Clinical presentation and genetic variants in patients with autoinflammatory diseases: results from the German GARROD registry.

To investigate clinical symptoms and genetic variants in patients from the German anti-IL-1 registry for autoinflammatory orphan diseases (GARROD) between 2013 and 2022. Multicentre, retrospective analysis of demographic, clinical and genetic data of patients with autoinflammatory diseases (AID) who received anti-IL-1 targeted therapy. The cohort comprised 152 patients with familial Mediterranean fever (FMF; n = 71), cryopyrin-associated periodic syndromes (CAPS; n = 43), TNF-receptor associated periodic syndrome (TRAPS; n = 19), mevalonate kinase deficiency (MKD; n = 3) and unclassified AID (uAID; n = 16). Inflammatory attacks started in 61.2% of the patients before the age of 18 years. The delay between the first AID attack and anti-IL-1 therapy was 17.8 years. Monogenetic AIDs were diagnosed by clinical symptoms. Genetic analyses confirmed the diagnosis in 87.3% of patients with FMF, 65.2% with CAPS and 94.8% with TRAPS. Among this group, heterozygous MEFV variants and variants of unknown significance (VUS) were detected in 22.5% of patients with FMF, 51.2% with CAPS and 47.4% with TRAPS. Patients with VUS were older at disease onset which is consistent with a milder phenotype. Twenty-four patients had secondary AA amyloidosis (AA) at initiation of anti-IL-1 therapy. The mean age of these patients was 16.4 years at their first attack and 44.9 years at the time of AA diagnosis. Turkish-Armenian ancestry correlated with MEFV variants and higher FMF disease activity compared to German ancestry. Molecular genetic analyses should substantiate the clinical diagnosis of a monogenetic AID. Our data support the concept of variable penetrance of VUS which can be associated with late-onset AID.

Pre-existing chronic kidney disease, aetiology of acute kidney injury and infection do not affect renal outcome and mortality.

BACKGROUND: We aimed to study the role of aetiology, pre-existing chronic kidney disease (CKD) and infections in acute kidney injury (AKI) on renal outcome and mortality. METHODS: This retrospective study analysed patients with AKI admitted to a university nephrology department from January 1st, 2020 through December 31st, 2020. Aetiology of AKI, underlying renal disease in case of pre-existing CKD and presence of infections were assessed. Development of renal function and risk of death were studied with follow-up until January 31st, 2023. RESULTS: Of 1402 patients screened, 432 patients (30.8%, 67.9 ± 15.4 years) fulfilled the inclusion criteria, half of the population presented with advanced CKD. Even though CKD patients were more often in need of chronic dialysis at time of discharge (6.9% vs 4.5%, p < .001), duration of hospital stay was shorter and in-hospital mortality tended to be lower when compared to AKI without prior renal disease. Neither aetiology of AKI nor pre-existing CKD had an impact on the combined endpoint of end-stage kidney disease and mortality (log rank 0.433 and 0.909). Overall, septic patients showed the highest in-hospital mortality (23.5%) and longest hospital stay (30.0 ± 22.8 days, p < .001), while patients with urosepsis had the shortest hospitalisation time (9.7 days) with lowest risk for dialysis (4.4%). Of note, outcome did not differ in patients with AKI when considering the infectious status. CONCLUSIONS: Overall renal outcome and mortality in AKI patients were not affected by the cause of AKI, pre-existent CKD or infectious status. Only severity of AKI had a negative impact on outcome.

Evaluation of simple diagnostic parameters in acute kidney injury in hospitalized patients-diagnostic recommendations for non-nephrologists.

Acute kidney injury (AKI) is very common in hospitalized patients, affecting patient's mortality and morbidity. Major causes are prerenal AKI and acute tubular necrosis (ATN). Even though a variety of parameters/indices exist, their reliability and practicability are controversial: in fact, there is a need for a simple diagnostic approach for AKI in in-patients with parameters easily obtained in any hospital. The objective of the study was: (1) to assess reliability of simple laboratory parameters/indices to differentiate pre-/intrarenal AKI; (2) to evaluate the most reliable and feasible parameters/indices; and (3) to identify the possible impact of confounding factors. Retrospectively, in-patients with AKI hospitalized in 2020 in a university nephrology department were included. Spot urine and 24-h collection urine was analyzed with urine sodium (UNa), urine specific gravity (USG), fractional excretion of sodium (FENa), fractional excretion of urea (FEUrea), urine osmolality (UOsm), urine to plasma creatinine ratio (UCr/PCr) and renal failure index (RFI). Overall, 431 patients were included. UNa, UOsm, USG and RFI showed high specificity > 85% for prerenal AKI, UNa and RFI provided good specificity for ATN. Loop diuretics, ACE inhibitors/AT1 blockers or pre-existing chronic kidney disease had no impact. In patients with AKI, UNa, USG and RFI: (1) proved to be very specific for prerenal AKI and showed high sensitivity for ATN; (2) can be easily determined using serum and spot urine; and (3) are not confounded by medication or comorbidities. These parameters/indices are helpful to identify the aetiology of AKI and to guide therapy, thereby improving patients' safety and outcome.

Tunneled central venous catheters for hemodialysis-unfairly condemned? Catheter-related complications in a university hospital setting.

BACKGROUND: Central venous catheters (CVCs) provide an immediate hemodialysis access but are considered to be of elevated risk for complications. It remains unclear, if CVCs per se have relevant impact on clinical outcome. We provide an assessment of CVC-associated complications and their impact on mortality. METHODS: In a single center retrospective study, CVC patients between JAN2015-JUN2021 were included. Data on duration of CVC use, complications and comorbidities was collected. Estimated 6-month mortality was compared to actual death rate. RESULTS: About 478 CVCs were analyzed. Initiation of dialysis was the main reason for CVC implantation. Death was predominant for termination of CVC use. Infections were rare (0.6/1000 catheter days), complications were associated with certain comorbidities. Actual 6-month mortality was lower than predicted (14.3% vs 19.6%). CONCLUSION: (1) CVCs are predominantly implanted for initiation of hemodialysis; (2) serious complications are rare; (3) complications are associated with certain comorbidities; and (4) CVC patients survive longer than predicted.

Erythrocyte Sedimentation Rate in Patients with Renal Insufficiency and Renal Replacement Therapy.

BACKGROUND: Determination of the erythrocyte sedimentation rate (ESR) is a simple diagnostic tool for estimating systemic inflammation. It remains unclear whether ESR is influenced by renal disease or renal replacement therapy (RRT). OBJECTIVE: To report the incidence and extent of ESR elevations in patients with chronic kidney disease (CKD) and the possible impact of RRT. METHODS: We performed a single-center, retrospective study in inpatients with or without renal disease and in those with RRT, comparing ESR levels and other laboratory and clinical information. RESULTS: A total of 203 patients were included. On average, ESR was elevated (mean [SD], 51.7 [34.6] mm/h), with no statistically significant difference between the patient groups. Only those receiving PD showed significantly higher ESR (78.3 [33.1] mm/h; P < .001). CONCLUSIONS: ESR testing can be used without restriction in patients with CKD and in patients undergoing hemodialysis and who have received kidney transplantation; however, this measurement should be monitored carefully in patients with PD.

Results from a national survey on COVID-19-associated mucormycosis in Germany: 13 patients from six tertiary hospitals.

BACKGROUND: Most COVID-19-associated mucormycosis (CAM) cases are reported from India and neighbouring countries. Anecdotally cases from Europe have been presented. OBJECTIVE: To estimate the disease burden and describe the clinical presentation of CAM in Germany. METHODS: We identified cases through German mycology networks and scientific societies, and collected anonymised clinical information via FungiScope®. RESULTS: We identified 13 CAM cases from six tertiary referral hospitals diagnosed between March 2020 and June 2021. Twelve patients had severe or critical COVID-19, eleven were mechanically ventilated for a median of 8 days (range 1-27 days) before diagnosis of CAM. Eleven patients received systemic corticosteroids. Additional underlying medical conditions were reported for all but one patient, five were immunocompromised because of malignancy or organ transplantation, three were diabetic. Eleven patients developed pneumonia. Mortality was 53.8% with a median time from diagnosis of mucormycosis to death of 9 days (range 0-214 days) despite treatment with liposomal amphotericin B and/or isavuconazole in 10 of 13 cases. CAM prevalence amongst hospitalised COVID-19 patients overall (0.67% and 0.58% in two centres) and those admitted to the intensive care unit (ICU) (1.47%, 1.78% and 0.15% in three centres) was significantly higher compared to non-COVID-19 patients (P < .001 for respective comparisons). CONCLUSION: COVID-19-associated mucormycosis is rare in Germany, mostly reported in patients with comorbidities and impaired immune system and severe COVID-19 treated in the ICU with high mortality compared to mainly rhino-orbito-cerebral CAM in patients with mild COVID-19 in India. Risk for CAM is higher in hospitalised COVID-19 patients than in other patients.

Relative incidence of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome in clinically suspected cases of thrombotic microangiopathy.

BACKGROUND: Data are lacking on the relative incidence of thrombotic thrombocytopenic purpura (TTP), haemolytic uraemic syndrome (HUS) caused by Shiga toxin-producing Escherichia coli (STEC) and atypical HUS (aHUS) in patients presenting with thrombotic microangiopathies (TMAs). METHODS: This was a prospective, cross-sectional, multicentre and non-interventional epidemiological study. Patients fulfilling criteria for TMAs (platelet consumption, microangiopathic haemolytic anaemia and organ dysfunction) were included in the study. The primary objective was to assess the relative incidence of TTP, STEC-HUS, aHUS and 'other' physician-defined diagnoses. The secondary objective was to develop an algorithm to predict a severe deficiency in ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity (≤10%) using routine laboratory parameters. A post hoc classification using the recent Kidney Disease: Improving Global Outcomes diagnostic criteria was then undertaken to further classify patient groups. RESULTS: aHUS was diagnosed with a relative incidence of 61%, whereas TTP, STEC-HUS and 'other' were diagnosed in 13, 6 and 20% of patients, respectively. In the post hoc analysis, 27% of patients with a TMA were classified as 'primary aHUS' and 53% as 'secondary aHUS'. Multivariate analysis revealed that severe deficiency in ADAMTS13 activity (≤10%) was unlikely to underlie TMA if platelet and serum creatinine were above threshold values of 30 × 109/L and 1.8 mg/dL, respectively (negative predictive value of 92.3 and 98.1, respectively, if one or both values were above the threshold). CONCLUSIONS: In this study, aHUS was the most common single diagnosis among patients presenting with a TMA. In the absence of an ADAMTS13 activity result, platelet count and serum creatinine may aid in the differential diagnosis.

Practical approaches to the management of autosomal dominant polycystic kidney disease patients in the era of tolvaptan.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease worldwide. The renal phenotype is characterized by progressive cystic enlargement of the kidneys leading to a decline in renal function, hypertension and often end-stage renal disease (ESRD). Supportive care with blood pressure control and management of pain, urinary infections and renal stone disease has, until recently, been the mainstay of treatment. With the recent approval of tolvaptan for use in ADPKD, the disease progression may now be targeted specifically. Algorithms that guide treatment initiation have been proposed but a more pragmatic and patient-individualized approach is often needed to make decisions regarding therapy. It is highly important to identify ADPKD patients with rapidly progressive disease who are likely to benefit most from this treatment and avoid treatment in patients that are unlikely to reach ESRD. METHODS AND RESULTS: Here we present a series of cases of ADPKD patients in whom therapy with tolvaptan has been considered and report the rationale for the treatment decisions based on available lifestyle, clinical, biochemical, radiological and genetic data. CONCLUSIONS: These cases provide a discussion for the use of tolvaptan in ADPKD within the nephrology clinic and allow insights into the practicalities of using this therapy outside of clinical trials.

Atypical hemolytic uremic syndrome in the setting of complement-amplifying conditions: case reports and a review of the evidence for treatment with eculizumab.

Atypical hemolytic uremic syndrome (aHUS) is a rare, genetic, progressive, life-threatening form of thrombotic microangiopathy (TMA) predominantly caused by dysregulation of the alternative pathway of the complement system. Complement-amplifying conditions (CACs), including pregnancy complications [preeclampsia, HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome], malignant hypertension, autoimmune diseases, transplantation, and others, are associated with the onset of TMA in up to 69 % of cases of aHUS. CACs activate the alternative pathway of complement and may be comorbid with aHUS or may unmask a previously undiagnosed case. In this review, three case reports are presented illustrating the onset and diagnosis of aHUS in the setting of different CACs (pregnancy complications, malignant hypertension, renal transplantation). The report also reviews the evidence for a variety of CACs, including those mentioned above as well as infections and drug-induced TMA, and the overlap with aHUS. Finally, we introduce an algorithm for diagnosis and treatment of aHUS in the setting of CACs. If TMA persists despite initial management for the specific CAC, aHUS should be considered. The terminal complement inhibitor eculizumab should be initiated for all patients with confirmed diagnosis of aHUS, with or without a comorbid CAC.

Increased Cardiovascular Risk in Patients with Adrenal Insufficiency: A Short Review.

Cardiovascular disease (CVD) is the most common cause of death in the world. Recent studies have shown an association between adrenal insufficiency (AI) and increased cardiovascular risk (CVR). Patients with AI receive glucocorticoid (GC) replacement therapy which can lead to varying levels of blood cortisol. It was shown that these imbalances in blood cortisol may lead to a higher prevalence of coronary heart disease, major adverse coronary events, and increased mortality. GC substitution is essential in the treatment of AI without which the disease has been shown to be fatal. The most frequently used GC formula for replacement therapy is hydrocortisone (HC). There is no uniform opinion on hydrocortisone replacement therapy. Alternative GC such as prednisolone is also in use. Overreplacement of GC may lead to adverse effects including obesity, high blood pressure, and hyperglycaemia. Outcome may vary between primary and secondary AI mainly due to differences in the renin-angiotensin-aldosterone system (RAAS). Furthermore, decreased blood levels of cortisol may lead to a compensatory secretion of inflammatory mediators such as Interleukin-1 (IL-1), Interleukin-6 (IL-6), and/or tumor-necrosis factor (TNF). Physicians and patients should be properly educated about the increased risk of CVD in patients with AI.

Prevalence and Predictors of Overweight and Obesity in Patients with Pituitary Dysfunctions.

BACKGROUND: Patients with hypothalamic-pituitary disorders (HPD) may be of increased risk to develop overweight and obesity, thereby fostering cardiovascular events. However, it remains unclear if patients with pituitary dysfunctions per se have an increased risk of becoming obese. OBJECTIVE: The objective of this study was to evaluate prevalence and to identify possible predictors of overweight and obesity in patients with pituitary dysfunctions. METHODS: A total of 121 out-patients having various causes for HPD were assessed for height and body weight; body mass index (BMI) was calculated and correlated with clinical features. Patients were divided into various subgroups depending on underlying conditions and therapeutic modalities. RESULTS: Most of the HPD patients were overweight or obese with males being significantly more affected. Of interest, patients with macroadenomas suffered significantly more often from overweight and obesity than individuals with microadenomas (73.4% vs. 43.5%, p= 0.006). Increased BMI (≥25 kg/m2) tended to be more common in patients with prolactinomas (70.0%), hormone deficiencies (76.1%) and hormone replacement therapies (76.6%) than in a healthy population. CONCLUSION: In conclusion, we showed that patients with HPD: (i) frequently suffer from overweight and obesity; (ii) prevalence of overweight and obesity however is comparable to that in the general population; (iii) only patients with macroadenomas seem to have a significantly higher risk; (iv) hormone deficiencies and hormonal replacement therapy may foster weight gain and (v) radiation and surgical tumour therapy per se do not seem to be additional risk factors for weight gain.

Exploring the Impact of Short- and Long-Term Hydrocortisone Replacement on Cognitive Function, Quality of Life and Catecholamine Secretion: A Pilot Study.

Hydrocortisone (HC) substitution is essential in the treatment for patients with adrenal insufficiency (AI). Current replacement regimens however only incompletely mimic the physiological circadian rhythm of cortisol secretion, thereby resulting in subclinical temporary hypo- and hypercortisolism. Several studies point toward impairment of cognitive functions under these conditions, in part due to affected catecholamine secretion. Aim of this study was to evaluate the influence of long-term versus short-term HC replacement therapy on the adrenomedullary system and cognitive functions. Fourteen patients with primary or secondary AI were divided into two groups, depending on the duration of disease and HC replacement therapy (<15 years). All subjects underwent standardized neurocognitive testing; in addition, cortisol and catecholamine levels as well as physiological parameters and quality of life (QoL) were assessed. Patients with HC replacement therapy ≥15 years (n = 7) received significantly higher equivalent glucocorticoid doses than those with a shorter lasting therapy (n = 7; p = 0.048). Neuropsychological tests, QoL, physiological parameters, and cortisol levels did not differ significantly between both groups. Of note, norepinephrine levels were significantly lower in patients on short-term HC replacement therapy (p = 0.025). However, there were no significant differences in catecholamines with respect to the underlying pathophysiology, gender, or age. Irrespective of the duration of use, male patients scored significantly better for single aspects of QoL, whereas females performed significantly better in the attention test. Overall, we showed that duration of cortisol replacement therapy may have an impact on catecholamine release, but does not seem to affect cognitive functions and QoL.

No stress after 24-hour on-call shifts?

OBJECTIVES: Irregular sleep patterns can adversely affect physiological functions and have been associated with increased physiological and psychological stress. Nocturnal work of physicians during 24-hour on-call shifts (OCS) disrupts the sleep/wake cycle. Chronic exposure to distress has been shown to affect cardiovascular homeostasis and to impair performance in neurocognitive and simulated clinical tasks. METHODS: In a prospective cohort study, biochemical and physiological stress parameters were assessed in 11 female and 9 male physicians (median age: 32 years, range 26-42 years) before a normal working day and after a 24-hour OCS in internal medicine. In addition, various tests of attentional performance (TAP) were conducted. RESULTS: The levels of thyroid stimulating hormone (TSH) were significantly higher after a 24- hour OCS, while there were no significant changes in cortisol, epinephrine, and norepinephrine levels. Heart rate variability and skin resistance increased following an OCS, although the differences were not statistically significant. Intrinsic alertness was comparable, while phasic alertness was significantly improved following a 24-hour OCS. Focused attention tended to be better following a night shift. There was no correlation with age or medical working experience; however, men experienced more stress than women. CONCLUSIONS: Following a 24-hour OCS, (i) TSH may be an early and sensitive biochemical predictor of stress; (ii) other classical biochemical stress parameters do not depict the psychological stress perceived by physicians; (iii) there may be a mismatch between experienced and objective stress levels; (iv) neurocognitive functions are not impaired, while performance may even be improved; and (v) men might be more sensitive to distress.