Renal Cell Carcinoma in Kidney Allografts: A Case Series from a Single Center

In kidney transplant recipients, renal cell carcinoma (RCC) occurs either in the native kidney or, less frequently, in the grafted kidney. Here, we report a series of rare cases involving 5 patients from a single center who developed RCC in their grafts. The diagnosis was made serendipitously by ultrasound. The time lapse post-transplant varied from 4 to 17 years. Surgical treatment consisted of nephron-sparing surgery (NSS) in four cases and a secondary radical nephrectomy in one case. All tumors were less than 4 cm in diameter. The histopathology was clear cell type in four cases and papillary RCC in one case. Patients treated by NSS retained kidney function for 2 years or more, and none of them presented early neoplasia recurrence. In conclusion, NSS can be performed safely in grafted kidneys to treat incidental RCC. It prevents an immediate return to dialysis for patients.     

Expression of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 in Acute Rejection of Human Renal Allografts

Background

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed on various cell types and mediates homophilic cell adhesion. CEACAM1 plays an important role in cell morphogenesis and angiogenesis. Furthermore, CEACAM1 regulates adhesive activity of immune-competent cells, suggesting an additional role in inflammatory processes.

Methods

Therefore, in the present study the expression of CEACAM1 was analysed retrospectively in renal biopsies from kidney transplant recipients (stable graft [Ctr; n = 18], acute vascular rejection [AVR; n = 14], acute tubulointerstitial rejection [AIR; n = 9], and combined vascular and interstitial rejection [AVIR; n = 7]). Expression patterns of CEACAM1 were determined using immunohistochemistry and quantitative morphometry.

Results

All biopsy specimens from patients with stable grafts showed low CEACAM1 levels, suggesting a constitutive expression in renal transplants. In patients with acute rejection, CEACAM1 was markedly up-regulated. AVR revealed the highest tubular CEACAM1 levels (4.9 ± 0.5% [AVR] vs 2.2 ± 0.3% [Ctr] of tubular area; P < .05), whereas interstitial rejections showed the highest glomerular expressions (4.5 ± 0.5% [AIR] vs 0.9 ± 0.1% [Ctr] of glomerular area; P < .05).

Conclusions

An up-regulated expression of CEACAM1 in tubular and/or glomerular cells is an indicator of acute inflammatory processes in biopsy specimens from patients with acute renal allograft rejections and, therefore, might be used as a new clinical marker.     

Infiltrates in Protocol Biopsies from Renal Allografts

In renal transplantation, clinical decisions are based primarily on the Banff classification of biopsies. However, the incorporation of 'minor or nonspecific' cellular infiltrates into the Banff classification and their interpretation is uncertain. We analyzed 833 protocol and 306 indicated biopsies to test whether such infiltrates are harmless or whether they have a bearing on outcomes. We characterized morphology, localization and cellular composition of infiltrates, and correlated these findings to the Banff classification and allograft outcome. We found that protocol biopsies had the same prevalence of infiltrates as indication biopsies (87% vs. 87%). Diffuse cortical infiltrates, the hallmark of cellular rejection were more common in indication biopsies and related to tubulitis and a rise in serum creatinine. However, in biopsies with cellular rejection according to Banff criteria, we observed an increase in all infiltrate types (specific and nonspecific) and all cell types (T cells, B cells, histiocytes). The only predictor of allograft function outcome was persistent inflammation in sequential biopsies, irrespective of type, localization and composition of the cellular infiltrates. As detected by sequential biopsies, persistence of any inflammation including those infiltrates currently not considered by the Banff classification should be regarded as a morphological correlate of ongoing allograft damage.     

Avascular Necrosis in Cadaveric Renal Allografts1

While it has been known for many years that avascular necrosis of the femoral head can occur in the absence of any obvious æetiological factor, the proportion of patients receiving steroid therapy who develop this lesion, while low, is much higher than that in the adult population in general. This is a report of 6 such cases, occurring in a series of 34 patients with functioning renal grafts. The reasons for the development of the lesion are discussed, with special consideration of the possible role of infection in the ætiology.     

Early Function in Renal Allografts from Cadaver Donors

A low incidence of non-function in a series of 67 cadaveric renal transplants is reported. Methods of preservation of function in kidneys from cadaver donors are discussed. Of particular importance are the avoidance of prolonged ischemia, and the avoidance of transplantation in the presence of antibodies toxic to the donor's leucocytes.     

Subclinical Acute Antibody-Mediated Rejection in Positive Crossmatch Renal Allografts

Subclinical antibody-mediated rejection (AMR) has been described in renal allograft recipients with stable serum creatinine (SCr), however whether this leads to development of chronic allograft nephropathy (CAN) remains unknown. We retrospectively reviewed data from 83 patients who received HLA-incompatible renal allografts following desensitization to remove donor-specific antibodies (DSA). Ten patients had an allograft biopsy showing subclinical AMR [stable SCr, neutrophil margination in peritubular capillaries (PTC), diffuse PTC C4d, positive DSA] during the first year post-transplantation; 3 patients were treated with plasmapheresis and intravenous immunoglobulin. Three patients had a subsequent rise in SCr and an associated biopsy with AMR; 5 others showed diagnostic or possible subclinical AMR on a later protocol biopsy. One graft was lost, while remaining patients have normal or mildly elevated SCr 8-45 months post-transplantation. However, the mean increase in CAN score (cg + ci + ct + cv) from those biopsies showing subclinical AMR to follow-up biopsies 335 +/- 248 (SD) days later was significantly greater (3.5 +/- 2.5 versus 1.0 +/- 2.0, p = 0.01) than that in 24 recipients of HLA-incompatible grafts with no AMR over a similar interval (360 +/- 117 days), suggesting that subclinical AMR may contribute to development of CAN.     

Abdominal Aortic Aneurysm Repair in Patients with Renal Allografts

Aortic reconstruction is being reported in an increasing number of patients after renal transplantation as a result of improved renal graft survival and life expectancy. Aortic surgery in these patients places the pelvic allograft at risk for ischemic damage. We present two separate modalities that have been successfully used in protecting the renal transplant from prolonged warm ischemia during abdominal aortic aneurysm (AAA) repair in two cases. One technique involves an aortofemoral shunt using the perirenal aorta for proximal cannulation and the other technique utilizes an indwelling shunt through the prosthetic graft. Both patients had an uneventful recovery with no evidence of renal dysfunction and their renal function has been stable on long-term follow-up. These cases illustrate two useful alternatives in providing pulsatile perfusion to a transplanted kidney in the iliac fossa during AAA repair. They have been used successfully as simpler alternatives to temporary axillofemoral bypass or extracorporeal pump oxygenation in preventing postoperative renal dysfunction.     

Analysis of Renal Cell Populations Using Monoclonal Antibodies

Monoclonal antibodies have proved invaluable in identification and characterization of hemopoietic cell surface macromolecules. We have used a number of these monoclonal antibody probes for immunohistochemical analysis of interstitial cell populations in diseased human kidney tissues and in certain prototypic cutaneous cellular immune reactions. The studies demonstrate that the relative proportions of T-cell subpopulations present in graft rejection (OKT8⁺ exceeding OKT4⁺) differ from those observed in drug nephrotoxicity and end-stage kidney disease. In this regard graft rejection resembles graft versus host disease of skin but not delay ed-type hyper sensitivity. However, analysis of cell populations in interstitial infiltrates from various forms of chronic renal disease (glomerulonephritis, end-stage renal disease of varied etiologies) failed to demonstrate any unique or characteristic profile. These studies led to the recognition that certain monoclonal antibodies directed against B- and leukemic cell surface antigens also bind to normal renal cells and that nephron development in the human fetus is characterized by differential binding of these probes.     

Donor Age and Renal P-Glycoprotein Expression Associate with Chronic Histological Damage in Renal Allografts

The contributions of donor kidney quality (partially determined by donor age), allograft rejection, and calcineurin inhibitor nephrotoxicity on the progression of histologic damage of renal allografts are not completely defined. Moreover, the determinants of individual susceptibility to calcineurin inhibitor nephrotoxicity are not known but may include variability in drug transport and metabolism. In a prospective cohort of 252 adult renal allograft recipients treated with a combination of tacrolimus, mycophenolate mofetil, and corticosteroids, we studied 744 renal allograft biopsies obtained regularly from time of transplantation for 3 yr. We assessed determinants of histologic evolution, including tacrolimus exposure, renal P-glycoprotein (ABCB1) expression, and polymorphisms in the CYP3A4, CYP3A5, and ABCB1 genes. Within the first 3 yr after transplantation, we noted a progressive increase in interstitial fibrosis, tubular atrophy, glomerulosclerosis, and vascular intimal thickening. Older donor age, absence of P-glycoprotein expression at the apical membrane of tubular epithelial cells, and combined donor–recipient homozygosity for the C3435T variant in ABCB1 significantly associated with increased susceptibility to chronic allograft damage independent of graft quality at implantation. Changes in graft function over time reflected these associations with donor age and ABCB1 polymorphisms, but it was acute T cell-mediated and antibody-mediated rejection that determined early graft survival. In conclusion, the effects of older donor age reach beyond the quality of the allograft at implantation and continue to be important for histologic evolution in the posttransplantation period. In addition, ABCB1 genotype and expression of P-glycoprotein in renal tubular epithelial cells determine susceptibility to chronic tubulointerstitial damage of transplanted kidneys.Progressive renal allograft dysfunction resulting from cumulative histologic damage to the allograft is the major cause of late renal allograft loss after recipient death with a functioning graft.^1,2 The evolution of renal allograft histology therefore can be regarded as a valuable surrogate marker for long-term graft outcome.³ This evolution has been described in detail by Nankivell et al. using renal allograft biopsies obtained at preset time points after transplantation in kidneys of pristine quality at implantation.⁴ In this study, the kidneys were recovered from a selected group of relatively young donors, and the majority of recipients (kidney–pancreas transplants in all but 1) were treated with a combination of the older formulation of cyclosporine in combination with azathioprine and corticosteroids.⁴However, with the increasing use of kidneys from older or extended criteria donors for transplantation, poor graft quality at implantation emerges as an important determinant of long-term outcome.^5,6 Therefore, the experience of Nankivell et al. may no longer be representative for current clinical practice. In addition, immunosuppressive drug combinations have improved over the past few decades,^7,8 and this has an impact on both histologic and functional evolution of allografts.^9–11 On one hand, although the newer immunosuppressive protocols have reduced the incidence of acute cellular rejection, rejection phenomena continue to play a major role in this histologic evolution. On the other hand, immunosuppressive drugs can elicit direct (e.g., nephrotoxicity of calcineurin inhibitors) and indirect (diabetes mellitus, hyperlipidemia, and hypertension) side effects, which also contribute to renal allograft injury.^12,13The complementary impact of these phenomena (donor kidney quality, allograft rejection, and calcineurin inhibitor nephrotoxicity) on the progression of histologic allograft damage has not been studied in patients treated with the current powerful immunosuppressive protocols nor within the wide range of donor graft quality. Moreover, the determinants of individual susceptibility to calcineurin inhibitor nephrotoxicity are not well known. Previous animal and human studies have suggested a role of decreased P-glycoprotein (ABCB1 or MDR1, the multidrug efflux transporter involved in tacrolimus transport¹⁴) expression^15–17 or activity¹⁸ and genetic polymorphisms in ABCB1^19,20 in the development of calcineurin inhibitor nephrotoxicity.The current study was undertaken to assess the determinants of the histologic evolution of renal allografts in the first years after transplantation in 252 patients treated with a combination of tacrolimus, mycophenolate mofetil, and corticosteroids against a background of varying degrees of pre-existing histologic damage in the donor kidney at implantation.^8,11 In addition, the determinants of individual susceptibility to calcineurin inhibitor nephrotoxicity were evaluated, including extensive tacrolimus exposure data, P-glycoprotein expression, and polymorphisms in ABCB1, CYP3A4, and CYP3A5 of both donor and recipients. Finally, this study examined the features that predict lower MDRD glomerular filtration rate during follow-up and assessed the main determinants of early graft survival.     

免疫吸附治疗在肾移植致敏受者中的应用

目的：探讨蛋白A免疫吸附（immunoads Orption，IA）治疗对清除肾移植致敏受者体内特异性抗HLA抗体的疗效和安全性。方法：10例肾移植致敏（PRA〉50％）受者用彤新蛋白A免疫吸附柱行IA治疗，测定治疗前后血免疫球蛋白及PRA水平。结果：10例患者IA治疗次数为4～15次（中位数9）。所有患者IA治疗后血清总IgG水平都明显下降（P〈0．001），IgA和IgM也较治疗前显著降低（P〈0．01）。PRA8例转阴，1例〈30％，1例仍为100％。结论：对于肾移植致敏受者，IA是一种特异性高、安全有效的治疗措施。     

Characterization of Urinary Peptide Biomarkers of Acute Rejection in Renal Allografts

We previously demonstrated that 4.7 kDa and 4.4 kDa peptides are useful in diagnosing acute rejection in renal transplant recipients. The aim of this study was to characterize these polypeptides and assess their potential as biomarkers. The polypeptides were identified as human beta-Defensin-1 (4.7 kDa) and alpha-1-antichymotrypsin (4.4 kDa), by tandem mass spectrometry and ProteinChip immunoassay. The urinary abundance of both polypeptides, assessed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS), revealed a reduction in beta-Defensin-1 while alpha-1-antichymotrypsin increased in patients with rejection (p < 0.05) compared with clinically stable transplants. The area under the curve (AUC) for the receiver operator characteristic (ROC) curve for the diagnosis of rejection for the ratio of both peptides combined was 0.912. Longitudinal analysis confirmed a reduction in beta-Defensin-1 with a reciprocal increase in alpha-1-antichymotrypsin as rejection developed. The difference in urinary beta-Defensin-1 levels quantified by radioimmunoassay was 176.8 +/- 122.3 pg/mL in stable patients compared with 83.2 +/- 52.2 pg/mL in patients with acute rejection, with an ROC AUC of 0.749 (p < 0.01). Immunohistochemistry (IHC) confirmed reduced beta-Defensin-1 expression in the renal parenchyma of patients experiencing acute rejection. In conclusion, the ratio of beta-Defensin-1 and alpha-1-antichymotrypsin excretion in the urine is a novel, potentially useful candidate biomarkers of acute rejection.     

Misleading Diagnosis of Renal Artery Stenosis by Magnetic Resonance Angiography in a Patient with Primary Aldosteronism

A 24-year-old woman presented with severe hypertension. A diagnostic evaluation for secondary hypertension was undertaken. A duplex ultrasonography followed by a magnetic angiography suspected fibromuscular dysplasia. Unexpectedly, a contrast-enhanced angiography performed for renal angioplasty showed normal renal arteries. Primary aldosteronism was then evoked on the basis of decreased plasma renin and increased plasma aldosterone and aldosterone/renin ratio. After a CT-scan disclosed a left adrenal tumour, the patient underwent a left laparoscopic adrenalectomy. Pathological findings confirmed a benign adrenocortical adenoma. Blood pressure and aldosterone levels were normalized after surgery. Thus, clinicians should be aware of false-positive results of magnetic resonance angiography that could hide other causes of secondary hypertension.     

Fundamental Role for HO-1 in the Self-Protection of Renal Allografts

Tissue attenuates to injury by the effects of heme oxygenase (HO)-1. The induction of HO-1 expression is modulated by a (GT)(n) dinucleotide polymorphism in the promoter of the gene, of which increased activity is associated with short (S) (27 repeats). Graft survival was associated with donor and not with recipient HO-1 gene polymorphism (log rank p = 0.005; hazard ratio 0.51, 95% CI 0.32-0.83). The beneficial effect of the donor HO-1 genotype was observed in grafts exposed to prolonged cold ischemia time and acute rejection. Patients who received a kidney from L-homozygotes lost their graft significantly more often to chronic allograft nephropathy (CAN) than carriers of S-alleles (p = 0.015). Multivariate analysis showed reduced risk for graft failure in kidneys with S-alleles in comparison to L-homozygotes (odds ratio 0.50, 95% CI 0.27-0.93, p = 0.03). Kidneys that are carriers of HO-1 S-allele are less vulnerable to tissue injury resulting in less CAN and better graft survival.     

Three-Month Experience With Tacrolimus Once-Daily Regimen in Stable Renal Allografts

Introduction

MR-4, the new oral formulation of tacrolimus that allows once-daily dosing, may improve patient compliance. The purpose of this study was to evaluate the safety and efficacy parameters among a group of stable renal allografts after conversion to MR-4.

Methods

We enrolled 82 stable kidney recipients, who had received their grafts 43.9 ± 38.3 months prior. They were of mean age 56 ± 12 years and included 70.7% men. Sixty-six patients were converted on a milligram-for-milligram basis from their total daily dose; the remaining patients were converted at the physician's discretion. Three patients were excluded: 1 because of the development of abdominal pain, and 2 because of dosing errors. Tacrolimus trough levels and renal function tests were evaluated at entry and on days 7, 30, and 90.

Results

Only 5 (7.6%) converted patients required a later dose adjustment. In the group of 61 patients who did not require this adjustment, the mean tacrolimus trough levels decreased during the first week (6.8 ± 1.7 to 5.8 ± 2.0; P < .000). Thirty-eight patients completed 3 months of follow-up. Their tacrolimus trough levels, serum creatinine levels, and proteinuria remained stable. The number of capsules per patient needed after the conversion to MR-4 was lower (3.9 ± 1.6 versus 2.9 ± 1.0; P < .000). There were no cases of acute rejection episodes.

Conclusion

Based on a milligram-for-milligram conversion, only 7.6% of our patients required a dose adjustment. With this conversion, an initial decrease in tacrolimus trough levels was documented at day 7, which remained stable to the end of the study. The patients needed a lower number of capsules. These results supported the safety of MR-4.     

Localization, Etiology and Impact of Calcium Phosphate Deposits in Renal Allografts

Hypercalcemia, hypophosphatemia and renal phosphate wasting are common after kidney transplantation. Animal data suggest that these alterations in mineral metabolism may contribute to calcium phosphate (CaPhos) deposition in the kidney and renal dysfunction. We tested the hypothesis that CaPhos deposition is highly prevalent in the early posttransplant period and is related to a disturbed mineral metabolism. For this purpose, biomarkers of mineral metabolism and renal calcium and phosphorus handling were prospectively assessed in 201 renal transplant recipients. CaPhos deposits were observed in 4.6, 30.4 and 24.7% of protocol biopsies obtained at the time of engraftment, and 3 and 12 months thereafter, respectively. In multivariate logistic regression analysis, high calcium and low serum phosphorus levels were independently associated with renal CaPhos deposition at month 3. The extent of CaPhos deposition correlated significantly with the severity of mineral metabolism disturbances. Renal function after a mean follow-up of 33 months was similar in patients with and without CaPhos deposition at month 3. In conclusion, our data demonstrate that CaPhos deposition is highly prevalent in the early posttransplant period and suggest that a disordered mineral metabolism is implicated in its pathogenesis. The clinical relevance of CaPhos deposition remains to be established.     

Cytomegalovirus-Induced Glomerular Vasculopathy in Renal Allografts: A Report of Two Cases

Cytomegalovirus (CMV) remains a major viral pathogen complicating renal transplantation. Tubulointerstitial nephritis is the commonly acknowledged and well-characterized pathologic feature of renal allograft CMV disease. There is controversy about whether there is a distinct entity as a CMV glomerulopathy in the absence of tubulointerstitial disease. We describe two patients with renal allograft dysfunction who displayed distinct features of CMV glomerular vasculopathy, in the absence of overt viral cytopathic changes involving the tubules.     

Renal Angiography During Halothane Anaesthesia in the Dog

An Hunden wurde das renovaskuläre Verhalten unter dem Einfluß von Halothan angiographisch studiert. Die Tiere wurden in einem halboffenen Narkosesystem mit 2% Halothan in 5 1 Sauerstoff/min anaesthesiert. Die selektive, renale Angiographic wurde 30-40 Minuten nach Beginn der Halothannarkose und vorangehender Hyperventilation mit dem beschriebenen Narkosegasgemisch vorgenommen. Es kam in jedem Fall zu einer arteriellen Hypotonic, ebenso wie zu einer respiratorischen Azidose, welche durch Hyperventilation beseitigt wurde. Die renalen Präarteriolen reagierten unter der Halothannarkose mit einer Vasodilation. Es scheint gerechtfertigt anzunehmen, daß diese Vasodilation, unabhängig von der variablen Zusammensetzung der Blutgase und des Blut-pH-Wertes, ein direkter oder indirekter Effekt des Halothans ist.