the native kidneys in all renal transplant patients of a renal outpatient clinic who received a transplant between 1970 and 1998 and presented between 1997 and 2003 (n = 916) was initiated prospectively. A total of 561 patients were screened. RESULTS A total of 129 (23%) patients had ACKD; 46 (8.2%) patients had complex renal cysts (Bosniak classification, category IIF to III); and eight (1.5%) patients had newly diagnosed renal cell carcinoma, seven of which were associated with ACKD (category IV). One patient had renal cell carcinoma in the transplanted kidney. Together with 19 patients of the cohort with formerly diagnosed renal cell carcinoma (18 of them associated with ACKD), the prevalence of renal cell carcinoma among all patients was 4.8%; among the patients with ACKD, it was 19.4% (without ACKD 0.5%; P = 0.0001); and among the patients with complex renal cysts (category IIF to III), it was 54.4%. The patients with ACKD were older (54 +/- 13 versus 51 +/- 14 yr; P = 0.048), more often male (65 versus 54%; P = 0.03), more often had heart disease (44 versus 29%; P = 0.001), had larger kidneys (6.9 and 6.8 cm versus 6.0 and 5.9 cm; P < 0.001), and had more calcifications (29 versus 15%; P = 0.002). Renal cell carcinoma was bilateral in 26% of cases. Tumor histology was clear cell carcinoma in 58% and papillary carcinoma in 42% of cases; one patient had both. Only one patient had a lung metastasis, and no patient died. CONCLUSIONS Renal cell carcinoma occurs often after renal transplantation and that especially patients with ACKD should routinely be screened. Because ACKD after renal transplantation seems to be less frequent (23%) than during dialysis treatment (30 to 90%), renal transplantation may inhibit renal cell carcinoma.

Protocol biopsies in renal transplantation: Insights into patient management and pathogenesis

A 1‐day symposium on the application of protocol biopsies in renal transplantation was held in Boston, 21 July 2006. Representatives from centers with extensive experience in the use of protocol biopsies for routine patient care and research reported results on the pathological findings and their value in patient management. The consensus was that protocol biopsies, in experienced hands, are a safe and valuable means of detecting subclinical disease that can benefit from modification of therapy. Furthermore, molecular studies reveal evidence of activity or progression not readily appreciated by histological techniques. Wider application is expected in multicenter clinical trials to predict and validate outcomes. The principal barrier to wider use of protocol biopsies is knowledge of the benefits of intervention.

The effect of cyclosporine on the progression of human immunodeficiency virus type 1 infection transmitted by transplantation-data on four cases and review of the literature

Two women and two men were infected with the human immunodeficiency virus type 1 (HIV-1) transmitted by renal transplantation from i.v. drug-addicted donors in 1984. The four recipients were treated with cyclosporin and methylprednisolone (one patient only for three months because of early graft failure). Two patients died 66 and 74 months after transplantation, one of endocarditis and one of cerebral hemorrhage. Despite several infections including urinary tract infection (n=8), peritonitis (n=1), shunt infection (n=1), bronchitis (n=1), salmonellosis (n=1), herpes stomatitis (n=2), herpes zoster (n=1), and cytomegalovirus (n=1), and despite treatment of several rejection episodes (n=8), none of them had or has infections typical of the acquired immunodeficiency syndrome (AIDS). However, two patients developed cervical lymphadenopathy and one.

Recurrent and De Novo Renal Disease After Kidney Transplantation With or Without Cyclosporine A

We evaluated the clinical course of 700 renal transplantations, including 1,305 transplant histologies performed in 611 patients between 1970 and 1988, to estimate the influence of cyclosporine A (CsA) after kidney transplantation on the incidence of recurrent or de novo renal disease. Primary renal disease recurred in 11 of 583 functioning transplants (1.9%) with transplant loss in seven patients (1.2%): focal segmental glomerulosclerosis (FSGS, three patients); membranous glomerulonephritis (GN, one patient); mesangiocapillary GN (one patient); rapidly progressive IgA nephropathy (one patient); hemolytic-uremic syndrome (HUS, three patients); and oxalosis in two transplants (one patient). De novo renal disease occurred in six patients (1.0%), including mesangiocapillary GN type I (three patients); nonpurulent focal GN in septicemia (one patient); HUS (one patient); and nodular glomerulosclerosis in steroid diabetes (one patient). De novo membranous GN was seen in 14 additional cases (2.4%). No statistically significant difference could be established between the treatment groups without (n = 225) and with (n = 358) CsA in recurrent and de novo renal disease (n = 7/225 v 10/358, NS); in recurrent and de novo GN (n = 4/225 v 6/358, NS); in recurrent FSGS (n = 1/7 v 2/8, NS); in recurrent and de novo HUS (n - 1/1 v 2/7, NS); and in de novo membranous GN (n = 7/225 v 7/358, NS). Transplant loss by recurrent and de novo GN was higher without than with CsA (n = 4/4 v 1/6, P = 0.004). On the basis of our investigation, we conclude that recurrent and de novo renal disease in the transplant occur rarely and are not prevented by CsA. However, even if the incidence of transplant GN is unchanged by CsA treatment, its clinical course seems to be mitigated. CsA treatment also does not increase the incidence of HUS.

Elevated numbers of circulating endothelial cells in renal transplant recipients

Background. Damage of microvascular endothelial cells is a salient feature of acute vascular rejection and chronic allograft nephropathy, yet specific blood markers of ongoing endothelial injury are currently unavailable. Circulating endothelial cells have recently been established as a novel marker of endothelial damage in a variety of vascular disorders. Methods. We studied 129 renal transplant recipients who underwent percutaneous graft biopsy. Circulating endothelial cells were isolated with immunomagnetic anti‐CD146‐coated Dynabeads. Cells were stained with acridine and counted. To verify their endothelial origin, staining for Ulex europaeus lectin 1 (UEA‐1) was performed in parallel. Twenty‐one healthy controls were also studied. Results. On biopsy, seven patients had acute vascular rejection, 15 patients had acute tubulointerstitial rejection, 14 patients had borderline rejection, and 93 patients had no rejection. Patients with acute vascular rejection had the highest cell numbers (72±39 cells/mL) when compared with all other patients (P<0.02). Regardless of their biopsy findings, however, all other renal transplant recipients had significantly higher numbers of circulating endothelial cells (25±20 cells/mL) than healthy controls (7±5 cells/mL, P<0.001). Finally, there was a significant correlation of cell numbers and serum cyclosporine A trough levels. By contrast, there was no correlation with serum creatinine, age, or the number of immunosuppressive drugs. Conclusions. The number of circulating endothelial cells is a novel marker of endothelial damage in renal transplant recipients. Further studies must now evaluate the origin of these cells, corroborate the clinical significance of our findings, and delineate the influence of calcineurin inhibitors.