The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials.

The kidney sessions of the 2017 Banff Conference focused on 2 areas: clinical implications of inflammation in areas of interstitial fibrosis and tubular atrophy (i-IFTA) and its relationship to T cell-mediated rejection (TCMR), and the continued evolution of molecular diagnostics, particularly in the diagnosis of antibody-mediated rejection (ABMR). In confirmation of previous studies, it was independently demonstrated by 2 groups that i-IFTA is associated with reduced graft survival. Furthermore, these groups presented that i-IFTA, particularly when involving >25% of sclerotic cortex in association with tubulitis, is often a sequela of acute TCMR in association with underimmunosuppression. The classification was thus revised to include moderate i-IFTA plus moderate or severe tubulitis as diagnostic of chronic active TCMR. Other studies demonstrated that certain molecular classifiers improve diagnosis of ABMR beyond what is possible with histology, C4d, and detection of donor-specific antibodies (DSAs) and that both C4d and validated molecular assays can serve as potential alternatives and/or complements to DSAs in the diagnosis of ABMR. The Banff ABMR criteria are thus updated to include these alternatives. Finally, the present report paves the way for the Banff scheme to be part of an integrative approach for defining surrogate endpoints in next-generation clinical trials.

Real Time Central Assessment of Kidney Transplant Indication Biopsies by Microarrays: The INTERCOMEX Study.

The authors conducted a prospective trial to assess the feasibility of real time central molecular assessment of kidney transplant biopsy samples from 10 North American or European centers. Biopsy samples taken 1 day to 34 years posttransplantation were stabilized in RNAlater, sent via courier overnight at ambient temperature to the central laboratory, and processed (29 h workflow) using microarrays to assess T cell- and antibody-mediated rejection (TCMR and ABMR, respectively). Of 538 biopsy samples submitted, 519 (96%) were sufficient for microarray analysis (average length, 3 mm). Automated reports were generated without knowledge of histology and HLA antibody, with diagnoses assigned based on Molecular Microscope Diagnostic System (MMDx) classifier algorithms and signed out by one observer. Agreement between MMDx and histology (balanced accuracy) was 77% for TCMR, 77% for ABMR, and 76% for no rejection. A classification tree derived to provide automated sign-outs predicted the observer sign-outs with >90% accuracy. In 451 biopsy samples where feedback was obtained, clinicians indicated that MMDx more frequently agreed with clinical judgment (87%) than did histology (80%) (p = 0.0042). In 81% of feedback forms, clinicians reported that MMDx increased confidence in management compared with conventional assessment alone. The authors conclude that real time central molecular assessment is feasible and offers a useful new dimension in biopsy interpretation. ClinicalTrials.gov NCT#01299168.

From Humoral Theory to Performant Risk Stratification in Kidney Transplantation.

The purpose of the present review is to describe how we improve the model for risk stratification of transplant outcomes in kidney transplantation by incorporating the novel insights of donor-specific anti-HLA antibody (DSA) characteristics. The detection of anti-HLA DSA is widely used for the assessment of pre- and posttransplant risks of rejection and allograft loss; however, not all anti-HLA DSA carry the same risk for transplant outcomes. These antibodies have been shown to cause a wide spectrum of effects on allografts, ranging from the absence of injury to indolent or full-blown acute antibody-mediated rejection. Consequently, the presence of circulating anti-HLA DSA does not provide a sufficient level of accuracy for the risk stratification of allograft outcomes. Enhancing the predictive performance of anti-HLA DSA is currently one of the most pressing unmet needs for facilitating individualized treatment choices that may improve outcomes. Recent advancements in the assessment of anti-HLA DSA properties, including their strength, complement-binding capacity, and IgG subclass composition, significantly improved the risk stratification model to predict allograft injury and failure. Although risk stratification based on anti-HLA DSA properties appears promising, further specific studies that address immunological risk stratification in large and unselected populations are required to define the benefits and cost-effectiveness of such comprehensive assessment prior to clinical implementation.

The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology.

The XIII Banff meeting, held in conjunction the Canadian Society of Transplantation in Vancouver, Canada, reviewed the clinical impact of updates of C4d-negative antibody-mediated rejection (ABMR) from the 2013 meeting, reports from active Banff Working Groups, the relationships of donor-specific antibody tests (anti-HLA and non-HLA) with transplant histopathology, and questions of molecular transplant diagnostics. The use of transcriptome gene sets, their resultant diagnostic classifiers, or common key genes to supplement the diagnosis and classification of rejection requires further consensus agreement and validation in biopsies. Newly introduced concepts include the i-IFTA score, comprising inflammation within areas of fibrosis and atrophy and acceptance of transplant arteriolopathy within the descriptions of chronic active T cell-mediated rejection (TCMR) or chronic ABMR. The pattern of mixed TCMR and ABMR was increasingly recognized. This report also includes improved definitions of TCMR and ABMR in pancreas transplants with specification of vascular lesions and prospects for defining a vascularized composite allograft rejection classification. The goal of the Banff process is ongoing integration of advances in histologic, serologic, and molecular diagnostic techniques to produce a consensus-based reporting system that offers precise composite scores, accurate routine diagnostics, and applicability to next-generation clinical trials.

C1 Inhibitor in Acute Antibody-Mediated Rejection Nonresponsive to Conventional Therapy in Kidney Transplant Recipients: A Pilot Study.

Complement inhibitors have not been thoroughly evaluated in the treatment of acute antibody-mediated rejection (ABMR). We performed a prospective, single-arm pilot study to investigate the potential effects and safety of C1 inhibitor (C1-INH) Berinert added to high-dose intravenous immunoglobulin (IVIG) for the treatment of acute ABMR that is nonresponsive to conventional therapy. Kidney recipients with nonresponsive active ABMR and acute allograft dysfunction were enrolled between April 2013 and July 2014 and received C1-INH and IVIG for 6 months (six patients). The primary end point was the change in eGFR at 6 months after inclusion (M+6). Secondary end points included the changes in histology and DSA characteristics and adverse events as evaluated at M+6. All patients showed an improvement in eGFR between inclusion and M+6: from 38.7 ± 17.9 to 45.2 ± 21.3 mL/min/1.73 m(2) (p = 0.0277). There was no change in histological features, except a decrease in the C4d deposition rate from 5/6 to 1/6 (p = 0.0455). There was a change in DSA C1q status from 6/6 to 1/6 positive (p = 0.0253). One deep venous thrombosis was observed. In a secondary analysis, C1-INH patients were compared with a similar historical control group (21 patients). C1-INH added to IVIG is safe and may improve allograft function in kidney recipients with nonresponsive acute ABMR.

Late Failing Heart Allografts: Pathology of Cardiac Allograft Vasculopathy and Association With Antibody-Mediated Rejection.

In heart transplantation, there is a lack of robust evidence of the specific causes of late allograft failure. We hypothesized that a substantial fraction of failing heart allografts may be associated with antibody-mediated injury and immune-mediated coronary arteriosclerosis. We included all patients undergoing a retransplantation for late terminal heart allograft failure in three referral centers. We performed an integrative strategy of heart allograft phenotyping by assessing the heart vascular tree including histopathology and immunohistochemistry together with circulating donor-specific antibodies. The main analysis included 40 explanted heart allografts patients and 402 endomyocardial biopsies performed before allograft loss. Overall, antibody-mediated rejection was observed in 19 (47.5%) failing heart allografts including 16 patients (40%) in whom unrecognized previous episodes of subclinical antibody-mediated rejection occurred 4.5 ± 3.5 years before allograft loss. Explanted allografts with evidence of antibody-mediated rejection demonstrated higher endothelitis and microvascular inflammation scores (0.89 ± 0.26 and 2.25 ± 0.28, respectively) compared with explanted allografts without antibody-mediated rejection (0.42 ± 0.11 and 0.36 ± 0.09, p = 0.046 and p < 0.0001, respectively). Antibody-mediated injury was observed in 62.1% of failing allografts with pure coronary arteriosclerosis and mixed (arteriosclerosis and atherosclerosis) pattern, while it was not observed in patients with pure coronary atherosclerosis (p = 0.0076). We demonstrate that antibody-mediated rejection is operating in a substantial fraction of failing heart allografts and is associated with severe coronary arteriosclerosis. Unrecognized subclinical antibody-mediated rejection episodes may be observed years before allograft failure.

Mastering the risk of HLA antibodies in kidney transplantation: an algorithm based on pretransplant single-antigen flow bead techniques.

The utilization of sensitive techniques of detection of HLA antibodies to define and measure sensitization has greatly evolved in recent years. We present here an approach to minimize the risk of HLA antibodies in kidney transplantation based on the evaluation of graft accessibility of sensitized patients by calculated PRA (cPRA) and estimation of potential matched donors (PMD) using a national simulation software program. This study included all registered patients on our waiting list (WL) for deceased donor (DD) kidney transplants. All patients were screened by single-antigen flow bead (SAFB) techniques. Of the 502 registered patients, 174 (34.7%) were sensitized. Among these, 48.3% (84 pts) had a cPRA>85%. For 75.3% of sensitized patients (90 pts with cPRA≤85% and 41 pts with cPRA>85%), the flow of PMD was considered sufficient to allow a transplant avoiding all unacceptable antigens. The 41 patients with a cPRA>85% (48.8%) had a satisfactory donor flow in the framework of the national prioritization program for highly sensitized patients. Finally, 43 sensitized patients (24.7%) were deemed eligible for a strategy of higher immunological risk through desensitization protocols or transplantation against HLA-DSAs. This approach provides a logical and systematic strategy to rationalize the access of sensitized patients to kidney transplantation minimizing the risk of HLA antibodies.

Outcome of subclinical antibody-mediated rejection in kidney transplant recipients with preformed donor-specific antibodies.

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.

Comparison of combination Plasmapheresis/IVIg/anti-CD20 versus high-dose IVIg in the treatment of antibody-mediated rejection.

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.

Clinical relevance of preformed HLA donor-specific antibodies in kidney transplantation.

Since the pioneering work of Patel and Terazaki, the presence of an anti-donor anti-body of the IgG isotype, as demonstrated by a lymphocytotoxic assay on T cells, has been a contraindication to transplantation, due to the very high rate of graft loss reported (>80% in the first few weeks posttransplant). The advent of more sensible and specific techniques of detection of anti-HLA antibodies (such as ELISA or Luminex techniques) has questioned this dogma, with a number of reports showing that transplantation, despite the presence of an donor-specific antibody (DSA), could be done without excessive graft losses, despite higher rates of rejection. We thus decided to retrospectively screen a cohort of 237 patients consecutively transplanted in our unit. 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). Kidney graft survival at 8 years was significantly worse in patients with DSA. The incidence of AMR in patients with DSA was 9-fold higher than in patients without DSA and led to a significantly worse graft survival. The prevalence for AMR in patients with DSA detected on historic serum was 32.3% and was significantly more elevated in patients with strongly positive DSA (score 6-8) and in patients with his-toric positive crossmatches. Interestingly, those patients with DSA that did not experience AMR had the same graft survival as patients without DSA. Thus, the presence of preformed DSA is strongly associated with increased graft loss in kidney transplants, related to an increased risk of AMR. Our findings demonstrate the importance of detection and charac-terization of DSA before transplantation. Stratification of this immunological risk should be used both to determine kidney allocation and to devise specific strategies for these patients.

[Antibody-mediated acute rejection]. / Rejet aigu médié par anticorps.

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.

A simple clinico-histopathological composite scoring system is highly predictive of graft outcomes in marginal donors.

The predictive value of pre-implantation biopsies versus clinical scores has not been studied extensively in marginal donors. Pre-implantation biopsies were performed in 313 kidneys from donors that were > or = 50 years of age (training set, n = 191; validation set, n = 122). The value of the donor clinical parameters and histological results in predicting 1-year estimated glomerular filtration rate (eGFR) <25 mL/min/1.73 m(2) was retrospectively evaluated. In multivariate analysis, the only clinical parameters associated with low eGFR were donor hypertension and a serum creatinine level > or =150 micromol/L before organ recovery. Clinical scores (Nyberg and Pessione) were not significantly associated with graft function. Regarding histological parameters, univariate analysis showed that glomerulosclerosis (GS) (p = 0.02), arteriolar hyalinosis (p = 0.03) and the Pirani (p = 0.02) and chronic allograft damage index (CADI) (p = 0.04) histological scores were associated with low eGFR. The highest performance in predicting low eGFR was achieved using a composite score that included donor serum creatinine (> or =150 micromol/L or <150 micromol/L), donor hypertension and GS (> or =10% or <10%). The validation set confirmed the critical importance of taking into account biopsy and clinical parameters during marginal donor evaluation. In conclusion, clinical scores are weak predictors of graft outcomes with marginal donors. Instead, a simple and convenient composite score strongly predicts graft function and survival and may facilitate optimal allocation of marginal donors.

Renal histopathological lesions after lung transplantation in patients with cystic fibrosis.

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.

Clinical relevance of preformed HLA donor-specific antibodies in kidney transplantation.

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.

Determinants of poor graft outcome in patients with antibody-mediated acute rejection.

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.

Acute oxalate nephropathy: A new etiology for acute renal failure following nonrenal solid organ transplantation.

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.

Membranous nephropathy and cancer: Epidemiologic evidence and determinants of high-risk cancer association.

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.

[Inhibin and cyberning]. / Inhibine et cybernines.

Inhibin is a peptidic gonadal hormone which preferentially suppresses FSh secretion and synthesis. As its purification is not yet achieved, only bioassays are available, performed with testicular extracts or follicular fluid. Its secretion by granulosa cells and Sertoli cells is partly spontaneous, partly stimulated by androgens and FSH. In women, folliculogenesis is controlled by inhibin induced FSH fluctuations. But inhibin acts also at the gonadal level like the cybernis, peptidic substances secreted by the ovary, which modulate ovarian effects of gonadotrophins. Five of them have been identified : the oocyte maturation inhibitor, the luteinization inhibitor, the FSH binding inhibitor (implied in follicular atresia), the LH receptor binding inhibitor (involved in luteolysis), and gonadocrinins (which bind to ovarian LHRH-receptors). The discovery of these ovarian peptides leads to new concepts in folliculogenesis and luteolysis and may provide a new therapeutic approach in contraception and sterility fields.

[Role of histaminergic H1 and H2 receptors in prolactin release in humans]. / Rôle des récepteurs histaminergiques H1 et H2 dans la prolactinosécrétion chez l'homme.

Histamine is considered as a neurotransmitter, since it is present in hypothalamus and pituitary gland. It has been reported to stimulate prolactin (PRL) release in rats and humans; it seems to be involved in the control of LH release in rats. But cimetidine, an H2 antagonist also induces PRL release in humans. To investigate the relationship between the PRL secretion and possible histaminergic pathways, the response of PRL and LH was studied for 180 minutes in 10 normal subjects (5 men, 5 women) after H1 antagonist (diphenhydramine 50 mg iv), H2 antagonist (cimetidine 300 mg iv) and placebo. Diphenhydramine and placebo injection resulted in a decrease of PRL from 0800 until 11.00 hours, suggesting a spontaneous diurnal variation. Cimetidine induced a short but significant rise of PRL before a similar diurnal secretory pattern. LH levels were unaffected by H1 and H2 antagonists. These data suggest that PRL and LH secretion in humans is unresponsive to H1 histaminergic pathways. The specific action of cimetidine remains to be defined.