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Background: Diarrhea of unspecified cause frequently occurs after renal transplantation and is usually ascribed to mycophenolic acid toxicity. Norovirus (NoV) and sapovirus (SaV) have been sporadically reported to cause chronic diarrhea in immunocompromised patients., Methods: We undertook a retrospective study (2008-2009) to examine the clinical and epidemiologic significance of NoV and SaV infections in adult renal transplant recipients hospitalized for acute or chronic diarrhea., Results: Ninety-six renal transplant recipients were hospitalized for diarrhea at our institution during a 16-month period, 87 of whom were included in the study, including 46 patients with chronic diarrhea. Among 41 patients with unexplained diarrhea, 20 patients were screened for NoV/SaV, 16 of whom were positive. Fifteen of them (94%) had chronic diarrhea. When compared with bacterial and parasitic infections, NoV/SaV infections were associated with a greater weight loss at the time of admission, a 8.7-fold longer duration of symptoms and a more frequent need for mycophenolic acid dosage reduction. Eighty-one percent of patients hospitalized for NoV/SaV-associated diarrhea experienced acute renal failure. Five and one patients subsequently had biopsy-diagnosed active graft rejection and oxalate nephropathy, respectively. Ten of the 14 patients who underwent a longitudinal study of NoV/SaV stool's clearance exhibited a prolonged viral shedding period with a median time of 289 days (107-581 days)., Conclusions: Our study indicates that NoV/SaV infection causes posttransplant chronic diarrhea potentially complicated by severe kidney graft impairment.

In heart transplants, the significance of very late rejection (after 7 years post-transplant, VLR) detected by routine endomyocardial biopsies (EMB) remains uncertain. Here, we assessed the prevalence, histopathological and immunological phenotype, and outcome of VLR in clinically stable patients. Between 1985 and 2009, 10 662 protocol EMB were performed at our institution in 398 consecutive heart transplants recipients. Among the 196 patients with >7-year follow-up, 20 (10.2%) presented subclinical ≥3A/2R-ISHLT rejection. The VLR group was compared to a matched control group of patients without rejection. All biopsies were stained for C4d/C3d/CD68 with sera screened for the presence of donor-specific antibodies (DSAs). In addition to cellular infiltrates with myocyte damage, 60% of VLR patients had evidence of intravascular macrophages. C4d and/or C3d-capillary deposition was found in 55% VLR EMB. All cases of VLR associated with microcirculation injury had DSAs (mean DSA(max) -MFI = 1751 ± 583). This entity was absent from the control group (p < 0.0001). Finally, after a similar follow-up postreference EMB of 6.4 ± 1 years, the mean of CAV grade was 0.76 ± 0.18 in the control group compared to 2.06 ± 0.26 in the VLR group respectively, p = 0.001). There was no difference in patient survival between study and control groups. In conclusion, VLR is frequently associated with complement-cascade activation, microvascular injury and DSA, suggesting an antibody-mediated process. VLR is associated with a dramatic progression to severe CAV in long-term follow-up., (©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

In biopsies of renal allografts, arteriosclerosis is often more severe than expected based on the age of the donor, even without a history of rejection vasculitis. To determine whether preformed donor-specific antibodies (DSAs) may contribute to the severity of arteriosclerosis, we examined protocol biopsies from patients with (n=40) or without (n=59) DSA after excluding those with any evidence of vasculitis. Among DSA-positive patients, arteriosclerosis significantly progressed between month 3 and month 12 after transplant (mean Banff cv score 0.65 ± 0.11 to 1.12 ± 0.10, P=0.014); in contrast, among DSA-negative patients, we did not detect a statistically significant progression during the same timeframe (mean Banff cv score 0.65 ± 0.11 to 0.81 ± 0.10, P=not significant). Available biopsies at later time points supported a rate of progression of arteriosclerosis in DSA-negative patients that was approximately one third that in DSA-positive patients. Accelerated arteriosclerosis was significantly associated with peritubular capillary leukocytic infiltration, glomerulitis, subclinical antibody-mediated rejection, and interstitial inflammation. In conclusion, these data support the hypothesis that donor-specific antibodies dramatically accelerate post-transplant progression of arteriosclerosis., (Copyright © 2011 by the American Society of Nephrology)

IgA nephropathy (IgAN) often shows lesions morphologically identical with those of focal segmental glomerulosclerosis (FSGS). In order to determine the possible role of FSGS in IgAN lesions, we measured glomerular capsular adhesions, often the first step toward FSGS, in biopsies from 127 patients with IgAN, 100 with lupus nephritis, and 26 with primary FSGS. Capsular adhesions with no lesions in the underlying tuft, consistent with podocyte abnormality or loss, were found regularly in FSGS and IgAN, but infrequently in lupus. Fifteen biopsies of patients with IgAN were studied immunohistochemically using markers for podocytes, Bowman's parietal epithelial cells, proliferating cells, and macrophages. Cytokeratins CK-8 and C2562 differentiated normal podocytes (negative) from parietal epithelial cells (variably positive). There was focal loss of the podocyte markers synaptopodin, glomerular epithelial protein 1 (GLEPP-1), nephrin, and vascular endothelial growth factor (VEGF), particularly at sites of capsular adhesions in otherwise histologically normal glomeruli. Cells displaying the parietal epithelial cell markers PAX2 (paired box gene 2) and the cytokeratins were also positive for the proliferating cell marker, proliferating cell nuclear antigen. These cells gathered at sites of adhesion, and in response to active lesions in the tuft, grew inward along the adhesion onto the tuft, forming a monolayer positive for parietal markers and the podocyte marker Wilms tumor protein-1 (WT-1). These cells deposited a layer of collagen over the sclerosing tuft. Thus, all biopsies of patients with IgAN had changes basically identical to those classically described in FSGS. Hence, our study strongly suggests that podocytopathy of a type similar to that in primary FSGS occurs frequently in IgAN.

It is well known that lesions morphologically identical with focal segmental glomerulosclerosis (FSGS) may appear in IgA nephropathy (IgAN). Capsular adhesions without underlying abnormalities in the tuft, often the first sign of FSGS, are frequent in IgAN. In this retrospective study, a new cohort of 128 adult patients with IgAN was used to validate the new Oxford classification system of IgAN, and shown to have highly significant associations with clinical and outcome parameters. We then used these patients to determine the extent to which IgAN could be accounted for in terms of FSGS. Some form of lesion consistent with FSGS, notably hyalinosis and collapsing glomerulopathy, was found in 101 of these patients. No glomerular lesions were found in 16 patients, and 11 had mild lesions not definable as FSGS. Those with FSGS had significantly worse renal survival at 80 months than those without. Comparison of pure forms of FSGS (excluding collapsing glomerulopathy) with cases of FSGS having other glomerular lesions (mesangial hyperplasia, endocapillary hypercellularity, glomerular necroses, extracapillary proliferation) revealed that those with FSGS and other superimposed lesions did significantly worse than cases of pure FSGS at 80 months following diagnosis. Importantly, patients with pure FSGS had relatively poor survival even without other superimposed glomerular abnormalities. Thus, the majority of cases of IgAN can be interpreted as representing one or another variant of FSGS. Hence, interpreting IgAN in terms of FSGS emphasizes the role that podocyte lesions may play in the pathogenesis and progression of this disease.

The significance of C4d-Banff scores in protocol biopsies of kidney transplant recipients with preformed donor-specific antibodies (DSA) has not been determined. We reviewed 157 protocol biopsies from 80 DSA+ patients obtained at 3 months and 1 year post-transplant. The C4d Banff scores (1,2,3) were associated with significant increments of microcirculation inflammation (MI) at both 3 months and 1 year post-transplant, worse transplant glomerulopathy and higher class II DSA-MFI (p < 0.01). Minimal-C4d had injury intermediate between negative and focal, while focal and diffuse-C4d had the same degree of microvascular injury. A total of 54% of patients had variation of C4d score between 3 months and 1 year post-transplant. Cumulative (3 month + 1 year) C4d scores correlated with long-term renal function worsening (p = 0.006). However, C4d staining was not a sensitive indicator of parenchymal disease, 55% of C4d-negative biopsies having evidence of concomitant MI. Multivariate analysis demonstrated that the presence of MI and class II DSA at 3 months were associated with a fourfold increased risk of progression to chronic antibody-mediated rejection independently of C4d (p < 0.05). In conclusion, the substantial fluctuation of C4d status in the first year post-transplant reflects a dynamic humoral process. However, C4d may not be a sufficiently sensitive indicator of activity, MI and DSA being more robust predictors of bad outcome., (©2010 The Authors Journal compilation©2010 The American Society of Transplantation and the American Society of Transplant Surgeons.)

IgA nephropathy is the primitive glomerulonephritis the most frequently encountered worldwide. In about one case out of three, it is responsible for the progression from progressive renal failure to end-stage renal failure. The pathophysiological mechanisms of this disease which is mediated by immune complexes remain unclear. The presentation, clinical progression and optical microscope aspect of the renal biopsy may widely vary, making any histological classification very difficult. Most therapeutic studies include the patients only on clinical criteria of severity. The only consensual management is that of patients with a nephropathy and mild glomerular lesions and a nephritic syndrome, or with an extracapillar glomerulonephritis and a rapidly progressive renal failure; corticoids are indicated in former cases while corticoids must be combined with immunosuppressive agents in the latter ones. Corticotherapy may be considered in patients with a proteinuria higher than 1g/day without renal failure. In any patient with primitive IgA nephropathy, the overall management used for chronic glomerulopathy must be initiated, including, in case of arterial hypertension or proteinuria, the renin-angiotensin system blockade., (Copyright © 2010 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.)

The clinical importance of preexisting HLA antibodies at the time of transplantation, identified by contemporary techniques, is not well understood. We conducted an observational study analyzing the association between preexisting donor-specific HLA antibodies (HLA-DSA) and incidence of acute antibody-mediated rejection (AMR) and survival of patients and grafts among 402 consecutive deceased-donor kidney transplant recipients. We detected HLA-DSA using Luminex single-antigen assays on the peak reactive and current sera. All patients had a negative lymphocytotoxic cross-match test on the day of transplantation. We found that 8-year graft survival was significantly worse (61%) among patients with preexisting HLA-DSA compared with both sensitized patients without HLA-DSA (93%) and nonsensitized patients (84%). Peak HLA-DSA Luminex mean fluorescence intensity (MFI) predicted AMR better than current HLA-DSA MFI (P = 0.028). As MFI of the highest ranked HLA-DSA detected on peak serum increased, graft survival decreased and the relative risk for AMR increased: Patients with MFI >6000 had >100-fold higher risk for AMR than patients with MFI <465 (relative risk 113; 95% confidence interval 31 to 414). The presence of HLA-DSA did not associate with patient survival. In conclusion, the risk for both AMR and graft loss directly correlates with peak HLA-DSA strength. Quantification of HLA antibodies allows stratification of immunologic risk, which should help guide selection of acceptable grafts for sensitized patients.

Background: This study assesses the immunologic, functional, and histologic course of kidney recipients with preformed donor-specific alloantibodies (DSA) receiving deceased donor kidneys according to two prophylactic strategies that have been sequentially applied posttransplant., Methods: The first strategy combined posttransplant quadritherapy/intravenous immunoglobulin (group 1, n=36) and the second added to the above protocol anti-CD20/plasmapheresis (group 2, n=18). All patients had a concomitant evaluation of glomerular filtration rate, protocol biopsies, and DSA mean intensity of fluorescence (MFI) at 3 month and 1 year posttransplant., Results: Peak and day-0 class-I or II DSAmax-MFI were similar in both groups. The rate of acute antibody-mediated rejection (AMR) was similar in both groups (19.6% vs. 16.6%, respectively). At 1 year posttransplant, group 2 was characterized by lower microcirculation inflammation lesions (glomerulitis+capilaritis score of 1.8+/-0.2 vs. 2.7+/-0.2, respectively, P=0.03), a lower rate of transplant glomerulopathy (7% vs. 38%, P=0.02), and a lower rate of chronic AMR (41.3% vs. 13.3%, respectively, P=0.03). The decline in DSA-MFI from day 0 to 1 year was 44%+/-13% in group 1 compared with 80%+/-8% in group 2 (P=0.02). Finally, the 1-year glomerular filtration rate was 43+/-16 vs. 54+/-16 mL/min/1.73 m(2) in groups 1 and 2, respectively (P=0.04)., Conclusion: This study raises the possibility that a more intensive day 0 prophylactic immunosuppressive strategy combining intravenous immunoglobulin/anti-CD20/plasmapheresis in this high-risk population, despite similar rates of early acute clinical humoral rejection, is associated with significant differences in long-term function and chronic AMR rate. Future prospective randomized studies are needed to assess the best strategies to be applied in light of the pretransplant immunologic risk stratification.

Persistence of donor-specific anti-HLA antibodies (DSA) associated with antibody-mediated graft injuries following kidney transplantation predicts evolution toward chronic humoral rejection and reduced graft survival. Targeting plasma cells, the main antibody-producing cells, with the proteasome inhibitor bortezomib may be a promising desensitization strategy. We evaluated the in vivo efficacy of one cycle of bortezomib (1.3 mg/m(2)x 4 doses), used as the sole desensitization therapy, in four renal transplant recipients experiencing subacute antibody-mediated rejection with persisting DSA (>2000 [Mean Fluorescence Intensity] MFI). Bortezomib treatment did not significantly decrease DSA MFI within the 150-day posttreatment period in any patient. In addition, antivirus (HBV, VZV and HSV) antibody levels remained stable following treatment suggesting a lack of efficacy on long-lived plasma cells. In conclusion, one cycle of bortezomib alone does not decrease DSA levels in sensitized kidney transplant recipients in the time period studied. These results underscore the need to evaluate this new desensitization agent properly in prospective, randomized and well-controlled studies.

Purpose: Septic shock is one of the leading causes of acute kidney injury. The mechanisms of this injury remain mostly unknown notably because of the lack of data on renal histological lesions in humans., Methods: Kidney biopsy was performed immediately post-mortem in consecutive patients who died of septic shock. Comparisons were made with specimens from eight patients who died of trauma on scene and nine ICU patients that died of non-septic causes., Results: Nineteen septic patients were included, 11 were male, and age was 72 +/- 12 years. Anuria occurred in all patients 2.2 +/- 1.4 days before death. Seven patients had disseminated intravascular coagulation. In all patients we observed (1) acute tubular lesions whose intensity correlated with blood lactate concentration; (2) intense infiltration by leukocytes, mainly monocytic, in glomeruli and interstitial capillaries as compared to controls; (3) presence of tubular cell apoptosis proved by the presence of apoptotic bodies (2.9% of tubular cells) significantly more frequently than in controls and confirmed by TUNEL and activated caspase-3 staining. Arteriolar/arterial thromboses were observed in only 4 of 19 patients, without any association with presence of disseminated intravascular coagulation., Conclusions: Kidney lesions in septic shock go beyond those associated with simple acute tubular injury, notably capillary leukocytic infiltration and apoptosis. Vascular thrombosis, however, did not appear to play a major role in the majority of patients. The extent to which these lesions are specific to sepsis or are common to all multi-organ failure independent of its cause is yet to be elucidated. Electronic supplementary material The online version of this article (doi:10.1007/s00134-009-1723-x) contains supplementary material, which is available to authorized users.

Purpose of Review: Terminology for posttransplant renal arterial lesions is confusing, with multiple terms being applied, the more common among them being the comprehensive terms, transplant arteriosclerosis and transplant atherosclerosis; endarteritis, for intimal lesions with an inflammatory component; and finally for advanced lesions with or without intimal inflammation, transplant arteriopathy. However, these latter lesions may present the appearance of banal arteriosclerosis, albeit more advanced expected on the basis of donor age. This review explores the distinctions to be drawn among these various descriptive terms., Recent Findings: Cell-mediated arterial lesions due to T-cell cell-endothelial interactions and antibody-mediated lesions, due to antiendothelial cell antibodies, show many common features: myofibroblasts, some of recipient origin, laying down extracellular matrix. However, they differ in that cell-mediated intimal lesions initially have a prominent leukocytic component, usually absent in antibody-mediated lesions. The antibodies most frequently implicated are antihuman leukocyte antigen class I and class 2 antibodies. With the exception of a sometimes more cellular intima and initial absence of dense collagen and elastic fibers, these latter lesions resemble those of arteriosclerosis of aging., Summary: Many instances of lesions designated as transplant arteriopathy are morphologically similar or identical to typical renal arteriosclerosis and could equally be regarded as accelerated arteriosclerosis.

Background: The relevance of borderline change (BL) and subclinical cellular rejection (SCR) observed in renal transplantation remains to be determined. Several studies have shown in BL and SCR the presence of a Th1 immune response, qualitatively similar to but quantitatively reduced in comparison with infiltrates typical of acute cellular rejection (ACR)., Methods: To elucidate the role of regulatory T cells (Tregs) in the local control of the allogenic response, we studied their presence by immunohistochemistry in 24 biopsies with graft dysfunction (12 ACR and 12 BL) and in 16 protocol biopsies at 1 year (eight SCR and eight subclinical BL)., Results: The proportion of Tregs in CD4 T infiltrates was higher in BL and SCR when compared with ACR. Moreover, their presence was correlated with the intensity of interstitial inflammation (r=-0.35, P=0.027, n=40) and with graft function at the time of the biopsy (r=-0.37, P=0.018, n=40)., Conclusion: These data suggest Treg recruitment at the acute phase of the allogenic response, where they could act to diminish the interstitial inflammation and its associated lesions.

Henoch-Shönlein purpura (HSP) is an immunoglobulin A (IgA) vasculitis that affects the small vessels. It is a multi-organ system disease that may include cutaneous purpura, arthralgia, acute enteritis and nephritis. Nephritis is characterized by mesangial proliferation with IgA deposits. Neurological, pulmonary, cardiac or genitourinary complications occur rarely. The acute stage progresses by successive flare-ups of limited duration. Although the cause is unknown, it is clear that IgA plays a central role in the immunopathogenesis of HSP. The syndrome usually affects children in which evolution is generally favourable. In adults the disease is rare and seems different from children with much more severe manifestations and prognosis. Short-term outcome, in children as in adults, depends on the severity of gastrointestinal manifestations. Long-term outcome depends on renal involvement. In studies with enough observation time, as much as one third of the patients will progress to end stage renal failure. The benign manifestations of the disease are managed by appropriate symptomatic measures. In case of severe involvement, including severe gastrointestinal complications or proliferative glomerulonephritis, immunosuppressive drugs may be required including steroids. These specific treatments are still controversial and their efficacy has to be evaluated.

This study describes clinical relevance of subclinical antibody-mediated rejection (SAMR) in a cohort of 54 DSA-positive kidney transplant recipients receiving a deceased donor. In 3 months screening biopsies, 31.1% of patients met the criteria of SAMR. A total of 48.9% had an incomplete form of SAMR (g+/ptc+/C4d-negative) whereas 20% had no humoral lesions. Patients with SAMR at 3 months had at 1 year: a higher C4d score, ptc score, and arteriosclerosis score, higher rate of IFTA (100% vs. 33.3%, p < 0.01) and a higher rate of transplant glomerulopathy (43% vs. 0%, p = 0.02) compared to patients without 3-month SAMR. Patients with SAMR at 3 months exhibited at 1 year a higher class II MFImax-DSA and a lower mGFR compared to patients without SAMR (39.2 +/- 13.9 vs. 61.9 +/- 19.2 mL/min/1.73 m(2) respectively, p < 0.01). The group of patients with C4d-negative SAMR at 3 months developed more ptc and IFTA lesions, and lower GFR at 1 year in comparison to biopsies without humoral lesions. SAMR is a frequent entity in KTR with preexisting DSAs and promotes subsequent GFR impairment and development of chronic AMR. C4d-negative SAMR patients displayed an intermediate course between the no-SAMR group and the C4d+ SAMR group. Screening biopsies may be useful to recognize patients more likely to develop SAMR.

Due to its structure, the glomerular capillary has a filtration function since it is interposed between the blood stream and the urinary space exposed to circulating plasma proteins, which are likely to form a deposit. The role of renal biopsy is to diagnose glomerulonephritis and systemic autoimmune diseases, on the basis of two samples: one for light microscopy and the other for immunofluorescence (IF). Electron microscopy has specific indications. IF is necessary to identify immune deposits. Renal biopsy has made possible the identification and characterization of lesions such as those related to the new viral diseases that emerged over the last decade: cryoglobulinemia and hepatitis C virus (HCV), the BK virus, the positivity of the C4d marker in humoural rejection of transplants, glomerular lesions due to monoclonal immunoglobulin. Besides, the recent molecular biology techniques as applied in renal transplantation are likely to improve the matching donors/recipients, and to treat graft rejections as revealed by gene expression in the renal tissue.

Renal biopsy plays a central role in the investigational approach of the nephrologist. The technique has significantly improved over the past two decades as a result of the introduction of ultrasonography and automated-gun biopsy devices. Percutaneous renal biopsy has become a relatively safe procedure with life-threatening complications occurring in less than 0.1% of biopsies in recent reports. However, percutaneous kidney biopsy is not without risk. Overt complications occurring in up to 13% of the cases, and 6 to 7% of complications were considered major, needing for an intervention such as transfusion of blood product or invasive procedure (radiographic or surgical). Major complications were apparent in more than 90% of patients by 24 hours. In situations in which the potential benefit of obtaining renal histology outweighs the risks of the procedure, transjugular kidney biopsy or surgical biopsy offers an attractive alternative. At present, we have no definite predictive indicators of postbiopsy bleeding complication, with the exception of age, gender, advanced renal insufficiency and the baseline partial thromboplastin time. Bleeding time is not significantly predictive and has been reported to have substantial limitations as a screening test. The use of the PFA-100 may replace the bleeding time and is now considered as a more valuable screening test for prebiopsy identification and management of patients with impaired haemostasis. Four groups of patients benefit from the findings of renal biopsy: those with a nephrotic syndrome, those with a renal disease in a context of systemic disorder, those with acute renal failure and those with a renal transplant. Some patients with non-nephrotic proteinuria, hematuria and chronic renal failure may also benefit from the procedure.

Different strategies appear to improve the success in treatment of antibody-mediated rejection (AMR), although no one best method has yet emerged. The objective of this study was to compare the efficacy of the combination of Plasmapheresis/intravenous immunoglobulin (IVIg)/anti-CD20-based regimes versus high-dose IVIg alone in the treatment of AMR. Group A (12 patients) was treated with high-dose IVIg between January 2000 and December 2003; group B (12 patients) was treated by Plasmapheresis/IVIg/anti-CD20 between January 2004 and December 2005. Graft survival at 36 months was 91.7% in group B versus 50% in group A (p = 0.02). Donor-specific human leukocyte antigens (DSA) levels detected by Luminex single antigen (Luminex SA) and ELISA, 3 months postrejection are significantly lower in group B than in group A: DSA ELISA class 2 score 6-8 (p = 0.02), DSA mean intensity of fluorescence (MFI) max (p = 0.009) and DSA mean MFI (p = 0.0004). The persistence of elevated DSA levels posttreatment is more frequent in patients with graft loss as compared to those with preserved renal function: score 6-8 on ELISA (p = 0.04); mean MFI (p = 0.00009) and MFImax (p = 0.018). We conclude that: (1) high dose IVIg alone is inferior to Plasmapheresis/IVIg/anti-CD20 as therapy for AMR and (2)DSA postrejection can be quantified using solid phase assays, showing that 3 months after AMR, DSA levels are higher in patients with graft loss.

Sarcoidosis is characterized by a disproportionate Th1 granulomatous immune response in involved organs. It is also associated with both peripheral and intratissular regulatory T cell (Treg) expansion. These cells exhibit powerful antiproliferative activity, yet do not completely inhibit the production of either tumor necrosis factor-alpha or interferon-gamma. The origin of the observed Treg amplification and, more importantly, its impact on the evolution of sarcoidosis remain unresolved issues. Here, we show that CD4(+)CD45RA(-)FoxP3(bright) Tregs proliferate and accumulate within granulomas. However, circulating and tissue Treg numbers are neither correlated with the dissemination of the disease nor correlated locally with the extent of granulomatous inflammation. Rather, we found a positive correlation between the presence of Tregs in renal granulomas and the degree of interstitial fibrosis (r = 0.46, P = 0.03, n = 20). Furthermore, Treg depletion accelerates in vitro granuloma growth in mononuclear cell cultures of healthy controls, but not in those from patients with active sarcoidosis. The results of this study show that although healthy Tregs suppress the initial steps of granuloma formation, they have no positive influence on sarcoidosis lesions. Our findings argue for a more preventive than curative effect of Tregs on inflammatory processes.

Angiogenesis inhibitor drugs (bevacizumab, sunitinib, sorafénib...) are now widely used for treatment of cancers, including colorectal, advanced renal cell and hepatocellular carcinomas, breast cancer). Vascular and renal side-effects of these drugs are not well known. Hypertension is one of the most common side effects. Incidence of hypertension may be different among angiogenis inhibitors and seems dose-depend. Arterial pressure can usually be controlled with anti-hypertensive medications, and treatment with angiogenesis inhibitors can be continued in most cases; however, serious hypertension-induced side effects were reported included malignant hypertension, stroke and reversible posterior leucoencephalopathy. Renal damage is infrequently reported: usually reversible mild or moderate proteinuria and in some rare cases nephritic syndrome, acute renal dysfunction, proliferative or collapsing glomerulonephritis, interstitial nephritis and thrombotic microangiopathy. Prolongation of the QT interval, congestive heart failure and left ventricular dysfunction have been reported in patients using tinibs. In the present guidelines, we recommend: (1) before the first administration of angiogenesis inhibitors: acute IV or oral antihypertensive medications should not be administered in a patient regardless of arterial pressure levels with postponing the administration because of hypertension is not recommended; (2) initial work-up should include ambulatory measurement of arterial pressure (by the general practitioner or by the patient using home blood pressure (three times in the morning and in the evening during three consecutive days) with a validated (cf: http://afssaps.sante.fr/) upper arm device: ideally, this device should be financed and provided by the pharmaceutical companies marketing the angiogenesis inhibitor drugs. Using 24-hour ambulatory blood pressure measurement is optional; (3) urine dipstick (and quantification if positive) and estimated glomerular filtration rate (using abbreviated MDRD rather than Cockcroft-Gault formula) must be performed before treatment and regularly during follow-up; (4) therapeutic management must be done in accordance with national or international guidelines (in France: http://www.has-sante.fr/); (5) optimal care is best achieved within a network of professionals including general practitioners, oncologists, cardiologists and nephrologists.

Antibody-mediated acute rejection is a frequent and severe complication of kidney transplantation. It has a poor prognosis and is often resistant to conventional treatment, which warrants treatment before transplantation to reduce the risk and after to improve the diagnosis, treatment, and follow-up. Before transplantation, the search for donor-specific anti-HLA antibodies using sensitive techniques (single antigen, ELISA) is essential to quantify the risk of acute rejection by antibodies, allowing grafts to be allocated in a fully informed manner. Monitoring and strict posttransplantation follow-up of at-risk patients also needs to be set up so that immunosuppression strategies can be modified if need be. After transplantation, treatment strategies consisting of (a) removing or blocking preexisting or de novo antibodies using high-dose IVIg or plasmapheresis or (b) inhibiting or depleting the cells producing antibodies by injecting anti-CD20 monoclonal antibodies or thymoglobulins have demonstrated their efficacy in treating antibody-mediated acute rejection. Since the persistence of donor-specific anti-HLA antibodies after an episode of antibody-mediated acute rejection is a factor of poor progression, suppression using these treatments and their posttransplantation follow-up are indispensable.

We have analyzed the evolution of renal status beyond the perioperative period in patients with cystic fibrosis (CF) undergoing lung transplantation and presented histological analysis of 15 patients biopsied for an episode of accelerated renal function loss (RFL). Episodes of accelerated RFL after the perioperative period occurred in 32.5% of patients and significantly raised the risk of end-stage renal disease (ESRD) (p < 0.001). The histologic lesions associated with these episodes differed according to the time of onset. Early onset (10 cases) was associated with tubulointerstitial lesions in the form of oxalate nephropathy (50%) and/or a pigmented tubulopathy (80%). This latter was correlated with treatment with antiviral agents (p = 0.002) and aminoside and glycopeptide antibiotics (p = 0.03) administered in the month preceding biopsy. Lesions in late episodes of accelerated RFL (5 cases) were principally vascular: arteriosclerosis and arteriolosclerosis (p = 0.007, p = 0.00002), correlated with diabetic glomerulosclerosis or focal segmental glomerulosclerosis in the absence of prominent diabetic changes. Specific calcineurin-inhibitor nephrotoxicity was present in 93.3% of biopsies associated with thrombotic microangiopathy in 46.7% of cases. The identification of specific etiologies of progressive kidney disease in patients with CF after lung transplantation should permit more effective post-transplant care of these patients.

This study analyzes the influence of preformed DSA, identified by HLA-specific ELISA assays, on graft survival and evaluates the incidence of antibody-mediated rejection (AMR) in patients with and without pregraft desensitization. Kidney graft survival at 8 years was significantly worse in patients with DSA (n = 43) than in those without DSA (n = 194)(p = 0.03). The incidence of AMR in patients with DSA is 9-fold higher than in patients without DSA (p < 0.001) and their graft survival is significantly worse than in DSA patients without AMR and in non-DSA patients (p = 0.005). The prevalence for AMR in patients with DSA detected on historic serum is 32.3% in nondesensitized patients and 41.7% in desensitized patients. The risk for AMR is significantly more elevated in patients with strongly positive DSA (score 6-8) compared to those with DSA score 4 (p < 0.001), and in patients with historic DSA+/CXM+ compared to those with DSA+/CXM- (p = 0.01). The presence of preformed DSA is strongly associated with graft loss in kidney transplants, related to an increased risk of AMR. Our findings demonstrate the importance of detection and characterization of DSA before transplantation. Stratification of this risk could be used to determine kidney allocation and to devise specific strategies for these patients.

Renal biopsies occasionally show a combination of thrombotic microangiopathy as a result of antiphospholipid syndrome and lupus nephritis. The thrombosis in this case preceded the onset of lupus probably by approximately 8 yr, consisting of repeated fetal loss and venous thrombosis. More severe disease may have both arterial and venous thrombotic manifestations, including pulmonary emboli and cerebrovascular lesions. The antiphospholipid syndrome bears no relationship to the class of lupus nephritis but is accompanied by more frequent and greater hypertension and greater azotemia and interstitial fibrosis, and is associated with worse outcomes than lupus nephritis without antiphospholipid syndrome.

This study analyzes the incidence and course of antibody-mediated rejection (AMR) in a cohort of 237 renal transplant patients followed for 30 +/- 20 months. Among these, 32 patients were considered to be at risk for AMR and received intravenous immunoglobulin (IVIg), either as preconditioning (Group A, n = 18) or at the time of transplant (Group B, n = 14). The prevalence of AMR was 27.8% in Group A, 57.1% in Group B and 3.9% in the remainder of the population. Although graft loss remains greater among AMR than for acute cellular rejection (ACR) or the overall transplant population, we have identified a good outcome group (GFR > 15 mL/min/1.73 m(2)) (n = 13), whose renal function at the end of follow-up was comparable to that of the general transplant population. The factors associated with bad outcome are: (1) immunologic: presence and/or persistence of donor-specific anti-HLA antibodies post-transplantation and (2) histologic: neutrophilic glomerulitis, peritubular capillary dilatation with neutrophil infiltrates and interstitial edema at the time of first biopsy; and at the time of late biopsy (3-6 months): lesions of vascular rejection, and monocyte/macrophage infiltrates in glomeruli and dilated peritubular capillaries. Persistence of C4d does not predict outcome. This study outlines for the first time the immunologic and histologic profiles of AMR patients with poor prognosis.

The association between membranous nephropathy (MN) and cancer is often mentioned in textbooks but poorly substantiated, and the characteristics of cancer-associated MN are unknown. To address these questions, we studied a cohort of 240 patients with MN, among them 24 had malignancy at the time of renal biopsy or within a year thereafter. The incidence of cancer was significantly higher in these patients than in the general population (standardized incidence ratio 9.8 [5.5-16.2] for men and 12.3 [4.5-26.9] for women). The frequency of malignancy increased with age. At the time of diagnosis, clinical presentation did not differ between the patients with cancer-associated MN and those with idiopathic MN, but smoking was more frequent among patients with cancer. Analysis of renal biopsies revealed that the number of inflammatory cells infiltrating the glomeruli was significantly higher in patients with cancer-associated MN (P = 0.001). The best cutoff value for distinguishing malignancy-related cases from controls was eight cells per glomerulus. Using this threshold led to a diagnosis of cancer-associated MN with a specificity of 75% and a sensitivity of 92%. In patients with cancer-associated MN, there was a strong relationship between reduction of proteinuria and clinical remission of cancer (P < 0.001). In conclusion, our study provides epidemiologic evidence of an excess of cancer risk in patients with MN. It also shows that age, smoking, and the presence of glomerular leukocytic infiltrates strongly increase the likelihood of malignancy in MN patients.

Acute renal insufficiency (ARI) is a frequent complication of nonrenal solid organ transplantation and may be responsible for an unfavorable outcome, particularly if dialysis is required. The etiology of post-transplantation ARI is poorly understood, with only isolated clinical cases being reported, most imputed to drug toxicity. We report here, the first three observations of irreversible ARI associated with acute oxalate nephropathy (AON) in the course of nonrenal organ transplants: a lung transplant and a lung-liver transplant in two patients with mucoviscidosis, and a cardiac transplant. The diagnosis of AON was made histologically. In all three cases, the ARI supervened after prolonged consumption of antibiotics capable of interfering with the colonic flora, and leading to enteric hyperoxaluria. The recognition of AON as a cause of post-transplantation, ARI underlines hyperoxaluria and digestive hyperabsorption of oxalate as specific risk factors for AON and should permit better posttransplant care of these patients.

Minimal change nephrotic syndrome (MCNS) is described as a paraneoplastic manifestation of classical Hodgkin's lymphoma (cHL). We reassessed the pathophysiological and clinical significance of this association. A retrospective study was performed to evaluate a cohort of adult patients who developed MCNS and cHL. Twenty-one patients recruited in 15 French centers were analyzed. cHL was associated with inflammatory and general symptoms in most cases. The morphological subtype was predominantly nodular sclerosis (71.4%). MCNS appeared before the diagnosis of lymphoma in eight patients (38.1%) and in this case, it was characterized by a nephrotic syndrome (NS) frequently resistant (50%) or dependent (12.5%) to steroid treatment. Interestingly, diagnosis (3-120 months after MCNS) and effective treatment of the hemopathy were associated with the disappearance of the MCNS. cHL was diagnosed before MCNS in nine patients (42.9%), and in this case, glomerulopathy was associated with cHL relapse in 55.5% of cases. In four patients (19%), the two diseases occurred simultaneously. Extensive immunohistochemical study of lymph nodes was performed in eight patients and did not reveal particular features. In conclusion, MCNS associated with cHL is frequently dependent or resistant to steroid regimen, but remission of NS is obtained with the cure of lymphoma.

The immune defect that could account for the multisystemic involvement that characterizes systemic lupus erythematosus (SLE) remains unknown. We hypothesized that iterative disease flares correspond to a recurrent defect in the peripheral immune suppression exerted by naturally occurring T regulatory cells (Tregs). Surprisingly, Tregs isolated from lupus patients show the same phenotypic and functional characteristics as corresponding cells found in healthy controls. A decrease in the proportion of circulating Tregs among other CD4+ T cells is nevertheless evidenced in active patients when this group is compared with healthy controls (0.57 +/- 0.24%, n = 45 vs 1.29 +/- 0.38%, n = 82, p < 0.0001) or with inactive patients (1.22 +/- 0.67%, n = 62, p < 0.0001). In contrast, the proportion of Tregs in other systemic autoimmune diseases such as primary Sjögren syndrome and inflammatory myopathy does not significantly differ from controls' values (1.15 +/- 0.46%, n = 21, p = 0.09 and 1.16 +/- 0.44%, n = 16, p = 0.43, respectively). Lupus Tregs do not accumulate in either the lymph nodes or the diseased kidneys and are not killed by a circulating soluble factor, but demonstrate in vitro a heightened sensitivity to Fas-induced apoptosis. Finally, we show that the extent of Treg depletion correlates with the clinical severity of the flare. SLE flares are therefore associated with a global Treg depletion and not with a phenomenon of tissue redistribution. In summary, we suggest that the physiopathology of SLE could be tied to a defect in the homeostatic control of the Treg subpopulation.

Background: A recently proposed reclassification of lupus nephritis divides class IV (diffuse proliferative) lupus nephritis into those cases with predominantly segmental proliferative lesions (class IV-S) and those with predominantly global proliferative lesions (class IV-G). This report explores the validity of this distinction and possible differences in pathogenesis between the 2 types of lesions., Methods: Patients from a previously reported series of severe lupus nephritis, with initial biopsies (Bx1) and control biopsies (Bx2) at 6 months after induction therapy were reclassified according to the newly proposed classification. From the original series of 65 patients, 15 patients were reclassified as having class IV-S lesions and 31 patients class IV-G lesions. Clinical data at both biopsies and follow-up were available on all patients selected., Results: Patients with IV-G lesions had worse proteinuria, lower serum hemoglobins, lower CH50s, and likely higher SCrs (P = .06) and lower C3s (P = .08) than class IV-S patients. Serum CH50 and C3 correlated negatively with severity of class IV-G lesions, but not at all with class IV-S lesions. Patients with class IV-G lesions had greater overall immune deposits and subendothelial deposits on IF and greater hyaline deposits on light microscopy. By contrast, class IV-S showed predominant mesangial deposits and a much higher rate of glomerular fibrinoid necroses (13.3 +/- 15.3% vs. 5.6 +/- 8.0% of viable glomeruli, P = .03). Other distinctions included the fact that membranoproliferative features were found only in class IV-G lesions, and glomerular monocyte/macrophages were much more frequent in this group than in class IV-S lesions (1.77 +/- 0.92 vs. 0.86 +/- 0.77, P = .008). Finally, class IV-G frequently involved all viable glomeruli (74.2% of cases), whereas segmental proliferative lesions never did (P < .0001). Survivals from doubling of SCr at 10 years did not differ between the 2 types at Bx1: 72.5% segmental versus 60.4% global, P= .53. However, among those with persistent lesions at Bx 2 (11 IV-S and 9 IV-G), there was a dramatic difference in 10-year survivals between IV-S lesions (63.6%) and IV-G lesions (0%), P = .08., Conclusion: There are definite clinical and morphologic differences between class IV-S and IV-G lesions. Data suggest that class IV-G lesions behave as an immune complex disease, having positive correlations with extent of immune deposits and negative correlations with serum complement levels, the model traditionally assumed for lupus nephritis as a whole. However, in class IV-S lesions, the presence of proportionally greater glomerular fibrinoid necroses and lack of correlation with extent of immune deposits suggest that these lesions may have a different pathogenesis.

Liver transplant recipients are at risk of chronic renal failure (CRF), customarily considered to be secondary to CsA/FK506 nephrotoxicity. We have examined renal biopsies from 26 liver transplant recipients with CRF. Before OLT, 5 patients had CRF, 8 were diabetic and 9 hypertensive. Renal biopsies were performed at a mean of 5 years after liver transplantation. Mean SCr was then 212 micromol/L, proteinuria was 1 g/24 h. Twelve patients were diabetic and 25 hypertensive. Histology revealed impressive renal destruction, with a mean of 45% interstitial fibrosis and 45% glomerular sclerosis. All biopsies showed severe arteriosclerosis. CRF can be attributed to four associated primary lesions: (i) specific chronic CsA/FK506 arteriolopathy; (ii) typical diabetic nephropathy; (iii) acute or chronic thrombotic microangiopathy attributed to CsA/FK506 or alpha-IFN and (iv) tubular changes related to administration of hydroxyethylstarch. At the end of the follow-up, after a mean of 6.4 years, 12 patients required dialysis, 13 had CRF and only 1 had normal renal function. Thus, CRF in OLT recipients is more complex than originally thought and should not be classified as anti-calcineurin nephrotoxicity without further investigations, including renal histology. These investigations have therapeutic potential, that is, they may lead to a more aggressive treatment of hypertension and/or diabetes.

Intra-vascular lymphoma is usually reported as a rare and fatal disorder. We describe here the first case of an intra-vascular lymphoma revealed by a nephrotic syndrome for which a durable remission has been obtained by 8 cycles of bi-mensual CHOP and Rituximab therapy. In this report, 18 fluorodesoxyglucose tomoscintigraphy is discussed as a tool for intra-vascular lymphoma extension and follow-up.

A 37-year-old female patient had a cardiac transplantation for dilated cardiomyopathy. She was sensitized by two pregnancies showing anti-human leukocyte antigen I and II antibodies. The pretransplantation crossmatch was negative, but she developed acute humoral rejection characterized by vascular C4d deposits, arteriolitis, and intravascular leukocyte accumulation and adhesion in venules. Although C4d deposits disappeared in 4 weeks, she had persistent endothelial cell activation (endothelial expression of ELAM-1, VCAM-1, or human leukocyte antigen class II) throughout the 6 months of follow-up. Although she received intensive immunosuppression, she presented three episodes of acute cellular rejection during that period of time. This case shows that C4d deposits represent a sensitive marker of acute humoral rejection in cardiac transplantation. Therefore, C4d immunofluorescence should be more frequently assessed in endomyocardial biopsies.

In the course of the antiphospholipid syndrome (APS), the renal involvement attributable to primary APS, APS nephropathy (APSN), corresponds to vaso-occlusive lesions of the intrarenal vessels, associated side-by-side, acute thromboses with chronic arterial and arteriolar lesions, leading to zones of cortical ischemic atrophy. A second retrospective study of 114 lupus patients was undertaken to determine whether APSN can be found in the course of systemic lupus and if there are biologic or clinical predictive factors of the presence of APSN. We showed the following

Background: This study was designed to review the prognosis and the predictors of renal outcome in patients with membranous lupus nephropathy (MLN) with no or mild mesangial proliferation., Methods: The medical records of patients (n=66) with biopsy-proven MLN, WHO class VA, and class VB without any past history of proliferative lupus nephropathy (PLN) were reviewed retrospectively., Results: The mean follow-up was 6.9+/-0.2 years and renal survival at 5 and 10 years was 97+/-2 and 88+/-6%. Twenty-nine patients underwent a second renal biopsy during follow-up. Fourteen of these patients (21%) had lesions of PLN. Among them, four reached end-stage renal disease (ESRD) despite immunosuppressive treatment. The probability of a transition from MLN to PLN at 10 years was 35+/-8%. Two other patients reached ESRD but did not have repeat renal biopsies and two had biopsy-proven progression to fibrosis. Independent risk factors associated with the doubling of creatinine were transition into PLN and the occurrence of a thrombosis during follow-up. The only predictor of ESRD was the haemoglobin level. PLN was not a predictor of ESRD but the efficient treatment of this form of lupus nephritis prevented that outcome., Conclusions: With a long follow-up, our study noted a high frequency of transition into PLN in a large cohort of patients with MLN. Steroid usage was not predictive of outcome and did not affect renal survival, a result that must be qualified in light of the highly variable duration of treatments with steroids. The early screening and treatment of PLN is the main benefit of the close follow-up of patients with MLN. Progression to ESRD with only fibrosis remains a rare event.

Objective: Primary amyloidosis is classical in the course of multiple myeloma (MM), but peripheral amyloid arthropathy is unusual. We evaluated the frequency and effect of amyloid arthropathy in a single center series of patients with MM., Methods: Retrospective analysis of cases of peripheral joint amyloidosis in a cohort of patients with MM., Results: Between 1978 and 1996, 11 patients (6 women, 5 men, mean age 59 yrs) were diagnosed with biopsy proven amyloid arthropathy in a cohort of 311 patients with MM. Arthritis was the first symptom of amyloidosis in all patients and occurred within the 6 months after MM diagnosis in most patients (7/11). Nine patients had light chain MM and X light chain was more common than kappa (6 vs 5). Shoulder hypertrophic arthropathy and rheumatoid arthritis-like polyarthritis were the 2 most common involved sites. In most cases, joint involvement was responsible for major limitations in activities of daily living. Amyloid deposits were clearly visible on magnetic resonance images (MRI), which also showed inflammatory synovitis in some cases. Control of MM was often associated with improvement of amyloid arthropathy, but additional rheumatological treatment--oral low dose prednisone or joint steroid injection--was often needed to achieve more complete relief. Amyloid arthropathy was not associated with decreased survival, except for patients with concomitant cardiac involvement., Conclusion: This series provides reliable information on amyloid arthropathy, especially regarding functional effects, anatomical lesions on MRI, and therapeutic options.

Background: Renal relapse in lupus nephritis has been shown to have ominous prognostic significance with the majority of patients progressing to doubling of serum creatinine (CRX2). However, not all patients do so. This report explores the roles of response of inflammation to therapy and of glomerular scarring and interstitial fibrosis and their potential reversal to outcome of renal relapse., Methods: Renal biopsies from 71 patients with lupus nephritis with an initial biopsy (Bx1) and systematic control biopsy (Bx2) after six months of therapy, as well as subsequent biopsies for clinical indications, were studied. The relationships of morphologic factors to renal relapse and its outcome as well as to CRX2 and end-stage renal disease (ESRD) were analyzed. Cox proportional hazards modeling was used to assess association of morphologic variables with outcomes., Results: Renal interstitial fibrosis and glomerular segmental scarring were partially reversible in 17 and 11 patients, respectively. This decline was associated with an excellent prognosis, with only one patient in each group (5.9% and 9.1% respectively) progressing to CRX2. All 18 patients who progressed to CRX2 either failed to respond to therapy (7 patients) as defined by normalization of serum creatinine (SCr) and reduction of proteinuria to < or =1 g/day, or relapsed after initial response (11 patients), as defined by recent rise of SCr > 50% and/or proteinuria > 3.5 g/day. However, relapse also occurred in 11 of 47 other patients without progression to CRX2. These patients showed a greater initial response of inflammation and deposits to therapy and fibrous lesions partially reversed in the period prior to relapse, so that active lesions were superimposed on a lower level of chronic lesions. By contrast, chronic lesions mounted steadily in those who progressed to CRX2. Cox proportional hazards modeling indicated a strong association of inflammatory variables with renal relapse, CRX2 and ESRD. However, the extent of immunoglobulin deposits was not significantly associated with any outcome. Finally, we found that failure of disease to remit also is associated with a high rate of CRX2 (64.8% vs. 13.0%, P = 0.00034)., Conclusions: Interstitial fibrosis and glomerular scarring in systemic lupus erythematosus are partially reversible, and this reversal is attended by an excellent outcome. The outcome of renal relapse is determined by the initial response of inflammatory and chronicity elements to therapy, those with prior partial reversal of interstitial and glomerular scarring having a good outcome, and those in whom fibrotic lesions have continued to increase and have a poor outcome. Inflammatory variables appear to be more important in determining outcome than immunoglobulin deposits.

Henoch-Schönlein Purpura nephritis (HSPN) has been extensively studied in children but, its natural history in adults is much less known. A cohort of 250 adults suffering HSP was retrospectively analyzed for a median follow-up period of 14.8 yr. All patients had biopsies consistent with HSP (predominant IgA mesangial deposits) associated with purpura, bowel angina, and/or abdominal pain. At presentation, palpable purpura was present in 96% of patients, and arthritis was reported in 61%, and gastrointestinal involvement in 48%. Thirty-two percent of the patients showed renal insufficiency (Creatinine clearance [CrCl] <50 ml/min), usually associated with proteinuria (99%) and/or hematuria (93%). Endocapillary glomerulonephritis was the most frequent lesion on renal biopsy (61%). At the end of follow-up, patient survival was only 74%. The first cause of death was carcinoma (most of them of respiratory or digestive tract). Regarding renal function, 11% of patients reached end-stage renal failure, 13% exhibited severe renal failure (CrCl <30 ml/min), and 14% moderate renal insufficiency (CrCl <50 ml/min). Clinical remission defined as the absence of proteinuria, hematuria, and a normal renal function was achieved in only 20%. This is a retrospective study; therefore, it is not possible to demonstrate any steroid and/or cyclophosphamide efficacy in diminishing the incidence of renal insufficiency. Multivariate analysis demonstrated that renal function impairment and proteinuria level at presentation and, on renal biopsy, the degree of interstitial fibrosis, percentage of sclerotic glomeruli, and presence of glomeruli with fibrinoid necrosis were associated with a poor renal prognosis. The data indicate that clinical presentation of HSPN in adults is severe and its outcome relatively poor, worse than in children. Identification of clinical and histologic prognostic factors may permit the design of appropriate therapeutic prospective studies.

Background: In selected young patients with type 1 diabetes mellitus and end-stage renal failure, simultaneous pancreas and kidney (SPK) transplantation is the treatment of choice. We conducted a retrospective, case-controlled study to compare the function, survival and pathology of renal allografts after SPK and kidney-alone (KA) transplantations., Methods: We studied 26 consecutive SPK patients and 67 KA controls matched for time of transplantation. Renal function was assessed by routine evaluation of serum creatinine and its course by the 1/serum creatinine vs time curve. Histologic evaluation of early biopsies (0-3 months post-transplantation, n=63), intermediate biopsies (3 months-1 year, n=75) and late biopsies (after 1 year, n=35) were performed by two independent reviewers., Results: SPK and KA recipients differed significantly with regard to donor and recipient age, time on the waiting list, HLA sensitization, renal cold ischaemia time (CIT) and the incidence of delayed graft function. Acute rejection was more frequent after SPK than KA (54 vs 27%; P=0.01), despite higher trough levels of calcineurin inhibitors. After SPK and KA, actuarial patient and renal allograft survival and renal function were comparable at 1 and 4 years. Severe chronic lesions, especially vascular lesions, and calcineurin-inhibitor nephrotoxicity were more frequent in intermediate and late biopsies in the SPK group., Conclusions: We confirmed that patient and graft survival is comparable between SPK and KA recipients. Despite the use of optimal organs and shorter CIT in SPK, renal graft function was not different in the two groups. Histologic chronic lesions were more severe in SPK than in KA recipients. This might be caused by acute rejection episodes or be due to more severe nephrotoxicity after SPK, because of higher doses of calcineurin inhibitors, or higher sensitivity to calcineurin-inhibitor nephrotoxicity.

We report a case of acute tubular necrosis in a patient with Crohn's disease treated by 5-amino-salicylate (Pentasa(R)) since one month. Normalization of renal biological parameters occurred rapidly after treatment withdrawal. This case raises the question of the optimal modalities of monitoring of renal function during treatment with 5-amino-salicylate.

In the course of the antiphospholipid syndrome (APS), the existence of vaso-occlusive lesions capable of affecting numerous organs is now well established. The renal involvement attributable to primary APS, APS nephropathy (APSN), corresponds to vaso-occlusive lesions of the intrarenal vessels, associating side-by-side, acute thromboses with chronic arterial and arteriolar lesions, leading to zones of cortical ischemic atrophy. A retrospective study of 114 lupus patients undergoing renal biopsy was undertaken to determine the following: (1) if APSN can be found in the course of systemic lupus erythematosus (SLE); (2) if certain clinical and biologic factors can permit the prediction of the presence of APSN; and (3) if APSN is a superadded renal morbidity factor in lupus patients. This study shows the following: (1) APSN occurs in SLE (32% of patients with renal biopsies) in addition to, and independently of, lupus nephritis; (2) APSN is statistically associated with lupus anticoagulant but not with anticardiolipin antibodies; (3) APSN is associated with extrarenal APS, mainly arterial thromboses and obstetrical fetal loss, but not with the venous thromboses of APS; (4) APSN is an independent risk factor, over and above lupus nephritis, that contributes to an elevated prevalence of hypertension, elevated serum creatinine, and increased interstitial fibrosis. Thus, it seems likely that, because of its associations with hypertension, elevated serum creatinine, and increased interstitial fibrosis, APSN may worsen the prognosis in these patients. APSN may also have therapeutic significance in that its recognition should permit a better balance between immunosuppressor and antithrombotic and/or vasoprotective therapy. Finally, this study suggests that APSN should be considered as an element to be included in the classification criteria of APS.

Background: Response of the renal tubules to proteinuria is implicated in progression of renal disease. Experimentally, proteinuria causes increased tubular synthesis of macrophagic and other chemokines, with increased tubular cellular proliferation and apoptosis, leading to interstitial inflammation and fibrosis. Clinically, diminution of proteinuria leads to the slowing of progression, but whether this leads to reduction in tubular lesions has not been directly demonstrated in humans., Methods: Initial (Bx1) and systematic six-month biopsies (Bx2) from 71 patients with lupus nephritis were studied, with a subset of 34 biopsies also stained for proliferating cell nuclear antigen (PCNA), the macrophage marker PGM1, and cytokeratins (AE1/AE3), and morphometric cell and tubular profile counts performed., Results: Positive correlations were found between increasing levels of proteinuria and the following light microscopic parameters: tubular epithelial pyknosis, tubular epithelial nuclear "activation," tubular lumenal macrophages, interstitial inflammation and fibrosis, but not with tubulointerstitial immunofluorescence. Significant positive correlations also were found with the following immunohistochemical parameters: PCNA in epithelial cells (r = 0.74) and tubular luminal cells (r = 0.47); tubular lumenal macrophages (r = 0.63) and tubular epithelial cells with acquired PGM1 staining (r = 0.36); and pyknotic tubular epithelial cells (r = 0.47). All showed strong correlations with serum creatinine (S(Cr)) as well. All were reduced at Bx2, generally in parallel to the reduction in proteinuria. Tubulointerstitial immune deposits appear to play only a minor role in the development of tubular epithelial lesions and the progression of renal disease in lupus. They show only limited correlation with SCr and no correlation with proteinuria. By multiple regression, they are not associated with tubular epithelial lesions, interstitial inflammation or interstitial fibrosis at either biopsy, whereas tubular epithelial lesions are strongly associated with interstitial inflammation at Bx1 and with interstitial fibrosis at Bx2. Cytokeratin correlated strongly with S(Cr) (r = 0.53, P = 0.002) but not with proteinuria (r = 0.27, NS), and was the sole immunohistochemical parameter to increase at Bx2. It appears to be a sensitive marker for tubular atrophy., Conclusions: In this study both proteinuria and SCr showed a hierarchy of correlations with morphologic variables: Tubular epithelial cell changes> tubular macrophages> interstitial inflammation> interstitial fibrosis, corresponding to current experimental models, but not previously demonstrated in humans.