Rare diseases affect fewer than 1 in 2000 individuals, but approximately 150 rare kidney diseases account for about 10

Minimal-Change-Disease (MCD) und fokal-segmentale Glomerulosklerose (FSGS) gehören zu den häufigsten Ursachen eines nephrotischen Syndroms. Histologisch sind beide Erkrankungen als Podozytopathien definiert durch eine Fußfortsatzverschmelzung der Podozyten, sichtbar in der Elektronenmikroskopie. Während die genaue Pathogenese lange unklar war, verdichten sich Hinweise, dass Anti-Nephrin-Antikörper in vielen Fällen von MCD eine zentrale Rolle spielen. Die Genese der FSGS ist komplex. Die Erkrankung ist charakterisiert durch den irreversiblen Verlust von Podozyten und eine resultierende fokale Sklerose im Glomerulus. Die Differenzierung zwischen primären, sekundären und genetischen Formen dieser Erkrankungen ist entscheidend für die Wahl der Therapie, da nur primäre Formen in der Regel eine Immunsuppression erfordern. Für die Behandlung stehen mehrere Therapieansätze zur Verfügung, darunter Steroide und Calcineurininhibitoren (CNI) wie Tacrolimus und Mycophenolat-Mofetil (MMF). FSGS und MCD unterscheiden sich in ihrer Therapieansprechrate, wobei die FSGS insgesamt eine schlechtere Prognose aufweist. Für die Zukunft werden zielgerichtete Therapien eine zunehmende Bedeutung haben, insbesondere bei genetisch bedingten Varianten der FSGS. Insgesamt bleibt die Therapie der MCD und der FSGS eine Herausforderung und erfordert eine maßgeschneiderte und sorgfältig abgestimmte Behandlung, basierend auf individuellen Patientenmerkmalen.

Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are glomerulopathies associated with nephrotic syndrome. Primary forms of these diseases are treated with various regimes of immunosuppression. Frequently relapsing or glucocorticoid-dependent courses remain challenging. Here, a B-cell-depleting strategy with rituximab represents a salvage option although data are sparse in the adult population. In particular, there is limited evidence on the efficacy of restoring remission after initial successful treatment with rituximab and whether patients benefit from an individualized, relapse-based approach. We identified 13 patients who received multiple therapies with rituximab from the FOrMe-registry (NCT03949972), a nationwide registry for MCD and FSGS in Germany, or from the University Hospital of Cologne. Disease status, changes in serum creatinine, proteinuria, and time to relapse were evaluated. Relapse-free survival was compared to the patients' previous therapy regimens. Through all treatment cycles, an improvement of disease activity was shown leading to a complete remission in 72% and partial remission in 26% after 3 ([Formula: see text]0.001) and 6 months ([Formula: see text]0.001). Relapse-free survival increased from 4.5 months (95%-CI 3-10 months) to 21 months (95%-CI 16-32 months) ([Formula: see text]0.001) compared to previous immunosuppression regimens with no loss in estimated glomerular filtration over time (p = 0.53). Compared to continuous B-cell depletion, an individualized relapse-based approach led to a reduced rituximab exposure and significant cost savings. Relapse-based administration of rituximab in patients with MCD/FSGS with an initial good clinical response did not result in a decreased efficacy at a median follow-up duration of 110 months. Thus, reinduction therapies may provide an alternative to continuous B-cell-depletion and reduce the long-term side effects of continuous immunosuppression.

Objective Achieving recommended targets of sodium correction is challenging to physicians treating hyponatraemia. Plasma sodium has to be increased effectively, yet overcorrection must be prevented. This is often hampered by a high variability of responses to treatment. Here, we sought to delineate factors influencing sodium evolution. Design We retrospectively analysed 3460 patients from the multinational Hyponatraemia Registry comprising a wide range of hyponatraemia aetiologies and treatment strategies. Methods Multivariable linear mixed effects models were applied to identify predictors of plasma sodium evolution within the first 24 h of treatment. Results Evolution of sodium levels over time showed a curvilinear pattern with steeper rise at earlier time points. Baseline sodium showed the most pronounced impact with an additional increment of 3.12 mEq/L for every 10 mEq/L initial sodium reduction. With sodium increments of 1.9 mEq/L and 1.4 mEq/L per 24 h, respectively, the entities hypovolaemic and thiazide-associated hyponatraemia were independent factors for sodium evolution. Therapeutic regimens using hypertonic saline (4.6 mEq/L/24 h), tolvaptan (3.4 mEq/L/24 h), or combination therapy (2.6 mEq/L/24 h) were also associated with a significantly larger sodium rise when compared with no active treatment. Conclusions Choice and dosing of active hyponatraemia therapy should be adjusted not only according to aetiology but most importantly to pretreatment sodium. Although counterintuitive, less aggressive therapy in more profound hyponatraemia might be safer but yet effective at least in less severe cases.

BACKGROUND:The von Willebrand factor-directed nanobody caplacizumab has greatly changed the treatment of immune thrombotic thrombocytopenic purpura (iTTP) in recent years. Data from randomized controlled trials established efficacy and safety.OBJECTIVES:This study aims to address open questions regarding patient selection, tailoring of therapy duration, obstacles in prescribing caplacizumab in iTTP, effect on adjunct treatment, and outcomes in the real-world setting.METHODS:We report retrospective, observational cohorts of 113 iTTP episodes treated with caplacizumab and 119 historical control episodes treated without caplacizumab. We aggregated data from the caplacizumab phase II/III trials and real-world data from France, the United Kingdom, Germany, and Austria (846 episodes, 396 treated with caplacizumab, and 450 historical controls).RESULTS:Caplacizumab was efficacious in iTTP, independent of the timing of therapy initiation, but curtailed the time of active iTTP only when used in the first-line therapy within 72 hours after diagnosis and until at least partial ADAMTS13-activity remission. Aggregated data from multiple study populations showed that caplacizumab use resulted in significant absolute risk reduction of 2.87% for iTTP-related mortality (number needed to treat 35) and a relative risk reduction of 59%.CONCLUSION:Caplacizumab should be used in first line and until ADAMTS13-remission, lowers iTTP-related mortality and refractoriness, and decreases the number of daily plasma exchange and hospital stay. This trial is registered at www.CLINICALTRIALS:gov as #NCT04985318.

Background Acute kidney injury (AKI) is a major risk factor for chronic kidney disease and increased mortality. Until now, no compelling preventive or therapeutic strategies have been identified. Dietary interventions have been proven highly effective in organ protection from ischemia reperfusion injury in mice and restricting dietary intake of sulfur‐containing amino acids (SAA) seems to be instrumental in this regard. The UNICORN trial aimed to evaluate the protective impact of restricting SAA intake before cardiac surgery on incidence of AKI. Methods and Results In this single‐center, randomized, controlled, double‐blind trial, 115 patients were assigned to a SAA‐reduced formula diet (LowS group) or a regular formula diet (control group) in a 1:1 ratio for 7 days before scheduled cardiac surgery. The primary end point was incidence of AKI within 72 hours after surgery, secondary end points included increase of serum creatinine at 24, 48, and 72 hours as well as safety parameters. Quantitative variables were analyzed with nonparametric methods, while categorical variables were evaluated by means of Chi‐square or Fisher test. SAA intake in the group with SAA reduced formula diet was successfully reduced by 77% (group with SAA reduced formula diet, 7.37[6.40–7.80] mg/kg per day versus control group, 32.33 [28.92–33.60] mg/kg per day, P<0.001) leading to significantly lower serum levels of methionine. No beneficial effects of SAA restriction on the rate of AKI after surgery could be observed (group with SAA reduced formula diet, 23% versus control group, 16%; P=0.38). Likewise, no differences were recorded with respect to secondary end points (AKI during hospitalization, creatinine at 24, 48, 72 hours after surgery) as well as in subgroup analysis focusing on age, sex, body mass index and diabetes. Conclusions SAA restriction was feasible in the clinical setting but was not associated with protective properties in AKI upon cardiac surgery. Registration URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03715868.

Osterholt, Thomas; Kuehne, Lucas; Grundmann, Franziska; Benzing, Thomas; Volker, Linus A.; Brinkkoetter, Paul T. Author Information

Caloric Restriction (CR) extends lifespan and augments cellular stress-resistance from yeast to primates, making CR an attractive strategy for organ protection in the clinic. Translation of CR to patients is complex, due to problems regarding adherence, feasibility, and safety concerns in frail patients. Novel tailored dietary regimens, which modulate the dietary composition of macro- and micronutrients rather than reducing calorie intake promise similar protective effects and increased translatability. However, a direct head-to-head comparison to identify the most potent approach for organ protection, as well as overlapping metabolic consequences have not been performed. We systematically analyzed six dietary preconditioning protocols - fasting mimicking diet (FMD), ketogenic diet (KD), dietary restriction of branched chained amino acids (BCAA), two dietary regimens restricting sulfur-containing amino acids (SR80/100) and CR - in a rodent model of renal ischemia-reperfusion injury (IRI) to quantify diet-induced resilience in kidneys. Of the administered diets, FMD, SR80/100 and CR efficiently protect from kidney damage after IRI. Interestingly, these approaches show overlapping changes in oxidative and hydrogen sulfide (H2S)-dependent cysteine catabolism as a potential common mechanism of organ protection.

The anti‐von Willebrand factor (VWF) nanobody caplacizumab directly prevents the fatal microthrombi formation in immune‐mediated thrombotic thrombocytopenic purpura (iTTP), thereby adding a new therapeutic principle to the treatment of this disorder. However, real‐world treatment modalities beyond clinical trials remain heterogeneous.

Advances in basic and clinical research have improved our understanding of the pathomechanisms underlying nephrotic syndrome caused by minimal change disease (MCD) and focal and segmental glomerulosclerosis (FSGS). These advances are reflected in the new 2021 KDIGO-Guidelines, which emphasize the clear distinction between primary, secondary and genetic causes. Proper classification is critical, as it directly affects the therapy of choice. While glucocorticoids still play a central in inducing remission in primary forms, calcineurin inhibitors, mycophenolate mofetil, cyclophosphamide and rituximab (off label) are viable adjuncts/alternatives to reduce or replace glucocorticoids in case of side effects or contraindications. Since SGLT-2-inhibitors have shown renoprotective effects in non-diabetic patients and may help to reduce proteinuria, they should be considered in all (adult) patients with chronic kidney disease, including MCD and FSGS patients. In the near future, Sparsentan, an endothelin type A and angiotensin receptor blocker may be added to the growing arsenal of proteinuria-reducing agents, with a phase 3 trail expected to be completed in late 2022. Finally, we recommend the inclusion of all MCD/FSGS patients in clinical registries (e. g. FOrMe Registry in Germany) to ensure adequate therapy and genetic testing if indicated. In addition, national registries are an invaluable source of clinical data that helps to refine our therapies towards individualized medicine.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare thrombotic microangiopathy (TMA), caused by autoantibodies against the metalloproteinase ADAMTS13. Subsequent accumulation of ultra-large von Willebrand factor (VWF) multimers induces platelet agglutination and microvascular thrombosis. Pregnancy is known to precipitate iTTP episodes and poses additional challenges to physicians, e.g. the combination with features of preeclampsia or HELLP syndrome, potentially increasing maternal mortality.1 Index cases are more often associated with fetal demise than cases with a prior history of iTTP, and the risk of pregnancy-associated iTTP and miscarriage correlates with reduced levels of ADAMTS13 activity and the presence of anti-ADAMTS13 antibodies during pregnancy.2, 3 The standard treatment of pregnancy-associated iTTP is immediate plasma exchange (PEX) and steroids with high response rates.1 The therapeutic repertoire for iTTP has recently been expanded by caplacizumab, directed against platelet-binding sites on VWF and limiting fatal microthrombi formation.4-10 To date, no data on the use of caplacizumab for pregnancy-associated iTTP are available.1 Animal data in guinea pigs did not report adverse effects.11 Here, we report the first use of caplacizumab in a 36-year-old pregnant woman with an acute iTTP episode. The patient was diagnosed with iTTP 13 years prior to this episode. Autoimmune activity, with ADAMTS13 activity below 10% and detectable anti-ADAMTS13 autoantibodies, had persisted since her last episode three years ago, despite intermittent rituximab treatment. The patient rejected further treatment intensification and immunosuppressive medication was discontinued one year before. During a follow-up visit, the patient reported to be pregnant at 11 + 4 weeks estimated gestational age (EGA). By then, ADAMTS13 activity was still below 10% with detectable anti-ADAMTS13 antibodies, indicating an increased risk for acute iTTP and miscarriage.2 With no signs of haemolytic activity or microthrombi formation, immunosuppressive medication with glucocorticoids and azathioprine was initiated. At 17 + 1 weeks EGA, the patient presented to our hospital with symptoms of a foodborne infection. Laboratory examination revealed microangiopathic haemolytic anaemia and thrombocytopenia (see Table I and Fig 1A). Ultrasound revealed a vital fetus with regular fetal growth. The patient received daily PEX and high-dose glucocorticoids, in addition to azathioprine. Platelet counts recovered within five days. After two additional sessions, PEX was discontinued, but the patient experienced an immediate exacerbation. By then, the fetus was still vital, with fetal growth within the lower limit of normal (see Fig 1B). Of note, an increased uterine vascular resistance with bilateral notching was present, indicating an increased risk for preeclampsia and severe intrauterine growth restriction (IUGR).12 Consequently, daily PEX was resumed but platelet count continued to decrease. Further therapeutic options including off-label therapies were thoroughly discussed. The patient emphatically expressed her firm wish to intensify treatment even if in off-label indications. Based on shared-decision making, ciclosporin, rituximab and caplacizumab were administered as off-label therapies. Platelet count normalised within three days, but ultrasound again demonstrated a noticeably high uteroplacental resistance with persistent bilateral notching. The fetal growth curve had further flattened, potentially deriving from early-onset placental insufficiency. A rebounding albuminuria to 647 mg/g creatinine, together with new onset hypertension and an elevated sFlt-1/PlGF ratio, led to the suspicion of preeclampsia resulting from placental iTTP manifestation. One week later, severe early-onset IUGR was diagnosed, with almost no interval growth and oligohydramnios and placental hydrops being present. Given the poor fetal prognosis, termination of pregnancy was agreed upon with the patient, to prevent potentially life-threatening iTTP and preeclampsia sequelae. Vaginal delivery was favoured and intrauterine fetocide by intracordal potassium injection was performed prior to labour at the patient’s request. After the patient’s informed consent, placental tissue, amniotic fluid and fetal blood samples were collected and further analysed. Placental histology revealed villous retardation, fetal vascular thrombosis, (maternal) intervillous thrombosis and fibrin deposition in decidual arterioles corresponding to atherosis, as in preeclampsia. However, mural hypertrophy of arterioles (characteristic of preeclampsia) was absent, suggesting chronic placental insufficiency and fetal thrombosis as major causes for severe early-onset IUGR. Whether thrombi in fetal vessels indicate a fetal iTTP manifestation remains elusive. The transplacental transfer of maternal anti-ADAMTS13 antibodies has been described before, but to our knowledge there are no reports of a fetal iTTP.13 There were no apparent bleeding complications, especially no signs of retroplacental haematoma. With the help of LC-HR-MS/MS analysis, we documented the transplacental transfer of caplacizumab (for methods see supplemental material). Caplacizumab was qualitatively identified in amniotic fluid and fetal blood above the assay’s limit of detection, as illustrated in Fig 1D. The estimated drug concentration was 50 ng/ml. The estimated concentration in maternal blood was within the expected range, according to published pharmacokinetics, and hence five- to tenfold higher.5 Whether the caplacizumab dose was insufficient to prevent any fetal thrombosis or whether the histologically proven thrombosis results from pre-caplacizumab microthrombi formation remains elusive. In conclusion, caplacizumab treatment in our patient appeared to be safe and effective, with a rapid platelet count normalisation within three days. The treatment rapidly improved the mother’s condition, but may have been applied too late to save fetal life. From our experience, what lessons can be learned with regard to future cases of iTTP in early pregnancy? First, iTTP is a devastating disease affecting the mother and the fetus, with a high risk of adverse outcomes. Even timely initiation of standard therapy – which was effective in previous acute iTTP episodes in the same patient – could not prevent IUGR and fetal loss. Therefore, in individual cases, rapid and determined initiation of caplacizumab treatment to prevent thrombotic microangiopathy seems reasonable, albeit off-label. Second, although caplacizumab may potentially increase the risk for pregnancy-specific haemorrhagic complications, e.g. a retroplacental haematoma, we believe that placental damage by ongoing TMA with an impaired placental perfusion poses a much greater risk to the fetus. In a prospective patient with iTTP in early pregnancy and high risk for miscarriage, we would administer caplacizumab as early as possible, flanked by glucocorticoids and PEX. Undoubtedly, this treatment must be based on shared decision-making, after thorough risk-benefit discussion. We would then stop PEX once TMA resolves and continue caplacizumab, depending on ADAMTS13 activity, disease severity, and drug tolerability. Dr. Völker reports grants from the Else-Kroener-Fresenius Stiftung (2015_A224) and speaker honoraria from Sanofi-Genzyme. Prof. Brinkkötter declares grants from the German Research Foundation (BR2955/8) and personal fees from Alexion, Sanofi-Genzyme, Bayer, Vifor, and Pfizer (speaker honoraria, advisory boards). All other authors declare no competing financial interest. L.K., L.A.V., M.T. and P.T.B. drafted the manuscript and prepared the figures. A.T., J.B. and M.T. designed and performed LC-MS/MS experiments. A.M. performed the histopathological analysis of the placenta. L.K., L.A.V., H. Hagmann, H. Hägele, T.O., I.G., B.G., M.K., T.B., P.T.B. were involved in patient management. All authors were involved in data collection and proofreading. The manuscript has been read and approved for submission to BJH by all authors. Written informed consent was obtained from the patient for publication of this short report and any accompanying images. A copy of the written consent is available for review by the corresponding author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Schwere Hyponatriämie 119mmol/l pisch imponierte an beiden Augen eine zirkulär verstrichene Papille mit Punktund Fleckblutungen sowie Exsudaten in allen Quadranten und Gefäßtortuositas, der Fundus wirkte ödematös, und es zeigte sich eine seröse Amotio. Es waren keine Foramen, Zellen oder Infiltrate im Glaskörper zu sehen. Nach Rücksprache mit den internistischen Kollegen erfolgte zur weiteren Abklärung eine infektiologische Diagnostik. Im weiteren Verlauf gab der Patient an,ursprünglichausNigeriazustammen. Während eines 2-wöchigen Aufenthaltes in seiner früheren Heimat entwickelte er ein starkes Krankheitsgefühl mit grippeähnlichen Symptomen sowie Sehstörungen inFormvonDoppelbildern.Dieophthalmologische Vorgeschichte war bis zu diesem Zeitpunkt leer. Weitere internistische und infektiologische Diagnostik ergab den Nachweis einer Parvovirus-Erstinfektion. Diese führte bei dem Patienten zu einer Enzephalitis mit passagerem Delir sowie zu einer thrombotischen Mikroangiopathie (TMA) mit Hämolyse und Thrombozytopenie. Eine daraus resultierende maligne Hypertonie führte zur Nierenschädigung, deren Funktion mittels pas-

Wearable devices are rapidly growing in popularity as individuals attempt to improve their health behaviors as they become more aware of their physical activity. Even with the adoption of wearable devices, many individuals are not achieving activity guidelines. The pairing of activity monitors with tailored engagement has been suggested to enhance compliance and outcomes. PURPOSE: To measure the effect of activity tracking devices with and without tailored engagement on weight and YMCA 3-Minute Step Test score in college-aged students, measured before and after a 12-week intervention. METHODS: Thirty-four college-aged participants were randomly assigned to 1 of 4 treatment groups: Actigraph GT3X accelerometer without engagement or step count (C) (n = 8), pedometer without engagement (P) (n = 9), pedometer with engagement (PE) (n = 10), or commercially-available iliac crest tracker with engagement (FBE) (n = 7). Participants were in the contemplation or preparation stage of change at recruitment and self-reported obtaining ≤ 60 min of structured physical activity per week. After baseline measurements of weight and cardiorespiratory fitness as evaluated by YMCA 3 minute step test, all groups were instructed to attempt to obtain 10,000 steps per day and how to wear the device properly. Participants were reminded to wear the device daily via text message and reported daily steps through a digital form. RESULTS: The overall difference in weight from baseline (171.5 ± 45.2 Ibs) to post intervention (172.9 ± 44.5 Ibs) was found to be not statistically significant between groups. There was no statistically significant difference regarding cardiorespiratory fitness from baseline 1 minute heart beat count 129.97 ± 14.1 BPM to post-intervention 126.15 ± 16.5 BPM. All groups produced a mean score in the ‘poor’ category at baseline. Group PE produced a mean score category of ‘average’ after the intervention. CONCLUSIONS: The use of wearable devices with or without engagement did not have a statistically significant effect on weight or cardiorespiratory fitness after a 12-week intervention. However, some individuals improved within YMCA fitness scores post-intervention, which may have clinical significance.