French ENT Society (SFORL) guidelines for the management of immunodeficient patients with head and neck cancer of cutaneous origin.

OBJECTIVES: The French ENT Society (SFORL) created a workgroup to draw up guidelines for the management of immunodeficient patients with head and neck cancer of cutaneous origin. The present guidelines cover diagnostic and therapeutic management and prevention of head and neck cancer of cutaneous origin in immunodeficient patients, and in particular in transplant patients and those with HIV infection. MATERIALS AND METHODS: The present guidelines were based on a critical multidisciplinary reading of the literature. Immunosuppression and its varieties are defined. The usual risk factors for skin cancer and those specific to immunodeficiency are presented. The prevention, assessment and management of cutaneous carcinoma, melanoma, Kaposi's sarcoma and lymphoma are dealt with. The level of evidence of the source studies was assessed so as to grade the various guidelines. When need be, expert opinions are put forward. RESULTS: Immunodeficient patients are at higher risk of head and neck skin tumors. The level of risk depends on the type of deficiency; there is an especially high risk of squamous cell carcinoma in transplant patients and of Kaposi's sarcoma in HIV-positive subjects. Various viruses are associated with skin cancers. Skin tumors are often evolutive in case of immunodeficiency, requiring rapid treatment. Management is generally the same as in immunocompetent subjects and should be discussed in a multidisciplinary team meeting. Immunosuppression may need to be modulated. In organ transplant patients, the only class of immunosuppressants with proven antitumoral efficacy are mTOR inhibitors, particularly in cutaneous squamous cell carcinoma. The rhythm of clinical surveillance should be adapted according to the risk of recurrence. Preventive measures should be undertaken. CONCLUSION: Skin cancers in immunodeficiency are highly evolutive, requiring the earliest possible treatment. Immunosuppression may need modulating. As the risk of recurrence may be elevated, careful surveillance should be implemented. Preventive measures should also be undertaken.

Human de novo papillary renal-cell carcinomas in a kidney graft: evidence of recipient origin with adenoma-carcinoma sequence.

Papillary renal-cell carcinoma (pRCC) is unusual for its occurrence in kidneys with chronic dysfunction, for its frequent multifocality and for its common association with papillary adenoma, a benign renal lesion morphologically indistinguishable from pRCC. Concomitant development of papillary adenoma and pRCC in five transplanted kidneys, where donor and recipient characteristics are well established, provided a unique opportunity for molecular studies of de novo pRCC carcinogenesis. We aimed to study this tumor type to determine whether or not the different papillary tumors have the same origin, and whether or not papillary adenomas are precursor lesions of pRCC. We performed XY-FISH in sex-mismatched kidney transplants, and polymorphic microsatellite DNA and high-resolution melting of mitochondrial DNA analyzes in all five patients on laser-microdissected tumor cells, then compared these molecular profiles to donor and recipient profiles. This study (i) identified the recipient origin of de novo papillary adenomas and pRCCs in a kidney transplant, (ii) demonstrated an identical origin for precursor cells of papillary adenomas and pRCCs and (iii) showed additional genetic alterations in pRCCs compared to papillary adenomas. This molecular approach of papillary tumors developed in transplanted kidney identified successive steps in carcinogenesis of human de novo papillary renal-cell carcinoma.

Renal transplantation in HIV-infected patients: the Paris experience.

Kidney transplantation is now considered as a reasonable option for HIV-infected patients with end-stage renal disease. We describe here a retrospective study conducted in five transplantation centers in Paris. Twenty-seven patients were included. Immunosuppressive protocol associated an induction therapy and a long-term treatment combining mycophenolate mofetil, steroids and either tacrolimus or cyclosporine. All the patients had protocol biopsies at 3 months and 1 year. Patient's survival was 100% at 1 year and 98% at 2 years. Graft survival at 1 and 2 years is 98% and 96% at 1 and 2 years, respectively. The mean glomerular filteration rate values at 12 and 24 months were 60.6 mL/min/1.73 m² (range 23-98) and 65.4 mL/min/1.73 m² (range 24-110), respectively. Acute cellular rejection was diagnosed in four cases (15%). Because of high trough levels of calcineurin inhibitor, protease-inhibitor therapies were withdrawn in 11 cases. HIV disease progression was not observed. One patient developed B-cell lymphoma. In conclusion, our study confirms the safety of renal transplantation in HIV-infected patients with few adverse events and a low incidence of acute rejection.

Pneumocystis jirovecii pneumonia in renal transplant recipients occurring after discontinuation of prophylaxis: a case­control study.

A case-control study was conducted to identify risk factors for Pneumocystis jirovecii pneumonia (PCP) in renal transplant recipients. Eleven cases of PCP were matched with 22 controls. Cases occurred a median of 18 months after transplantation, and none of the recipients was receiving prophylaxis. Univariate analysis showed that graft rejection, duration of steroid use, use of mammalian target of rapamycin (mTOR) inhibitors and lymphocytopenia at the time of prophylaxis discontinuation were risk factors for PCP. In the multivariate model, only graft rejection (OR 8.66, p 0.017) remained significantly associated with PCP. In patients with a history of graft rejection, PCP prophylaxis should be maintained, especially among those with lymphocytopenia.

[What tests are necessary before registration on the kidney transplant waiting list?]. / Quelles explorations faut-il réaliser avant l'inscription sur une liste de transplantation rénale ?

Before registering a patient on the kidney transplant waiting list, the medical file should be carefully studied looking for factors that may complicate the transplantation. Knowledge of the patient's history and the clinical examination will guide the choice of complementary examinations. The objectives of pretransplantation explorations are : 1) preventing graft rejection ; 2) ensuring that arterial and venous anastomoses are possible ; 3) ensuring that urine can be drained ; 4) preventing post-transplantation infections ; 5) not performing a transplantation on a subject with cancer ; and 6) avoiding any post-transplantation cardiovascular events. The list of the necessary explorations for renal transplantation should be as simple as possible so that registration on the transplant waiting list is not delayed, while being as complete as possible to prevent any complications that may compromise the results. It should be individualized to each patient.

Nephron sparing surgery is a feasible and efficient treatment of T1a renal cell carcinoma in kidney transplant: a prospective series from a single center.

PURPOSE: Renal cell carcinoma in a renal graft is a rare condition whose incidence will increase in the future. To our knowledge no standardized treatment has been established for this disease. We performed a prospective study of nephron sparing surgery for small renal cell carcinoma in renal grafts. MATERIALS AND METHODS: From January 2002 to December 2006, 2,050 renal graft recipients were followed at our transplantation center. Of these patients 7 were diagnosed with histologically confirmed renal cell carcinoma in the renal graft, 5 of whom presented with T1a renal cell carcinoma and prospectively underwent nephron sparing surgery. RESULTS: Five patients with 15 to 30 mm (median 20) renal cell carcinoma were included in the study and were treated with nephron sparing surgery. Median operative time was 110 minutes (range 60 to 150). Blood loss was less than 200 ml in each case. All tumors were pT1aN0M0 with negative margins. No postoperative complications were observed (hemorrhage, urinary fistulas, renal failure). Preoperative immunosuppressive treatment was not modified postoperatively. At 3 months after nephron sparing surgery and at a mean of 17.4 months of followup (range 5 to 54) no significant impairment of renal function or recurrence was observed. CONCLUSIONS: Nephron sparing surgery is a safe and efficient procedure for the treatment of renal cell carcinoma in renal grafts, resulting in the preservation of renal function and in short-term cancer control.

Prognostic value of plasminogen activator inhibitor type 1 mRNA in microdissected glomeruli from transplanted kidneys.

BACKGROUND: Plasminogen activator inhibitor type 1 (PAI-1) exerts antifibrinolytic and profibrotic activities. Inside the glomerulus, PAI-1 is mainly synthesized by mesangial cells. We hypothesized that thrombin, via its receptor protease activated receptor type 1 (PAR-1), present on the membrane of glomerular cells, is an important mediator of PAI-1 synthesis. METHODS: Using the technique of Peten et al., we microdissected the glomeruli of 23 kidney transplanted patients admitted in our department from 1993 to 1997, and we followed-up these patients for up to 5 years, with sometimes iterative renal biopsies. With this technique, we also microdissected the glomeruli of three patients who have had a nephrectomy for cancer (control patients). We investigated mRNA expression of the PAI-1, the thrombin receptor PAR-1, the alpha2 chain of type IV (alpha2 IV) collagen, and of a housekeeping gene (cyclophilin) by reverse transcription-polymerase chain reaction. The results were correlated with the renal function and the histological findings classified into acute rejection (9 biopsies), chronic rejection (22 biopsies), or normal (8 biopsies). RESULTS: A significant up-regulation of PAI-1 and alpha2 IV collagen mRNA was observed in acute rejection (P<0.05) when compared to normal kidneys. A positive correlation exists between alpha2 IV collagen mRNA level and the degree of cellular infiltration. A negative correlation was found between the level of mRNA of PAR-1 and the degree of vascular thrombosis (P=0.005) and glomerulosclerosis (P=0.04). A positive correlation was found between the degradation of renal function and the mRNA level of PAI-1 at the time of the renal biopsy (P<0.05). CONCLUSIONS: These results suggest that glomerular PAI-1 mRNA may be predictive of the long-term renal graft function.

Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients.

BACKGROUND: Sirolimus, a promising new immunosuppressive drug for organ transplantation, is currently associated with side effects, such as thrombocytopenia and hyperlipidemia. METHODS: Eight renal transplant recipients, who developed unexplained interstitial pneumonitis during sirolimus therapy, were extensively re-screened for all causes of pneumonitis. RESULTS: Interstitial pneumonitis was constantly characterized by bilateral interstitial infiltrates on chest x-rays and lung computed tomography scans, with marked general symptoms in all patients but one. Bronchoalveolar lavage (BAL) disclosed lymphocytic alveolitis (mainly of the CD4 type) in seven patients and alveolar hemorrhage in one. Transbronchial lung biopsies, performed in two patients, showed bronchiolitis obliterans with organizing pneumonia combined with lymphocytic interstitial pneumonitis. Pulmonary infections were ruled out by specific stainings and cultures of BAL, bronchial aspirates, and blood cultures. After the elimination of all possible causes, sirolimus-induced pneumonitis was considered probable. Discontinuation of sirolimus in seven cases and dose reduction in the remaining case dramatically improved clinical and radiological status within a few weeks and led to complete resolution within 3 months. CONCLUSIONS: Sirolimus is very probably responsible for interstitial pneumonitis on the following grounds: (a) occurrence of pneumonitis during sirolimus therapy; (b) absence of any other causes; and (c) resolution within 3 months of sirolimus discontinuation or dose reduction. Sirolimus should now be added to the list of possible causes of pulmonary complications after renal transplantation. Discontinuation or dose reduction of sirolimus led to complete and lasting resolution of symptoms.

Acute renal failure in the course of HIV infection: a single-institution retrospective study of ninety-two patients and sixty renal biopsies.

BACKGROUND: Acute renal failure syndromes are frequently encountered in patients with human immunodeficiency virus (HIV) infection. Most reported cases of acute renal failure are related to acute tubular necrosis, but many other causes of renal failure have been described in these patients. METHODS: The present work is a single-institution retrospective study of 92 HIV-infected patients with acute or rapidly progressing renal failure. In 60 cases, a renal biopsy was performed. For each patient we analysed clinical and pathological data, as well as the short-term prognosis. RESULTS: Ten different causes of acute or rapidly progressing renal failure were documented: (i) haemolytic uraemic syndrome (32 patients); (ii) acute tubular necrosis either of ischaemic-toxic origin (18 patients) or due to rhabdomyolysis (six patients); (iii) obstructive renal failure which was either extrinsic (two patients), drug-induced (13 patients) or secondary to paraprotein precipitation (one patient); (iv) HIV-associated nephropathy (14 patients); (v) acute interstitial nephritis (two patients); (vi) various glomerulonephritis (four patients). In most cases, renal failure was severe (the mean creatinine clearance at entry was 12 ml/min). Most patients had a significant improvement in renal function with only symptomatic treatment. Eighteen per cent of the patients died within 2 months of the diagnosis of renal failure. Renal biopsy seems important for the diagnosis but also for the prognosis, at least in the cases of haemolytic-uraemic syndrome, HIV-associated nephropathy and drug-induced micro-obstructive renal failure. CONCLUSION: Vascular and glomerular diseases are frequent causes of acute or rapidly progressing renal failure in HIV-infected patients. Renal biopsy appears to be safe and useful for the diagnosis and the prognosis of the renal failure. High mortality rate is only observed in patients with ischaemic/toxic causes of acute renal failure.

Human herpes virus-8 and other risk factors for Kaposi's sarcoma in kidney transplant recipients. Groupe Cooperatif de Transplantation d' Ile de France (GCIF).

BACKGROUND: The exact reasons for the high incidence of Kaposi's sarcoma (KS) after kidney transplantation are still unknown. Immunosuppression is classically considered as the main risk factor, but the relative risk contributed by the patient's geographic origin and by human herpes virus (HHV)-8 infection still has to be determined. METHODS: We carried out a retrospective and a prospective study among kidney transplant recipients (TP) to identify the risk factors for posttransplantation KS. Each of 30 KS patients was matched with two controls to investigate the association with geographic origin, immunosuppressive regimen, HHV-8 antibodies before and after transplantation, and other infections. Among TP with new onset of KS, we prospectively evaluated HHV-8 serology and viremia in response to decreased immunosuppression. RESULTS: African and Middle East origins, past infection with hepatitis B, hemoglobin level <12 g/dl, lymphocyte count <750/mm3 at the time of diagnosis and initial use of polyclonal antilymphocyte sera were risk factors for KS. After multivariate analysis, origin in Africa or Middle East and use of antilymphocyte sera for induction remained as independent risk factors. Sixty-eight percent (17/25) of TP with HHV-8 antibodies before or after transplantation developed KS compared with 3% (1/33) of seronegative TP (P<0.00001). HHV-8 DNA was detectable in seven of nine peripheral blood mononuclear cells (PBMC) and in six of six KS lesions at diagnosis; it became negative in PBMC in three of five patients in parallel with tumor regression. CONCLUSION: African and Middle East geographic origins, HHV-8 infection before and after kidney transplantation, and initial use of polyclonal antilymphocyte sera were independent risk factors for KS. The presence of HHV-8 antibodies before or after transplantation was highly predictive of the emergence of posttransplantation KS and conferred a 28-fold increased risk of KS (odds ratio=28.4; 95% confidence interval: 4.9-279). Detection of HHV-8 DNA within PBMC and KS lesions seems related to tumor burden and evolution.

Tissue-type plasminogen activator activity in HIV-associated HUS.

BACKGROUND: In children, haemolytic uraemic syndrome (HUS) is associated with high plasma plasminogen activator inhibitor type 1 (PAI-1), which may contribute to the persistence of renal glomerular and arteriolar thrombi. HUS has been described in HIV-infected patients, but the pathophysiology of HUS in these patients is poorly understood. The aim of the study was to investigate plasma fibrinolytic activity in 18 patients with HIV-associated HUS. METHODS: We measured tissue type plasminogen activator (t-PA) and PAI-1 activities in the plasma of 18 HIV-infected patients with biopsy-proven HUS (HIV+/HUS+) and 48 HIV-infected patients without HUS (HIV+/HUS-). RESULTS: Patients with HUS had a significantly higher serum creatinine, a lower platelet count and an increased incidence of cytomegalovirus (CMV) infection (72% of patients HIV+/HUS+, vs 25% of patients HIV+/HUS-). Unexpectedly, plasma PAI-1 activity was similar in both groups. However, t-PA activity was significantly higher in HUS cases (11.5 vs 4.5 U/ml, P=0.001). Patients with CMV infection, with or without HUS, had significantly increased t-PA level (P=0.01). Multivariate analysis identified high t-PA (RR=9.21) and CMV infection (RR=3.36) as risk factors for HUS. CONCLUSION: This study provides evidence that HIV-infected patients with HUS have high plasma t-PA activity. PAI-1 plasma activity is not significantly increased, as opposed to non-HIV-associated HUS. Thus, in the setting of HIV infection, HUS cannot be attributed to decreased fibrinolytic activity.

Renal cell carcinoma of native kidneys: prospective study of 129 renal transplant patients.

PURPOSE: We evaluated the prevalence of renal cell carcinoma of the native kidneys in renal transplant recipients as well as possible risk factors. MATERIALS AND METHODS: A total of 129 consecutive renal transplant recipients underwent ultrasound examination of the native kidneys as part of a routine evaluation. A record was made of acquired cystic kidney disease, defined as 3 cysts or more, and of suspicious masses. When a malignancy was suspected radical nephrectomy was performed. RESULTS: The overall prevalence of renal cell carcinoma of the native kidney was 5 in 129 recipients (3.9%). All cancers were limited to the kidney. No significant relationship was detected between renal cell carcinoma occurrence and patient age, dialysis (when initiated, type and duration), transplantation, drug regimen or incidence of acquired cystic kidney disease. CONCLUSIONS: The risk of renal cell carcinoma, a clinically significant cancer, was approximately 100 times greater in our renal transplant patients than in the general population but no significant risk factor could be identified. Routine ultrasonography for early diagnosis in asymptomatic patients on immunosuppressive therapy is strongly recommended to improve prognosis.

Retroperitoneal laparoscopic nephrectomy of native kidneys in renal transplant recipients.

BACKGROUND: The purpose of this study was to compare retroperitoneal laparoscopic nephrectomy in transplant recipients and in other patients scheduled for nephrectomy. METHODS: From February 1994 to July 1996, 15 transplant recipients and 17 other patients underwent a total of 36 retroperitoneal laparoscopic nephrectomies for various indications. Operative time, morbidity, and hospital stay were compared between the two groups. RESULTS: The average operating time for the 36 procedures was 95+/-38 min (range, 35-180 min). It was shorter in transplant recipients (81+/-32 min) than in other patients (100+/-39 min, P<0.05). There was one postoperative complication in the transplant recipient group. The average length of the postoperative hospitalization was 3.7+/-1.4 days (range, 2-8 days). CONCLUSIONS: The retroperitoneal laparoscopic approach for nephrectomy is as safe and effective in renal transplant recipients as in other patients. Postoperative stay and delay to resumption of oral immunotherapy are short. This approach has become our first-line approach for native nephrectomy in transplant recipients.

Thrombotic microangiopathy and cytomegalovirus disease in patients infected with human immunodeficiency virus.

Thrombotic microangiopathy (TMA) can occur during the course of human immunodeficiency virus (HIV) infection. Clinical and pathological data for 29 patients with TMA and HIV infection were recorded. In a retrospective case-control study, we analyzed the link between opportunistic infections or drug therapies and TMA. Twenty-five patients (mean CD4+ cell count +/- SD, 71.9 +/- 18.3/mm3) had renal impairment, and four had neurological dysfunction. In one-half the cases, the disease was progressive with isolated fragmentation anemia appearing several months before the clinical symptoms. The diagnosis of TMA was confirmed by histological examination of kidney biopsy specimens (18 cases). Endothelial cytomegalovirus (CMV) inclusions were associated with TMA in nine of 18 cases, whereas histological examination did not detect CMV in any control specimens (P < .001). The case-control study demonstrated a link between TMA and clinical CMV infection (odds ratio, 3.9; 95% confidence interval, 1.1-14). We conclude that TMA is a late complication of HIV infection and can be associated with systemic CMV infection in this setting.

Long-term benefit of intravenous immunoglobulins in cadaveric kidney retransplantation.

Renal retransplantation can be hampered by the presence of anti-HLA alloantibodies. Previous studies have documented in vitro and in vivo suppression of these antibodies by intravenous immunoglobulins (IVIg). We conducted a randomized study in 41 patients, who have received a second cadaveric transplant between 1989 and 1994. They all were treated with a quadruple-immunosuppressive protocol. In addition, 21 patients received 0.4 g/kg/day of IVIg, on the first 5 days after transplantation. The two groups of patients were identical for age, sex, duration of the first graft, duration of cold ischemia, anti-HLA sensitization, HLA matching, the number of acute rejection episodes, and the incidence of cytomegalovirus infection. The 5-year survival rate was significantly higher in the group of patients treated with IVIg: 68% versus 50% in the control group. The only significant factor associated with IVIg infusion and better survival was a shorter delay of graft function (3.4 +/- 1.0 days versus 9.9 +/- 1.6 days). In conclusion, this randomized study demonstrates that IVIg treatment is associated with better long-term graft survival in retransplanted patients. This beneficial effect may be related to a long-lasting immunosuppressive effect of IVIg and/or to an early protective effect of the graft against ischemia.

[Kidney surgery using lumbar endoscopy: initial experiences]. / Chirurgie rénale par lomboscopie: expérience initiale.

OBJECTIVES: To evaluate the feasibility, safety and clinical value of lumboscopy for the treatment of upper urinary tract diseases. METHODS: Six nephrectomies, one renal biopsy and one renal cystectomy were performed by retroperitoneoscopy (lumboscopy) in 7 patients. These cases represent the beginning of our experience. The operating time, incidence of intraoperative or postoperative complications and length of hospital stay were studied. RESULTS: The mean operating time was 134 min for nephrectomy, 180 min for cystectomy and 30 min for renal biopsy. No complications were observed. No conversion into laparotomy was required. The mean postoperative hospital stay was 3 days in the patients who were submitted to a single operation. CONCLUSION: Lumboscopy is a relatively easy, safe and reliable technique, and its use in urology warrants further study and development. Dissection of the retroperitoneal space with low pressure CO2 is possible and simplifies the procedure, without increasing the risks for the patient. The indications, especially for nephrectomy, are currently under evaluation.