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.

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.

Acute and concomitant deterioration of hyponatremia and renal dysfunction associated with heart and liver failure.

BACKGROUND: Although hyponatremia with concomitant renal dysfunction has been described anecdotally, little is known about how these two conditions are related, which type of renal dysfunction usually occurs, and which patients are at risk. METHODS: From 3029 measured serum sodium (S(Na)) concentrations in 3 months, patients with at least one S(Na) < or =125 mmol/l were selected, and divided in patients with at least 1 S(Creat) > or =125 micromol/l (study group, n=20), and patients whose S(Creat) remained normal (control group, n=50). RESULTS: During the first 5 days of hospitalization, S(Creat) almost doubled in the study group from 125 +/- 40 micromol/l to 207 +/- 72 micromol/l, while S(Na) decreased concurrently from 130 +/- 2 mmol/l to 122 +/- 3 mmol/l. The peak S(Creat) and S(Na) values coincided, and the average courses were highly correlated (r = 0.88, p < 0.001). The study group more often had heart failure (10/20 vs. 1/50, p < 0.001) and liver failure (7/20 vs. 4/50, p = 0.009), and received more often loop diuretics (13/20 vs. 12/50, p = 0.002), spironolactone (11/20 vs. 7/50, p = 0.001), and/or angiotensin-converting enzyme inhibitors (5/20 vs. 2/50, p = 0.02). Four patients were admitted to the intensive care (10 in control group, p = 1.0), and 5 patients died (10 in control group, p = 0.7). CONCLUSIONS: Renal dysfunction is common in severe hyponatremia and usually develops in an acute-on-chronic fashion with concomitant deterioration of both conditions. This concourse is associated with heart failure, liver failure, and/or a renal drug regimen. Given the recent results of clinical trials, this patient group may be especially suitable for treatment with vasopressin antagonists.