Recurrence of membranous nephropathy after kidney transplantation: A multicenter retrospective cohort study.

Membranous nephropathy (MN) is a leading cause of kidney failure worldwide and frequently recurs after transplant. Available data originated from small retrospective cohort studies or registry analyses; therefore, uncertainties remain on risk factors for MN recurrence and response to therapy. Within the Post-Transplant Glomerular Disease Consortium, we conducted a retrospective multicenter cohort study examining the MN recurrence rate, risk factors, and response to treatment. This study screened 22,921 patients across 3 continents and included 194 patients who underwent a kidney transplant due to biopsy-proven MN. The cumulative incidence of MN recurrence was 31% at 10 years posttransplant. Patients with a faster progression toward end-stage kidney disease were at higher risk of developing recurrent MN (hazard ratio [HR], 0.55 per decade; 95% confidence interval [CI], 0.35-0.88). Moreover, elevated pretransplant levels of anti-phospholipase A2 receptor (PLA2R) antibodies were strongly associated with recurrence (HR, 18.58; 95% CI, 5.37-64.27). Patients receiving rituximab for MN recurrence had a higher likelihood of achieving remission than patients receiving renin-angiotensin-aldosterone system inhibition alone. In sum, MN recurs in one-third of patients posttransplant, and measurement of serum anti-PLA2R antibody levels shortly before transplant could aid in risk-stratifying patients for MN recurrence. Moreover, patients receiving rituximab had a higher rate of treatment response.

The Swiss Kidney Stone Cohort: A Longitudinal, Multicentric, Observational Cohort to Study Course and Causes of Kidney Stone Disease in Switzerland.

BACKGROUND: Kidney stone disease has a high prevalence worldwide of approximately 10% of the population and is characterized by a high recurrence rate. Kidney stone disease results from a combination of genetic, environmental, and lifestyle risk factors, and the dissection of these factors is complex. METHODS: The Swiss Kidney Stone Cohort (SKSC) is an investigator-initiated prospective, multicentric longitudinal, observational study in patients with kidney stones followed with regular visits over a period of 3 years after inclusion. Ongoing follow-ups by biannual telephone interviews will provide long-term outcome data. SKSC comprises 782 adult patients (age >18 years) with either recurrent stones or a single stone event with at least one risk factor for recurrence. In addition, a control cohort of 207 individuals without kidney stone history and absence of kidney stones on a low-dose CT scan at enrolment has also been recruited. SKSC includes extensive collections of clinical data, biochemical data in blood and 24-h urine samples, and genetic data. Biosamples are stored at a dedicated biobank. Information on diet and dietary habits was collected through food frequency questionnaires and standardized recall interviews by trained dieticians with the Globodiet software. CONCLUSION: SKSC provides a unique opportunity and resource to further study cause and course of kidney disease in a large population with data and samples collected of a homogeneous collective of patients throughout the whole Swiss population.

Differences in the Food Consumption Between Kidney Stone Formers and Nonformers in the Swiss Kidney Stone Cohort.

OBJECTIVE: Diet has a major influence on the formation and management of kidney stones. However, kidney stone formers' diet is difficult to capture in a large population. Our objective was to describe the dietary intake of kidney stone formers in Switzerland and to compare it to nonstone formers. METHODS: We used data from the Swiss Kidney Stone Cohort (n = 261), a multicentric cohort of recurrent or incident kidney stone formers with additional risk factors, and a control group of computed tomography-scan proven nonstone formers (n = 197). Dieticians conducted two consecutive 24-h dietary recalls, using structured interviews and validated software (GloboDiet). We took the mean consumption per participant of the two 24-h dietary recalls to describe the dietary intake and used two-part models to compare the two groups. RESULTS: The dietary intake was overall similar between stone and nonstone formers. However, we identified that kidney stone formers had a higher probability of consuming cakes and biscuits (odds ratio (OR) [95% CI] = 1.56[1.03; 2.37]) and soft drinks (OR = 1.66[1.08; 2.55]). Kidney stone formers had a lower probability of consuming nuts and seeds (OR = 0.53[0.35; 0.82]), fresh cheese (OR = 0.54[0.30; 0.96]), teas (OR = 0.50[0.3; 0.84]), and alcoholic beverages (OR = 0.35[0.23; 0.54]), especially wine (OR = 0.42[0.27; 0.65]). Furthermore, among consumers, stone formers reported smaller quantities of vegetables (ß coeff[95% CI] = - 0.23[- 0.41; - 0.06]), coffee (ß coeff = - 0.21[- 0.37; - 0.05]), teas (ß coeff = - 0.52[- 0.92; - 0.11]) and alcoholic beverages (ß coeff = - 0.34[- 0.63; - 0.06]). CONCLUSION: Stone formers reported lower intakes of vegetables, tea, coffee, and alcoholic beverages, more specifically wine, but reported drinking more frequently soft drinks than nonstone formers. For the other food groups, stone formers and nonformers reported similar dietary intakes. Further research is needed to better understand the links between diet and kidney stone formation and develop dietary recommendations adapted to the local settings and cultural habits.

Collagen IVα345 dysfunction in glomerular basement membrane diseases. I. Discovery of a COL4A3 variant in familial Goodpasture's and Alport diseases.

Diseases of the glomerular basement membrane (GBM), such as Goodpasture's disease (GP) and Alport syndrome (AS), are a major cause of chronic kidney failure and an unmet medical need. Collagen IVα345 is an important architectural element of the GBM that was discovered in previous research on GP and AS. How this collagen enables GBM to function as a permselective filter and how structural defects cause renal failure remain an enigma. We found a distinctive genetic variant of collagen IVα345 in both a familial GP case and four AS kindreds that provided insights into these mechanisms. The variant is an 8-residue appendage at the C-terminus of the α3 subunit of the α345 hexamer. A knock-in mouse harboring the variant displayed GBM abnormalities and proteinuria. This pathology phenocopied AS, which pinpointed the α345 hexamer as a focal point in GBM function and dysfunction. Crystallography and assembly studies revealed underlying hexamer mechanisms, as described in Boudko et al. and Pedchenko et al. Bioactive sites on the hexamer surface were identified where pathogenic pathways of GP and AS converge and, potentially, that of diabetic nephropathy (DN). We conclude that the hexamer functions include signaling and organizing macromolecular complexes, which enable GBM assembly and function. Therapeutic modulation or replacement of α345 hexamer could therefore be a potential treatment for GBM diseases, and this knock-in mouse model is suitable for developing gene therapies.

Incidence of new onset glomerulonephritis after SARS-CoV-2 mRNA vaccination is not increased.

Numerous cases of glomerulonephritis manifesting shortly after SARS-CoV-2 vaccination have been reported, but causality remains unproven. Here, we studied the association between mRNA-based SARS-CoV-2 vaccination and new-onset glomerulonephritis using a nationwide retrospective cohort and a case-cohort design. Data from all Swiss pathology institutes processing native kidney biopsies served to calculate incidence of IgA nephropathy, pauci-immune necrotizing glomerulonephritis, minimal change disease, and membranous nephropathy in the adult Swiss population. The observed incidence during the vaccination campaign (January to August 2021) was not different from the expected incidence calculated using a Bayesian model based on the years 2015 to 2019 (incidence rate ratio 0.86, 95% credible interval 0.73-1.02) and did not cross the upper boundary of the 95% credible interval for any month. Among 111 patients 18 years and older with newly diagnosed glomerulonephritis between January and August 2021, 38.7% had received at least one vaccine dose before biopsy, compared to 39.5% of the general Swiss population matched for age and calendar-time. The estimated risk ratio for the development of new-onset biopsy-proven glomerulonephritis was not significant at 0.97 (95% confidence interval 0.66-1.42) in vaccinated vs. unvaccinated individuals. Patients with glomerulonephritis manifesting within four weeks after vaccination did not differ clinically from those manifesting temporally unrelated to vaccination. Thus, vaccination against SARS-CoV-2 was not associated with new-onset glomerulonephritis in these two complementary studies with most temporal associations between SARS-CoV-2 vaccination and glomerulonephritis likely coincidental.

Renal AAV2-Mediated Overexpression of Long Non-Coding RNA H19 Attenuates Ischemic Acute Kidney Injury Through Sponging of microRNA-30a-5p.

BACKGROUND: Renal ischemia-reperfusion (I/R) injury is a major cause of AKI. Noncoding RNAs are intricately involved in the pathophysiology of this form of AKI. Transcription of hypoxia-induced, long noncoding RNA H19, which shows high embryonic expression and is silenced in adults, is upregulated in renal I/R injury. METHODS: Lentivirus-mediated overexpression, as well as antisense oligonucleotide-based silencing, modulated H19 in vitro. In vivo analyses used constitutive H19 knockout mice. In addition, renal vein injection of adeno-associated virus 2 (AAV2) carrying H19 caused overexpression in the kidney. Expression of H19 in kidney transplant patients with I/R injury was investigated. RESULTS: H19 is upregulated in kidney biopsies of patients with AKI, in murine ischemic kidney tissue, and in cultured and ex vivo sorted hypoxic endothelial cells (ECs) and tubular epithelial cells (TECs). Transcription factors hypoxia-inducible factor 1-α, LHX8, and SPI1 activate H19 in ECs and TECs. H19 overexpression promotes angiogenesis in vitro and in vivo. In vivo, transient AAV2-mediated H19 overexpression significantly improved kidney function, reduced apoptosis, and reduced inflammation, as well as preserving capillary density and tubular epithelial integrity. Sponging of miR-30a-5p mediated the effects, which, in turn, led to target regulation of Dll4, ATG5, and Snai1. CONCLUSIONS: H19 overexpression confers protection against renal injury by stimulating proangiogenic signaling. H19 overexpression may be a promising future therapeutic option in the treatment of patients with ischemic AKI.

Safety of Kidney Biopsy when Performed as an Outpatient Procedure.

INTRODUCTION: Kidney biopsy remains the gold standard for the diagnosis of most renal diseases. A major obstacle to performing a biopsy is safety concerns. However, many safety measures are not evidence based and therefore vary widely between centers. We sought to determine the rate and timing of kidney biopsy complications in our center, to compare the complication rate between native and transplant kidney biopsies, to evaluate the feasibility of performing kidney biopsies as an outpatient procedure and the value of a postbiopsy ultrasound before discharge, and to identify risk factors for complications. METHODS: We performed a single-center, retrospective, observational study at the Division of Nephrology of the University Hospital Zurich including all patients who underwent renal biopsy between January 2005 and December 2017. Major bleeding (primary outcome) and any other bleeding or nonbleeding complications (secondary outcomes) were compared between native and transplant kidney biopsies and between inpatient and outpatient procedures and correlated with clinical factors possibly affecting bleeding risk. RESULTS: Overall, 2,239 biopsies were performed in 1,468 patients, 732 as inpatient and 1,507 as outpatient procedures. Major bleeding was observed in 28 (3.8%) inpatient and in 15 (1.0%) outpatient procedures, totaling to 43 (1.9%) of all biopsies. Major bleeding requiring intervention amounted to 1.0% (0.5% of outpatient procedures). Rate of major bleeding was similar between native and transplant kidneys. 13/15 (87%) bleeding episodes in planned outpatient procedures were detected during the 4-h surveillance period. Risk factors for bleeding were aspirin use, low eGFR, anemia, cirrhosis, and amyloidosis. Routine postbiopsy ultrasound did not change management. CONCLUSIONS: Kidney biopsy is an overall safe procedure and can be performed as an outpatient procedure in most patients with an observation period as short as 4 h. The value of routine postbiopsy ultrasound is questionable.

Dialysis after graft loss: a Swiss experience.

BACKGROUND: Patients returning to dialysis after graft loss have high early morbidity and mortality. METHODS: We used data from the Swiss Transplant Cohort Study to describe the current practice and outcomes in Switzerland. All patients who received a renal allograft between May 2008 and December 2014 were included. The patients with graft loss were divided into two groups depending on whether the graft loss occurred within 1 year after transplantation (early graft loss group) or later (late graft loss group). Patients with primary non-function who never gained graft function were excluded. RESULTS: Seventy-seven out of 1502 patients lost their graft during follow-up, 40 within 1 year after transplantation. Eleven patients died within 30 days after allograft loss. Patient survival was 86, 81 and 74% at 30, 90 and 365 days after graft loss, respectively. About 92% started haemodialysis, 62% with definitive vascular access, which was associated with decreased mortality (hazard ratio = 0.28). At the time of graft loss, most patients were on triple immunosuppressive therapy with significant reduction after nephrectomy. One year after graft loss, 77.5% (31 of 40) of patients in the early and 43.2% (16 out of 37) in the late-loss group had undergone nephrectomy. Three years after graft loss, 36% of the patients with early and 12% with late graft loss received another allograft. CONCLUSION: In summary, our data illustrate high mortality, and a high number of allograft nephrectomies and re-transplantations. Patients commencing haemodialysis with a catheter had significantly higher mortality than patients with definitive access. The role of immunosuppression reduction and allograft nephrectomy as interdependent factors for mortality and re-transplantation needs further evaluation.

Efficacy of neoadjuvant pertuzumab in addition to chemotherapy and trastuzumab in routine clinical treatment of patients with primary breast cancer: a multicentric analysis.

PURPOSE: Neoadjuvant combination treatment with chemotherapy (CTX), trastuzumab (TZM), and pertuzumab (PTZ) has been shown to result in higher pathological complete response rates (pCR) in comparison with treatment with chemotherapy and trastuzumab (CTX/TZM). This analysis was aimed at real-world validation of these results from prospective randomized trials. METHODS: In a retrospective analysis conducted in the PRAEGNANT network, patients were eligible for inclusion if they had either received neoadjuvant therapy with CTX/TZM or chemotherapy, trastuzumab, and pertuzumab (CTX/TZM/PTZ) and subsequently underwent surgery for their primary breast cancer. The effect of the two neoadjuvant regimens on pCR in addition to commonly applicable predictors of pCR was analyzed in 300 patients from three study sites, using logistic regression analyses with treatment arm, age, clinical tumor stage, grading, and hormone receptor status as predictors. RESULTS: pCR with complete disappearance of all tumor cells was seen in 30.2% (n = 58) of patients treated with CTX/TZM and in 52.8% (n = 57) of those treated with CTX/TZM/PTZ. CTX/TZM/PTZ was positively associated with pCR (adjusted odds ratio 2.44; 95% CI 1.49-4.02). Mastectomy rates were not influenced by the therapy. CONCLUSIONS: The results of clinical trials were confirmed in this dataset of patients who were treated outside of clinical trials in everyday routine work. pCR rates can be improved by 20% with pertuzumab in routine clinical use.

Circular RNAs in Urine of Kidney Transplant Patients with Acute T Cell-Mediated Allograft Rejection.

BACKGROUND: Circular RNAs (circRNAs) have recently been described as novel noncoding regulators of gene expression. They are detectable in the blood of patients with acute kidney injury. We tested whether circRNAs were present in urine and could serve as new predictors of outcome in renal transplant patients with acute rejection. METHODS: A global circRNA expression analysis using RNA from urine of patients with acute T cell-mediated renal allograft rejection and control transplant patients was performed. Dysregulated circRNAs were confirmed in a cohort of 62 patients with acute rejection, 10 patients after successful antirejection therapy, 18 control transplant patients without rejection, and 13 stable transplant patients with urinary tract infection. RESULTS: A global screen revealed several circRNAs to be altered in urine of patients with acute rejection. Concentrations of 2 circRNAs including hsa_circ_0001334 and hsa_circ_0071475 were significantly increased. These were validated in the whole cohort of patients. hsa_circ_0001334 was upregulated in patients with acute rejection compared with controls. Concentrations of hsa_circ_0001334 normalized in patients with acute rejection following successful antirejection therapy. hsa_circ_0001334 was associated with higher decline in glomerular filtration rate 1 year after transplantation. CONCLUSIONS: CircRNA concentrations are significantly dysregulated in patients with acute rejection at subclinical time points. Urinary hsa_circ_0001334 is a novel biomarker of acute kidney rejection, identifying patients with acute rejection and predicting loss of kidney function.

Daratumumab for relapsed or refractory AL amyloidosis with high plasma cell burden.

Daratumumab, an anti-CD38 antibody, is effective in AL amyloidosis with low tumor burden. Data of daratumumab treatment in patients with AL amyloidosis but high tumor burden (≥10% bone marrow plasma cells) are limited. We report retrospective data of 10 consecutive patients with high tumor burden treated with daratumumab for relapsed/refractory AL amyloidosis. The median age at diagnosis was 62.3 years; all patients had cardiac involvement, and six (60%) patients had renal involvement. Median bone marrow plasma cell infiltration was 15% (range 10%-40%), and the median difference between involved and noninvolved free light-chains (dFLC) was 446 mg/L (range 102-1392 mg/L). Patients had a median of three prior lines of therapy, including bortezomib in all patients and lenalidomide in seven (70%) patients. The median time to first hematological response was 14 days (range 7-28 days), and the median time to best hematological response was 64 days (range 7-301 days). The hematological overall response was 90%, with high-quality response (≥ very good partial remission [VGPR]) in 70% of the patients. Fifty percent of the patients had a cardiac response after a median of 3.8 months (range 0.7-9.1). Infusion-related adverse events ≤ grade 2 occurred in seven (70%) patients and grade 3 adverse events in one patient. After a median follow-up time of 10 months, eight (80%) patients continued to receive daratumumab. We conclude that daratumumab is a very effective and safe treatment option in AL patients with relapsed/refractory disease and high disease burden at diagnosis. Daratumumab leads to rapid disease control and improvement of organ function.

Ultrasound-Assisted Tumor Surgery in Breast Cancer - A Prospective, Randomized, Single-Center Study (MAC 001).

PURPOSE: Breast-conserving therapy is associated with a risk of tumor-involved margins. For intraoperative orientation, non- palpable or indistinctly palpable lesions are wire-marked prior to surgery. Ultrasound-guided surgery has the potential to reduce the number of tumor-involved margins. In the MAC 001 trial we evaluated ultrasound-guided breast-conserving surgery compared to wire-guided surgery with regard to free tumor margins, duration of surgery and resection volume. MATERIALS AND METHODS: In this randomized, prospective, single-center controlled trial, patients with ductal invasive breast cancer were recruited for either ultrasound-guided or wire localization surgery. Primary outcomes were tumor-free resection margins, the reoperation rate and the resection volume in each group. The results were analyzed by intention to treat. The trial was registered under ClinicalTrials.gov NCT02222675. RESULTS: 56 patients were assessed, and 47 patients were evaluated in the trial. 93 % (25/27) of the patients in the ultrasound arm had an R0 reoperation compared to 65 % (13/20) in the wire localization control arm. This result was statistically significant (p = 0.026). No statistical difference was found for the resection volume or the duration of surgery between the two arms. No major complication was seen in either arm. CONCLUSION: Ultrasound-assisted breast surgery significantly increases the possibility of tumor-free margins and therefore reduces the risk of reoperations. Breast surgeons should be trained in ultrasound and ultrasound should be available in every breast surgery operating room.

Membrane-initiated effects of Serelys® on proliferation and apoptosis of human breast cancer cells.

Herbal extracts used for the alleviation of postmenopausal symptoms might have a lower risk of breast cancer development than hormone therapy. Serelys® is a product composed of purified pollen cytoplasm extracts. Recent experimental data revealed that estrogens might trigger a further proliferative effect on breast cancer cells via the progesterone receptor membrane component-1 (PGRMC1) in addition to the proliferative effect via intracellularly located receptors. MCF-7 and T47D cells were stably transfected with PGRMC1. Different concentrations of the extract alone and in combination with fixed concentrations of estradiol or a growth factor mixture were tested. Proliferation of treated cells was determined by the 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl-tetrazolium bromide (MTT)-test and apoptosis was determined using a Cell Death Detection ELISA kit (CDD). Serelys® was neutral in the cell lines transfected or not transfected with PGRMC1. It was also neutral in combination with estradiol or growth factors in terms of cell proliferation and cell apoptosis. Thus in contrast to hormone therapy Serelys® appears to trigger no further breast cancer risk when applied in the post menopause to women, who do or do not overexpress PGRMC1. Overall Serelys® may be an effective alternative for alleviating postmenopausal symptoms without increasing breast cancer risk.

Hyperandrogenemia and ovarian reserve in patients with Mayer-Rokitansky-Küster-Hauser syndrome type 1 and 2: potential influences on ovarian stimulation.

PURPOSE: This study aimed to analyze the hormone profiles, to detect the rate of hyperandrogenemia and to investigate the potential effect of Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) on ovarian reserve, as reflected by the serum Anti-Mullerian hormone (AMH) levels. Clinical implications were analyzed by including our own experiences with three patients after ovarian stimulation in preparation for uterus transplantation. METHODS: Serum samples of 100 patients with MRKHS (50 patients with MRKHS type 1 and 50 with type 2) were analyzed and compared to 50 individually age-matched healthy controls. Blood samples for hormone analyses were collected routinely during the clinical visit. RESULTS: The mean age was 20.0 years for MRKHS type 1, MRKHS type 2 and healthy controls. Compared to healthy controls, there was no significant difference in AMH values in the MRKH patients. As shown in previous studies, the proportion of hyperandrogenemia without clinical symptoms was significantly higher in MRKHS type 1 (52%; p < 0.001) and type 2 (56%; p < 0.001) patients when compared to age-matched controls. In preparation for uterus transplantation, three patients were stimulated with FSH/hMG for mean 14.2 days and the mean number of aspirated oocytes was 13.2 (3-22), while 8.3 (2-10) oocytes could be fertilized and cryopreserved. The mean fertilization rate was 51.2% (30-67%). CONCLUSION: The rate of hyperandrogenemia was significantly higher in MRKH patients compared to healthy age-matched controls. Though, ovarian reserve (AMH level) was not reduced compared to controls. Future studies are needed to identify optimal ovarian stimulation protocols as well as to implement a systematic multicenter reporting system.

Pregnancy-associated breast cancer: maternal breast cancer survival over 10 years and obstetrical outcome at a university centre of women's health.

PURPOSE: Pregnancy-associated breast cancer (PABC) is considered the second most common malignancy affecting pregnancy. The limited knowledge as to long-term survival is nonuniform. This retrospective study aims to contribute by a follow-up of pregnancies of breast cancer patients treated at a single university centre with focus on maternal long-term survival in relation to time point of diagnosis (before, during, and after pregnancy). METHODS: Data of 25 patients were reviewed for the period between 2000 and 2009 in relation to their neonatal and maternal outcome parameters as well as their maternal breast cancer outcomes by assessing maternal mortality at annual intervals up to a maximum of 10 years follow-up. RESULTS: Median age at diagnosis was 33 years. Maternal survival rate of the total collective came to 76% after 5 years and to 68% after 10 years. The newborns were healthy, 22% of them presented with a 1'Apgar score 5-7. Preterm delivery occurred in 53%. PABC significantly affected maternal survival compared to the national breast cancer cohort at 5 years and barely significantly at 10 years, with highly significant (p < 0.003) to significant (p < 0.01) effects at 5 and 10 years, respectively, for PABC diagnosed during and after pregnancy. CONCLUSIONS: The present findings on survival rates suggest that maternal medical assessment at the beginning of and during further course of pregnancy should include a scrutinized thorough breast examination. Conveying/delivering special competences to monitor these high-risk pregnancies at the interface of oncological care should be considered an obligatory part of academic medical education, obstetrical training and interprofessional midwifery education.

[Nephrological diagnostics with the general practitioner's toolbox]. / Nephrologische Diagnostik mit der Toolbox des Hausarztes.

Nephrological diagnostics with the general practitioner's toolbox Abstract. Kidney diseases are often asymptomatic or present nonspecifically and are frequently diagnosed by chance as part of a laboratory check up. In newly diagnosed renal failure, the physician should determine the dynamics (acute versus chronic) and identify the cause of the renal dysfunction based on history and additional tests. This is crucial to identify treatable kidney diseases and to provide patients with the adequate therapy. The identification of the underlying disease and determination of its severity are necessary to estimate the renal and cardiovascular prognosis. Finally, the degree of renal insufficiency is important for dose adjustment of renally eliminated drugs and assessment of possible complications of renal failure. Most general practitioners have the necessary diagnostic tools at their disposal to carry out the above assessments and decide when a specialist nephrological referral is advisable. To diagnose and stage renal failure, serum creatinine must be measured and the glomerular filtration rate (GFR) estimated. The second pillar is the examination of urine (proteinuria, albuminuria, urine sediment). Depending on the findings, further laboratory tests may be useful. Renal ultrasound is the primary imaging method in patients with acute and chronic renal failure. In this article, the above mentioned methods are described in more detail and their potential pitfalls are discussed.

Decidualization is Impaired in Endometrial Stromal Cells from Uterine Rudiments in Mayer-Rokitansky-Küster-Hauser Syndrome.

BACKGROUND/AIMS: Uterine rudiments from patients with Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) contain all tissues typically found in the uterus. Endometrium from the rudiments predominantly exhibits basalis-like features, and endometrial proliferative capacity in patients' epithelium and stroma is significantly lower. METHODS: This single-center, prospective study conducted at a major German university hospital compared in-vitro decidualization in cultured ESCs from MRKHS patients and hysterectomy controls. Primary ESC cultures were established from both sources. Hormone-induced prolactin and IGFBP-1 secretion served as a measure of their ability to undergo decidualization in response to hormonal stimulation. Expression levels of 8 key marker genes of decidualization were also determined. RESULTS: At day 9, mean secretion of prolactin and IGFBP-1 was significantly reduced by 89.0% and 99.5%, respectively, in MRKHS ESCs vs. hysterectomy controls, both indicating impaired decidualization of MRKHS ESCs. Key decidual markers confirmed impaired decidualization in MRKHS patients. CONCLUSION: Our results indicate that the ESCs from MRKHS patients lack hormone responsiveness as a potential sign of dysfunctional hormone receptor function, which may also play a role in the onset of MRKHS. Further studies are needed to corroborate our findings, directly address receptor function, and elucidate the role of other potential determinants of uterine development and adult function.

Hyperandrogenemia and high prolactin in congenital utero-vaginal aplasia patients.

Patients with the Mayer-Rokitansky-Küster-Hauser syndrome (MRKH) have a congenital utero-vaginal cervical aplasia, but normal or hypoplastic adnexa and develop with normal female phenotype. Some reports mostly demonstrated regular steroid hormone levels in small MRKH cohorts including single MRKH patients with hyperandrogenemia and a clinical presentationof hirsutism and acne has also been shown. Genetically a correlation of WNT4 mutations with singular MRKH patients and hyperandrogenemia was noted. This study analyzed the hormone status of 215 MRKH patients by determining the levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, 17-OH progesterone, testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG) and prolactin to determine the incidence of hyperandrogenemia and hyperprolactinemia in MRKH patients. Additional calculations and a ratio of free androgen index and biologically active testosterone revealed a hyperandrogenemia rate of 48.3%, hyperprolactinemia of 9.8% and combined hyperandrogenemia and hyperprolactinemia of 4.2% in MRKH patients. The rates of hirsutism, acne and especially polycystic ovary syndrome (PCOS) were in the normal range of the population and showed no correlation with hyperandrogenemia. A weekly hormone assessment over 30 days comparing 5 controls and 7 MRKH patients revealed high androgen and prolactin, but lower LH/FSH and SHBG levels with MRKH patients. The sequencing of WNT4, WNT5A, WNT7A and WNT9B demonstrated no significant mutations correlating with hyperandrogenemia. Taken together, this study shows that over 52% of MRKH patients have hyperandrogenemia without clinical presentation and 14% hyperprolactinemia, which appeals for general hormone assessment and adjustments of MRKH patients.