Altered placental macrophage numbers and subsets in pregnancies complicated with intrahepatic cholestasis of pregnancy (ICP) compared to healthy pregnancies.

INTRODUCTION: Intrahepatic cholestasis of pregnancy (ICP) can result in adverse outcomes for both mother and fetus. Inflammatory (M1 subset) or anti-inflammatory (M2 subset) macrophage polarisation is associated with various complications of pregnancy. However, the influence of ICP on macrophage numbers and polarisation remains unknown. This study analyses macrophage density and distribution in placentas of patients with ICP compared to controls. Clinical parameters were correlated to macrophage distribution and ursodeoxycholic acid use (UDCA). METHODS: This study included routinely collected placental tissue samples of 42 women diagnosed with ICP and of 50 control pregnancies. Immunohistochemical staining was performed on placental tissue using CD68 antibody as a pan-macrophage marker, CD206 antibody as an M2 and HLA-DR antibody as an M1 macrophage marker. Macrophage density (cells/mm2) and distribution (CD206+/CD68+ or CD206+/CD68+HLA-DR+) in both decidua (maternal tissue) and villous parenchyma (fetal tissue) were compared between groups. Macrophage density and distribution were correlated to clinical parameters for ICP patients. RESULTS: The density of CD68+ macrophages differed significantly between groups in villous parenchyma. In both decidua and villous parenchyma, CD206+/CD68+ ratio was significantly lower in ICP patients compared to controls (p = 0.003 and p=<0.001, respectively). No difference was found based on UDCA use or in CD68+HLA-DR+ cell density. Significant correlations were found between macrophage density and peak serum bile acids and liver enzymes. DISCUSSION: In ICP patients, an immune shift was observed in both decidual and villous tissue, indicated by a lower CD206+/CD68+ ratio. ICP seems to affect placental tissue, however more research is required to understand its consequences.

Fetal and post-natal outcomes in offspring after intrauterine metformin exposure: A systematic review and meta-analysis of animal experiments.

AIMS: The impact of maternal metformin use during pregnancy on fetal, infant, childhood and adolescent growth, development, and health remains unclear. Our objective was to systematically review the available evidence from animal experiments on the effects of intrauterine metformin exposure on offspring's anthropometric, cardiovascular and metabolic outcomes. METHODS: A systematic search was conducted in PUBMED and EMBASE from inception (searched on 12th April 2023). We extracted original, controlled animal studies that investigated the effects of maternal metformin use during pregnancy on offspring anthropometric, cardiovascular and metabolic measurements. Subsequently, risk of bias was assessed and meta-analyses using the standardized mean difference and a random effects model were conducted for all outcomes containing data from 3 or more studies. Subgroup analyses were planned for species, strain, sex and type of model in the case of 10 comparisons or more per subgroup. RESULTS: We included 37 articles (n = 3133 offspring from n = 716 litters, containing n = 51 comparisons) in this review, mostly (95%) on rodent models and 5% pig models. Follow-up of offspring ranged from birth to 2 years of age. Thirty four of the included articles could be included in the meta-analysis. No significant effects in the overall meta-analysis of metformin on any of the anthropometric, cardiovascular and metabolic offspring outcome measures were identified. Between-studies heterogeneity was high, and risk of bias was unclear in most studies as a consequence of poor reporting of essential methodological details. CONCLUSION: This systematic review was unable to establish effects of metformin treatment during pregnancy on anthropometric, cardiovascular and metabolic outcomes in non-human offspring. Heterogeneity between studies was high and reporting of methodological details often limited. This highlights a need for additional high-quality research both in humans and model systems to allow firm conclusions to be established. Future research should include focus on the effects of metformin in older offspring age groups, and on outcomes which have gone uninvestigated to date.

Higher beta-hydroxybutyrate ketone levels associated with a slower kidney function decline in ADPKD.

BACKGROUND AND HYPOTHESIS: Dysregulated energy metabolism is a recently discovered key feature of Autosomal Dominant Polycystic Kidney Disease (ADPKD). Cystic cells depend on glucose and are poorly able to use other energy sources such as ketone bodies. Raising ketone body concentration reduced disease progression in animal models of polycystic kidney diseases. Therefore, we hypothesized that higher endogenous plasma beta-hydroxybutyrate concentrations are associated with reduced disease progression in patients with ADPKD. METHODS: We analyzed data from 670 patients with ADPKD participating in the DIPAK cohort, a multi-center prospective observational cohort study. Beta-hydroxybutyrate was measured at baseline using nuclear magnetic resonance spectroscopy. Participants were excluded if they had type 2 diabetes, were using disease-modifying drugs (e.g. tolvaptan, somatostatin analogs), were not fasting, or had missing beta-hydroxybutyrate levels, leaving 521 participants for the analyses. Linear regression analyses were used to study cross-sectional associations and linear mixed-effect modeling for longitudinal associations. RESULTS: Of the participants, 61% were female, with an age of 47.3 ± 11.8 years, a height-adjusted total kidney volume (htTKV) of 834 (IQR 495-1327) ml/m, and an estimated glomerular filtration rate (eGFR) of 63.3 ± 28.9 mL/min/1.73m2. The median concentration of beta-hydroxybutyrate was 94 (IQR 68-147) µmol/L. Cross-sectionally, beta-hydroxybutyrate was neither associated with eGFR nor with htTKV. Longitudinally, beta-hydroxybutyrate was positively associated with eGFR slope (B = 0.35 ml/min/1.73m2 (95% CI 0.09 to 0.61), p = 0.007), but not with kidney growth. After adjustment for potential confounders, every doubling in beta-hydroxybutyrate concentration was associated with an improvement in the annual rate of eGFR by 0.33 ml/min/1.73m2 (95% CI 0.09 to 0.57, p = 0.008). CONCLUSION: These observational analyses support the hypothesis that interventions that raise beta-hydroxybutyrate concentration could reduce the rate of kidney function decline in patients with ADPKD.

Fasting before living-kidney donation: effect on donor well-being and postoperative recovery: study protocol of a multicenter randomized controlled trial.

BACKGROUND: One of the main effectors on the quality of life of living-kidney donors is postoperative fatigue. Caloric restriction (CR) and short-term fasting (STF) are associated with improved fitness and increased resistance to acute stress. CR/STF increases the expression of cytoprotective genes, increases immunomodulation via increased anti-inflammatory cytokine production, and decreases the expression of pro-inflammatory markers. As such, nutritional preconditioning by CR or STF represents a non-invasive and cost-effective method that could mitigate the effects of acute surgery-induced stress and postoperative fatigue. To investigate whether preoperative STF contributes to a reduction in fatigue after living-kidney donation, a randomized clinical trial is indicated. METHODS: We aim to determine whether 2.5 days of fasting reduces postoperative fatigue score in subjects undergoing living-kidney donation. In this randomized study, the intervention group will follow a preoperative fasting regime for 2.5 days with a low-dose laxative, while the control group will receive standard care. The main study endpoint is postoperative fatigue, 4 weeks after living-kidney donation. Secondary endpoints include the effect of preoperative fasting on postoperative hospital admission time, the feasibility of STF, and the postoperative recovery of donor and recipient kidney function. This study will provide us with knowledge of the feasibility of STF and confirm its effect on postoperative recovery. DISCUSSION: Our study will provide clinically relevant information on the merits of caloric restriction for living-kidney donors and recipients. We expect to reduce the postoperative fatigue in living-kidney donors and improve the postoperative recovery of living-kidney recipients. It will provide evidence on the clinical merits and potential caveats of preoperative dietary interventions. TRIAL REGISTRATION: Netherlands Trial Register NL9262 . EudraCT 2020-005445-16 . MEC Erasmus MC MEC-2020-0778. CCMO NL74623.078.21.

Parathyroidectomy versus cinacalcet for tertiary hyperparathyroidism; a retrospective analysis.

INTRODUCTION: Tertiary hyperparathyroidism (tHPT), i.e., persistent HPT after kidney transplantation, affects 17-50% of transplant recipients. Treatment of tHPT is mandatory since persistently elevated PTH concentrations after KTx increase the risk of renal allograft dysfunction and osteoporosis. The introduction of cinacalcet in 2004 seemed to offer a medical treatment alternative to parathyroidectomy (PTx). However, the optimal management of tHPT remains unclear. METHODS: A retrospective analysis was performed on patients receiving a kidney transplantation (KT) in two academic centers in the Netherlands. Thirty patients undergoing PTx within 3 years of transplantation and 64 patients treated with cinacalcet 1 year after transplantation for tHPT were included. Primary outcomes were serum calcium and PTH concentrations 1 year after KT and after PTx. RESULTS: Serum calcium normalized in both the cinacalcet and the PTx patients. PTH concentrations remained above the upper limit of normal (median 22.0 pmol/L) 1 year after KT, but returned to within the normal range in the PTx group (median 3.7 pmol/L). Side effects of cinacalcet were difficult to assess; minor complications occurred in three patients. Re-exploration due to persistent tHPT was performed in three (10%) patients. CONCLUSION: In patients with tHPT, cinacalcet normalizes serum calcium, but does not lead to a normalization of serum PTH concentrations. In contrast, PTx leads to a normalization of both serum calcium and PTH concentrations. These findings suggest that PTx is the treatment of choice for tHPT.

Yield of diagnostic tests in unexplained renal hypophosphatemia: a case series.

BACKGROUND: Isolated renal hypophosphatemia may be inherited or acquired. An increasing number of patients with unexplained renal hypophosphatemia is being referred to our clinics, but the optimal diagnostic work-up is not known. Therefore, the aim of this study was to assess the diagnostic yield in these patients. METHODS: We retrospectively evaluated all patients who were referred because of unexplained isolated renal hypophosphatemia to two academic tertiary referral centers in The Netherlands in the period of 2013-2017. RESULTS: We evaluated 17 patients. In five female patients renal hypophosphatemia could be attributed to the use of oral contraceptives. The other 12 patients had a median age of 48 years (10 males). There were no other signs of tubulopathy and none of the patients used drugs known to be associated with hypophosphatemia. FGF23 levels were above normal (> 125 RU/ml) in 2/12 patients. Genetic testing, performed in all patients, did not identify a mutation in genes known to be associated with renal phosphate wasting. A scan with a radiolabeled somatostatin analogue was performed in 8 patients. In one patient, with an FGF23 level of 110 RU/ml, an increased uptake of the somatostatin analog was observed due to tumor induced osteomalacia (TIO). CONCLUSIONS: Oral contraceptive use is an important but under-recognized cause of renal hypophosphatemia. The cause of isolated renal hypophosphatemia remained unexplained in the majority of other patients despite extensive and expensive additional investigations. The pre-test probability for tumor-induced osteomalacia or inherited renal hypophosphatemia in a patient with aspecific complaints and a normal FGF23 level is low. Further research is needed to investigate which patients should be screened for TIO. At present we suggest to perform somatostatin scans only in patients with severe complaints, elevated FGF23 levels, or progressive disease.

[Hydration to prevent contrast-induced nephropathy]. / Hydratie ter preventie van contrastnefropathie.

In 2007, a national guideline was issued in the Netherlands to prevent contrast-induced nephropathy. This guideline recommended preventive hydration with 0.9% NaCl in patients with reduced estimated glomerular filtration rate (eGFR 30-69 ml/min/1.73 m2) prior to administration of contrast. The recent AMACING study compared hydration versus no hydration, and found that hydration did not prevent contrast-induced nephropathy but did lead to complications and higher costs. The latest 2017 guideline recommends hydration only for patients with eGFR < 30 ml/min/1.73 m2. Although this is an improvement, an even more recent study, PRESERVE, showed no differences in the incidence of contrast-induced nephropathy between sodium chloride, sodium bicarbonate, acetylcysteine, or placebo - even in patients with lower eGFRs (15-60 ml/min/1.73 m2) undergoing elective angiography. This raises the question whether preventive measures are only effective in patients with the highest risk, i.e. hospitalized patients with multiple risk factors undergoing emergency procedures.

Systematic review of surgical and medical treatment for tertiary hyperparathyroidism.

BACKGROUND: A significant proportion of patients with chronic kidney disease and secondary hyperparathyroidism (HPT) remain hyperparathyroid after kidney transplantation, a state known as tertiary HPT. Without treatment, tertiary HPT can lead to diminished kidney allograft and patient survival. Parathyroidectomy was commonly performed to treat tertiary HPT until the introduction of the calcimimetic drug, cinacalcet. It is not known whether surgery or medical treatment is superior for tertiary HPT. METHODS: A systematic review was performed and medical literature databases were searched for studies on the treatment of tertiary HPT that were published after the approval of cinacalcet. RESULTS: A total of 1669 articles were identified, of which 47 were included in the review. Following subtotal and total parathyroidectomy, initial cure rates were 98·7 and 100 per cent respectively, but in 7·6 and 4 per cent of patients tertiary HPT recurred. After treatment with cinacalcet, 80·8 per cent of the patients achieved normocalcaemia. Owing to side-effects, 6·4 per cent of patients discontinued cinacalcet treatment. The literature regarding graft function and survival is limited; however, renal graft survival after surgical treatment appears comparable to that obtained with cinacalcet therapy. CONCLUSION: Side-effects and complications of both treatment modalities were mild and occurred in a minority of patients. Surgical treatment for tertiary HPT has higher cure rates than medical therapy.

Ferric carboxymaltose-induced hypophosphataemia after kidney transplantation.

BACKGROUND: Ferric carboxymaltose (FCM) can induce hypophosphataemia in the general population and patients with chronic kidney disease (CKD). Less is known about the effect of FCM in the kidney transplant population. It has been suggested that fibroblast growth factor 23 (FGF-23)-mediated renal phosphate wasting may be the most likely cause of this phenomenon. In the current study, the effects of FCM on phosphate metabolism were studied in a cohort of kidney transplant recipients. METHODS: Two index patients receiving FCM are described. Additionally, data of 23 kidney transplant recipients who received a single dose of FCM intravenously between 1 January 2014 and 1 July 2015 were collected. Changes in the serum phosphate concentration were analysed in all subjects. Change in plasma FGF-23 concentrations was analysed in the index patients. RESULTS: In the two index patients an increase in FGF-23 and a decrease in phosphate concentrations were observed after FCM administration. In the 23 kidney transplant patients, median estimated glomerular filtration rate was 42 ml/min/1.73 m2 ( range 10-90 ml/ min/1.73 m2). Mean phosphate concentration before and after FCM administration was 1.05 ±; 0.35 mmol/l and 0.78 ±; 0.41 mmol/l, respectively (average decrease of 0.27 mmol/l; p = 0.003). In the total population, 13 (56.5%) patients showed a transient decline in phosphate concentration after FCM administration. Hypophosphataemia following FCM administration was severe (i.e. < 0.5 mmol/l) in 8 (34.8%) patients. CONCLUSION: Administration of a single dose of FCM may induce transient and mostly asymptomatic renal phosphate wasting and hypophosphataemia in kidney transplant recipients. This appears to be explained by an increase in FGF-23 concentration.

[Fatal cerebral oedema during the treatment of diabetic ketoacidosis in an adult male]. / Fataal hersenoedeem bij behandeling van een volwassene met diabetische ketoacidose.

Diabetic ketoacidosis is relatively common, but the optimal treatment of this condition is still controversial. Cerebral oedema is a rare, but potentially fatal complication. We present the case of an adult patient who presented with de novo diabetic ketoacidosis that was complicated by cerebral oedema during treatment. In this article we discuss factors that may have played a role in the development of this complication. A prolonged hyperosmolar state in diabetic ketoacidosis may increase the risk of cerebral oedema as a result of cerebral compensatory mechanisms. In this group of patients, liberal doses of insulin, fluids and bicarbonate may lead to a decrease in the effective serum osmolarity which can lead to water shifts in the cerebrum. We suggest several adjustments to current treatment guidelines for patients with diabetic ketoacidosis who have undergone a prolonged period of hyperosmolar derangement, with the aim of decreasing the risk of cerebral oedema.

Measurement and interpretation of skin prick test results.

BACKGROUND: There are several methods to read skin prick test results in type-I allergy testing. A commonly used method is to characterize the wheal size by its 'average diameter'. A more accurate method is to scan the area of the wheal to calculate the actual size. In both methods, skin prick test (SPT) results can be corrected for histamine-sensitivity of the skin by dividing the results of the allergic reaction by the histamine control. The objectives of this study are to compare different techniques of quantifying SPT results, to determine a cut-off value for a positive SPT for histamine equivalent prick -index (HEP) area, and to study the accuracy of predicting cashew nut reactions in double-blind placebo-controlled food challenge (DBPCFC) tests with the different SPT methods. METHODS: Data of 172 children with cashew nut sensitisation were used for the analysis. All patients underwent a DBPCFC with cashew nut. Per patient, the average diameter and scanned area of the wheal size were recorded. In addition, the same data for the histamine-induced wheal were collected for each patient. The accuracy in predicting the outcome of the DBPCFC using four different SPT readings (i.e. average diameter, area, HEP-index diameter, HEP-index area) were compared in a Receiver-Operating Characteristic (ROC) plot. RESULTS: Characterizing the wheal size by the average diameter method is inaccurate compared to scanning method. A wheal average diameter of 3 mm is generally considered as a positive SPT cut-off value and an equivalent HEP-index area cut-off value of 0.4 was calculated. The four SPT methods yielded a comparable area under the curve (AUC) of 0.84, 0.85, 0.83 and 0.83, respectively. The four methods showed comparable accuracy in predicting cashew nut reactions in a DBPCFC. CONCLUSIONS: The 'scanned area method' is theoretically more accurate in determining the wheal area than the 'average diameter method' and is recommended in academic research. A HEP-index area of 0.4 is determined as cut-off value for a positive SPT. However, in clinical practice, the 'average diameter method' is also useful, because this method provides similar accuracy in predicting cashew nut allergic reactions in the DBPCFC. TRIAL REGISTRATION: Trial number NTR3572.

Dutch guideline for the management of electrolyte disorders--2012 revision.

Electrolyte disorders are common and often challenging in terms of differential diagnosis and appropriate treatment. To facilitate this, the first Dutch guideline was developed in 2005, which focused on hypernatraemia, hyponatraemia, hyperkalaemia, and hypokalaemia. This guideline was recently revised. Here, we summarise the key points of the revised guideline, including the major complications of each electrolyte disorder, differential diagnosis and recommended treatment. In addition to summarising the guideline, the aim of this review is also to provide a practical guide for the clinician and to harmonise the management of these disorders based on available evidence and physiological principles.

Complicated systemic lupus erythematosus pancreatitis: pseudocyst, pseudoaneurysm, but real bleeding.

We report the case of a 25-year-old patient with systemic lupus erythematosus (SLE) pancreatitis which was complicated by pseudocyst and pseudoaneurysm formation. The pseudoaneurysm progressed to intra-abdominal bleeding requiring endovascular coil embolization of the gastroduodenal artery. The pseudocyst and hematoma formed two large abdominal fluid collections causing symptoms due to a mass effect. These fluid collections were treated conservatively, while active SLE was treated with steroids, azathioprine, and immunoglobulins. She finally made a full recovery. To the best of our knowledge, this is the first report of a bleeding pseudoaneurysm complicating SLE pancreatitis. Although anecdotal, this case may serve as a useful example of the possible complications of SLE pancreatitis, including considerations on optimal management.

Fluid, electrolyte and acid-base disorders associated with antibiotic therapy.

Antibiotics are among the most frequently prescribed drugs in medicine. Their use, however, is often limited by associated renal toxic effects. The most common manifestation of these toxic effects is decreased glomerular filtration rate. However, they can also occur while renal function remains near to normal. This Review focuses on antibiotic-associated fluid, electrolyte and acid-base disorders that do not greatly reduce glomerular filtration. Renal tubules can be affected by antibiotics at various locations. In the proximal tubule, toxic effects of tetracyclines and aminoglycosides can result in complete proximal tubular dysfunction, also known as Fanconi syndrome. Aminoglycosides (and capreomycin) can also affect the loop of Henle and lead to a Bartter-like syndrome. In the collecting ducts, antibiotics can cause a diverse range of disorders, including hyponatremia, hypokalemia, hyperkalemia, renal tubular acidosis, and nephrogenic diabetes insipidus. Causative antibiotics include trimethoprim, amphotericin B, penicillins, ciprofloxacin, demeclocycline and various antitubercular agents. Here, we describe the mechanisms that disrupt renal tubular function. Integrated with the physiology of each successive nephron segment, we discuss the receptors, transporters, channels or pores that are affected by antibiotics. This insight should pave the way for pathophysiology-directed treatment of these disorders.

Guilty as charged: unmeasured urinary anions in a case of pyroglutamic acidosis.

A patient developed an unexplained metabolic acidosis with the characteristics of renal tubular acidosis. By correcting the serum anion gap for hypoalbuminaemia and analysing the urinary anions and cations, the presence of unmeasured anions was revealed. The diagnosis of pyroglutamic acidosis, caused by a combination of flucloxacillin and acetaminophen, was established. Strategies for solving complex cases of metabolic acidosis are discussed.