Development of a practical prediction score for chronic kidney disease after cardiac surgery.

BACKGROUND: Chronic kidney disease (CKD) is a frequent and serious complication of cardiac surgery. This study was designed to establish a scoring system, calculated in the immediate postoperative period, to assess the risk of CKD at 1 yr in patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS: We conducted a cohort study including patients with preoperative estimated glomerular filtration rate above 60 ml min-1 (1.73 m)-2 who underwent cardiac surgery with cardiopulmonary bypass. We identified risk factors for de novo CKD at 1 yr using logistic regression. We derived a risk score for CKD, and externally validated this score in a second cohort. RESULTS: The incidence of CKD was 18% and 23% in the derivation and validation cohorts, respectively. We developed a scoring system that included (i) the occurrence of postoperative acute kidney injury according to the Kidney Disease: Improving Global Outcomes criteria, (ii) age older than 65 yr, (iii) preoperative glomerular filtration rate <80 ml min-1 (1.73 m)-2, (iv) aortic cross-clamping time longer than 50 min, and (v) the type of surgery (aortic or cardiac transplantation). This score predicted CKD with good accuracy (area under the receiver operating characteristic curve: 0.81; 95% confidence interval: 0.77-0.86 in the derivation cohort), and with fair accuracy in the validation cohort (area under the receiver operating characteristic curve: 0.78; 95% confidence interval: 0.72-0.83). CONCLUSIONS: We provide an easy-to-calculate scoring system to identify patients at high risk of developing CKD after cardiac surgery with cardiopulmonary bypass. This system might help clinicians to target more accurately patients requiring monitoring of renal function after cardiac surgery, and to design appropriate interventional trials aimed at preventing CKD or mitigating its consequences.

Urinary mRNA for the Diagnosis of Renal Allograft Rejection: The Issue of Normalization.

Urinary messenger RNA (mRNA) quantification is a promising method for noninvasive diagnosis of renal allograft rejection (AR), but the quantification of mRNAs in urine remains challenging due to degradation. RNA normalization may be warranted to overcome these issues, but the strategies of gene normalization have been poorly evaluated. Herein, we address this issue in a case-control study of 108 urine samples collected at time of allograft biopsy in kidney recipients with (n = 52) or without (n = 56) AR by comparing the diagnostic value of IP-10 and CD3ε mRNAs-two biomarkers of AR-after normalization by the total amount of RNA, normalization by one of the three widely used reference RNAs-18S, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Hypoxanthine-guanine phosphoribosyltransferase (HPRT)-or normalization using uroplakin 1A (UPK) mRNA as a possible urine-specific reference mRNA. Our results show that normalization based on the total quantity of RNA is not substantially improved by additional normalization and may even be worsened with some classical reference genes that are overexpressed during rejection. However, considering that normalization by a reference gene is necessary to ensure polymerase chain reaction (PCR) quality and reproducibility and to suppress the effect of RNA degradation, we suggest that GAPDH and UPK1A are preferable to 18S or HPRT RNA.

Fibrosis progression according to epithelial-mesenchymal transition profile: a randomized trial of everolimus versus CsA.

Markers of epithelial-mesenchymal transition (EMT) may identify patients at high risk of graft fibrogenesis who could benefit from early calcineurin inhibitor (CNI) withdrawal. In a randomized, open-label, 12-month trial, de novo kidney transplant patients received cyclosporine, enteric-coated mycophenolate sodium (EC-MPS) and steroids to month 3. Patients were stratified as EMT+ or EMT- based on month 3 biopsy, then randomized to start everolimus with half-dose EC-MPS (720 mg/day) and cyclosporine withdrawal (CNI-free) or continue cyclosporine with standard EC-MPS (CNI). The primary endpoint was progression of graft fibrosis (interstitial fibrosis/tubular atrophy [IF/TA] grade increase ≥1 between months 3-12) in EMT+ patients. 194 patients were randomized (96 CNI-free, 98 CNI); 153 (69 CNI-free, 84 CNI) were included in histological analyses. Fibrosis progression occurred in 46.2% (12/26) CNI-free EMT+ patients versus 51.6% (16/31) CNI EMT+ patients (p = 0.68). Biopsy-proven acute rejection (BPAR, including subclinical events) occurred in 25.0% and 5.1% of CNI-free and CNI patients, respectively (p < 0.001). In conclusion, early CNI withdrawal with everolimus initiation does not prevent interstitial fibrosis. Using this CNI-free protocol, in which everolimus exposure was relatively low and administered with half-dose EC-MPS, CNI-free patients were overwhelmingly under-immunosuppressed and experienced an increased risk of BPAR.

Contribution of epithelial plasticity to renal transplantation-associated fibrosis.

Every year in the United States, 5000 renal transplant recipients start or restart dialysis because of the unusual propensity of these allografts to develop interstitial fibrosis and tubular atrophy (IF/TA). Although IF/TA often follows one or more identifiable events, our capacity to specifically treat, prevent, or even detect IF/TA at an early stage is poor. These limitations are largely related to our lack of adequate tools to assess graft failure over time. Data accumulated over the past 5 years have demonstrated that tubular epithelial cells may react to certain fibrogenic stimuli to engage in the process of epithelial-to-mesenchymal transition (EMT). In this review, we highlight the current view of EMT with a focus on both its role in the context of renal transplantation and the potential for utilizing markers of EMT to identify patients undergoing early IF/TA.

[Delayed graft function]. / Reprise retardée de fonction rénale.

Delayed return to kidney function after transplantation is characterized essentially by acute ischemic tubular necrosis. It remains frequent and has no curative treatment. However, an induction treatment of antilymphocyte serum may reduce the delay in recuperation. In patients with delayed function, the maintenance immunosuppressive treatment should take into account the excessive risk of acute rejection over the short term and the more rapid deterioration of renal function over the long term. This means that biopsies to screen for acute rejection should be done systematically before the end of the 3rd month and anticalcineurin toxicity-sparing treatment should be considered, replacing anticalcineurins immediately with belatacept or after the 3-month acute period with proliferation signal inhibitors, if the kidney histology tests permit. In all cases, the classical measures of kidney protection remain indispensable.

Chronic lymphocytic leukemia: a hazardous condition before kidney transplantation.

Long-term survival of patients with chronic lymphocytic leukemia (CLL) is over 10 years, and such patients are thus potential kidney recipients in the case of superimposed end-stage renal disease. However, the renal and patient outcome in this condition is unknown. We report the charts of four patients with CLL who were engrafted in France with a deceased-donor kidney and underwent routine triple immunosuppressive therapy. The results show that these patients developed severe infectious episodes (fatal in one case) and tumoral complications including rapid progression of CLL in two cases. Moreover, the graft may be infiltrated and damaged by monoclonal B cells: one patient lost his graft 14 months after transplantation. Various therapeutic options (modifications of the immunosuppressive regimen, anti-CD20 antibodies, irradiation of the graft) showed little (if any) efficacy. Therefore, we believe that CLL is a too hazardous condition to envisage solid organ transplantation with a routine immunosuppressive regimen, and we propose a more appropriate approach.

Risk factors for early epithelial to mesenchymal transition in renal grafts.

Epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells (TECs) may participate in the pathogenesis of renal fibrosis. We performed a prospective study of EMT markers in protocol biopsies obtained 3 months after engraftment from 56 patients who received deceased donor kidneys and who had stable renal function. The presence of EMT was examined, and quantified by immunohistochemical staining for vimentin and translocation of beta-catenin to the cytoplasm. EMT status was defined as the presence of EMT markers in > or = 10% of TECs. EMT features were virtually absent in implantation biopsies, whereas 41% of the grafts were EMT-positive in the absence of advanced chronic allograft nephropathy. Thirteen patients (23%) had borderline changes or acute rejection. EMT features were more frequent in these patients than in those with normal kidney grafts (vimentin expression, p = 0.003; beta-catenin translocation, p = 0.002). EMT in grafts corresponded with elevated serum creatinine of the donor before the recovery of kidney (p = 0.02) and longer cold ischemia time (p = 0.02). In contrast, the donor age had no influence on the expression of EMT markers. These results suggest that EMT is an early and frequent phenomenon in kidney transplants that could be triggered by immunological and/or ischemic tubular injury.

[Acute renal failure following ingestion of Cortinarius orellanus in 12 patients. Initial presentation and progress over a period of 13 years]. / Insuffisance rénale aiguë après ingestion de Cortinarius orellanus chez 12 patients. Présentation initiale et évolution sur une periode de treize annees.

INTRODUCTION: This study reports the largest series of acute renal failure following collective poisoning by Cortinarius orellanus since 1957. PATIENTS: Twelve men, in whom altered renal function appeared following ingestion of mushroom soup (Cortinarius orellanus) when they were 20 to 23 year-old, were followed up for 13 years. RESULTS: After a period of latency of between 2 to 5 days, the patients complained of asthenia, intense thirst and digestive and neurological disorders. On admission, 4 were anuretic and two exhibited polyuria. Leukocyturia was detected in all patients but without proteinuria. Renal biopsy was performed on day 14 in seven patients. It revealed severe tubulo-interstitial lesions with polymorphous cell infiltration, oedema, loose fibrosis and epithelial necrosis. Eight patients required haemodialysis. Nine patients received corticosteroids for less than 6 months. Over a follow-up period of 13 years, seven patients recovered normal renal function, four underwent transplantation and one was still under haemodialysis and died, victim of a car accident. CONCLUSION: The incidence of acute renal failure varies from 30 to 46%. It depends on individual sensitivity, pre-existing nephropathy and the cumulated dose of toxin ingested. Early and severe interstitial fibrosis, marked interstitial oedema and tubular epithelial necrosis are the most characteristics renal lesions. Renal failure regresses progressively over several months in 60% of cases. In the other patients, terminal renal failure appears immediately or after several years. The evolution is not influenced by corticosteroid therapy.

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.

[Plasminogen activator inhibitor type 1: physiology and role in renal physiopathology]. / L'inhibiteur de type 1 des activateurs du plasminogène: physiologie et rôle en physiopathologie rénale.

Plasminogen activator inhibitor type 1 plays a prominent part in the regulation of extra and intra-vascular fibrinolysis through the inhibition of plasmin formation. In addition to its role in the resolution of blood clots, PAI-1 is involved in a variety of other biological processes including extracellular remodeling, cellular mobility, embryo implantation, development and tumoral proliferation. Moreover, PAI-1 is also implicated in various pathological processes such as thromboembolic diseases, atherosclerosis and fibrosis formation, particularly in the kidney and the lung. Inhibition of PAI-1 activity or of PAI-1 synthesis by specific antibodies, peptidic antagonists, antisens oligonucleotides or decoy oligonucleotides has been obtained in vitro but need to be evaluated in vivo. All these findings may have new therapeutical implications, explaining the importance of studies on PAI-1 production and regulation.

[Primary hyperparathyroidism]. / Hyperparathyroïdie primitive.

Primary hyperparathyroidism is the third most frequent endocrine disorder. The condition required for diagnosis is inappropriately elevated secretion of parathyroid hormone (PTH) with respect to calcemia. Most often, the disease is due to a parathyroid adenoma, i.e. a monoclonal benign parathyroid tumor, less often to a parathyroid hyperplasia. The main tumorogenic mechanisms currently proposed are a DNA rearrangement in the PTH locus (transposition of the PTH promoter upstream to Cyclin D1/PRAD 1 gene) and a mutation of the gene responsible for multiple endocrine neoplasia type I. The clinical presentation has strikingly evolved towards a milder, asymptomatic form, frequently diagnosed on systematic screenings. Though the mechanism of hypercalcemia is better understood, several hypothesis are still being considered about the regulation of tumoral PTH secretion: the role of the expression of calcium-receptor in parathyroid gland cells, vitamin D receptor and estrogen receptor polymorphisms, etc. Surgery is still advised for symptomatic forms of the disease, either because of a bone involvement, or because of an evolutive nephrolithiasis. In the near future, the new calcium-receptor agonists could be a relevant therapeutic approach.

[Quality assurance in nursing: nursing standard. Nausea, gagging and vomiting during emetogenic cytostatic therapies. Report of research into the development and introduction of nursing standards]. / Qualitätssicherung in der Pflege: Pflegestandard Ubelkeit, Würgen und Erbrechen bei emetogenen Zytostatikatherapien. Forschungsbericht über die Entwicklung und Einführung eines Pflegestandards.

This report documents the introduction of standard-setting in the haemato-oncological reverse-isolation unit of the Kanton hospital, Basle. The topic is the prevention or reduction of nausea, choking and vomiting, and the treatment of patients who are receiving prolonged chemotherapy. The objective was quality assurance in nursing care. The definition of the desired outcome was the well-being and safety of patients. In addition the wish of the staff to increase their security in dealing with antiemetics was taken into consideration. The authors describe the basic problems they encountered in their strategies and actions for standard setting. By extensive use of measurement and evaluation it was possible, in cooperation with medical leadership, to develop instructional leaflets and checklists. Approximation to the intended outcome was achieved. The well being of patients and satisfaction of the safety-needs of staff and patients reached a high level. The report shows that the introduction of nursing standards requires great effort and a high level of commitment of the entire team. It also shows that the effort is worthwhile for patients and staff.

Mycoplasma, chlamydia, Epstein-Barr, herpes I and II, and AIDS infections among 100 consecutive infertile female patients and husbands: diagnosis, treatment, and results.

One hundred consecutive infertile patients were studied to determine the incidence of sexually transmitted diseases (STDs) among middle and upper income patients, most of whom were referred as longstanding failures by other physicians. There were no cases of syphilis, gonorrhea, or AIDS found among these patients. One patient was pregnant when first seen, and was eliminated. Genital mycoplasmas were cultured from 64 wives. Antibodies for past or recent infection with Chlamydia were present in only 23. Antibodies to Epstein-Barr virus and to herpes II were found in 92 and 65, respectively. If only the mycoplasmas, Chlamydia, and herpes II are considered possible causes of human infertility, only 7 of the 99 couples showed no evidence of ever having had any of these three infections. Edometrial histology was positive for the changes associated with Mycoplasma infection in 47 of the 86 patients biopsied. Of the 39 with negative biopsies, 24 yielded positive cultures for Mycoplasma. Hence, only 15 of the 99 patients were negative for Mycoplasma by both culture and/or endometrial histology. Treatment with the antibiotic of choice, as indicated by sensitivity testing of all Mycoplasma-positive cultures, was an important factor in producing 43 pregnancies during the first year of study. Two of these were ectopic; 11 were spontaneous abortions, with one of these women now pregnant again and in mid-trimester; 28 have delivered healthy babies; and two are still pregnant and doing well.

Prognostic value of subacute focal inflammation of the endometrium, with special reference to pelvic adhesions as observed on laparoscopic examination. An eight-year review.

The significance of the endometrial lesion known as subacute focal inflammation (SFI) (or the more descriptive term lymphoid aggregates [LA]) as a factor in reproductive failure is controversial. We correlated the pelvic findings of 262 consecutive laparoscopic procedures performed for infertility with the histologic diagnosis from an endometrial biopsy that had been obtained previously as part of the infertility evaluations. Pelvic adhesions were observed in 87.3% of women in whom the diagnosis of SFI had been made. Pelvic adhesions were observed in only 10.9% of women whose biopsies did not contain SFI. Of women with SFI on biopsy but without pelvic adhesions, 70.6% demonstrated American Fertility Society stage I endometriosis at laparoscopy. These findings are statistically significant (P less than .0001).

Dysplasia of the lower genital tract in the female monkey, Macaca fascicularis, the crab-eating macaque from Southeast Asia.

Seventy-eight female reproductive tracts from mature Macaca fascicularis caught in the wild were examined histologically for evidence of dysplasia in immature (metaplastic) and native (mature) squamous epithelium of the cervix and vagina. This series contained equal numbers of experimental animals and control and/or breeding colony animals. Five of 39 experimental animals showed dysplasia, whereas six animals with definite and two with questionable dysplasia were found in 39 control and breeding colony animals. On the basis of the foregoing facts, it would appear that these dysplastic lesions were of spontaneous origin and of undetermined etiology. Therefore, those investigators who experiment upon the reproductive tract of this species of monkey should be wary of interpreting any given experiment as "causing" dysplasia. Monkeys of this same species, born and reared in our Primate Center, have been examined for comparable dysplastic lesions of the lower female genital tract. None was found thus far but the study is continuing.