Betti Schaefer

Comparison of Molecular Adsorbents Recirculating System (MARS) dialysis with combined plasma exchange and haemodialysis in children with acute liver failure

BACKGROUND Molecular Adsorbents Recirculating System (MARS) is an extracorporeal liver support system eliminating albumin-bound and water-soluble substances. While it is increasingly applied in patients with acute liver failure (ALF), no comparison with standard dialysis methods has yet been performed. METHODS This is an analysis of ten children (0.1-18 years) with ALF, who underwent a total of 22 MARS sessions. Standard adult MARS sets were used in seven (23.5-72 kg) and MARS Mini in three children (2.8-13 kg). In eight children, MARS was alternated with combined plasma exchange (PE) and haemodialysis (HD) treatments. Mean treatment duration was 7.2 (6-10) h for MARS and 5.7 (4.5-6.6) h for PE/HD. RESULTS Standard MARS treatment only slightly decreased serum bilirubin (16.3 ± 6.5-13.8 ± 5.9 mg/dL) and ammonia (113 ± 62-99 ± 68 μmol/L) and international normalized ratio (INR) tended to increase (1.5 ± 0.3 and 2 ± 1.1). Mini-MARS did not reduce serum bilirubin (19.7 ± 3-20.5 ± 3.2 mg/dL), ammonia slightly decreased (70 ± 24-56 ± 9 μmol/L) and INR increased (2.5 ± 0.7-2.9 ± 1.1, all P = n.s.). In contrast, PE/HD reduced serum bilirubin (23 ± 8.4-14.7 ± 7 mg/dL), ammonia (120 ± 60-70 ± 40 μmol/L) and INR (2.4 ± 0.8-1.4 ± 0.1, all P < 0.05). Intraindividual comparison showed a slight increase in bilirubin by 2 ± 22% with MARS and a reduction by 37 ± 11% with PE/HD (P < 0.001 versus MARS) and a decrease in ammonia of 18 ± 27 and 39 ± 23% (P < 0.05). INR increased during MARS by 26 ± 41% and decreased with PE/HD by 37 ± 20% (P < 0.01). All treatment sessions were well tolerated. Five children died, including the three children treated with Mini-MARS. CONCLUSION Our experience suggests superior efficacy of combined PE/HD as compared to intermittent MARS therapy for treating ALF.

Optimizing peritoneal dialysis prescription for volume control: the importance of varying dwell time and dwell volume

Not only adequate uremic toxin removal but also volume control is essential in peritoneal dialysis (PD) to improve patient outcome. Modification of dwell time impacts on both ultrafiltration (UF) and purification. A short dwell favors UF but preferentially removes small solutes such as urea. A long dwell favors uremic toxin removal but also peritoneal fluid reabsorption due to the time-dependent loss of the crystalloid osmotic gradient. In particular, the long daytime dwell in automated PD may result in significant water and sodium reabsorption, and in such cases icodextrin should be considered. Increasing dwell volume favors the removal of solutes such as sodium due to the increased volume of diffusion and the recruitment of peritoneal surface area. A very large fill volume with too high an intraperitoneal pressure (IPP) may, however, result in back-filtration and thus reduced UF and sodium clearance. Based on these principles and the individual transport and pressure kinetics obtained from peritoneal equilibration tests and IPP measurements, we suggest combining short dwells with a low fill volume to favor UF with long dwells and a large fill volume to favor solute removal. Results from a recent randomized cross-over trial and earlier observational data in children support this concept: the absolute UF and UF relative to the administered glucose increased and solute removal and blood pressure improved.

The role of molecular adsorbent recirculating system dialysis for extracorporeal liver support in children

The majority of children with acute, acute-on-chronic, and progressive chronic liver failure require liver transplantation. Since organ availability is limited, extracorporeal liver support systems are increasingly applied to bridge the time until transplantation. At present, four different devices are available: the molecular adsorbent recirculating system (MARS), Prometheus dialysis, plasma exchange combined with hemodialysis (PE/HD), and single-pass albumin dialysis (SPAD). Randomized trials in adults have demonstrated efficient toxin removal, improved portal hypertension, hemodynamic stability, and improved hepatic encephalopathy compared with standard medical therapy. None of the liver support systems has yet been evaluated systematically in children. Knowledge of the specific indications and technical features of the different devices is essential if applied in children. MARS combines albumin dialysis with conventional hemodialysis and allows for efficient removal of water and protein-bound toxins without exogenous protein delivery and the associated infectious and allergic risks. It has successfully been applied in children with otherwise intractable cholestatic pruritus and with liver failure. The benefits, however, need to be balanced against the costs and the risk of volume and nitrogen overload if repeated plasma infusion is required. In cases of active bleeding, plasma exchange in combination with hemodialysis should be preferred.

Peritoneal Dialysis Tailored to Pediatric Needs

Consideration of specific pediatric aspects is essential to achieve adequate peritoneal dialysis (PD) treatment in children. These are first of all the rapid growth, in particular during infancy and puberty, which must be accompanied by a positive calcium balance, and the age dependent changes in body composition. The high total body water content and the high ultrafiltration rates required in anuric infants for adequate nutrition predispose to overshooting convective sodium losses and severe hypotension. Tissue fragility and rapid increases in intraabdominal fat mass predispose to hernia and dialysate leaks. Peritoneal equilibration tests should repeatedly been performed to optimize individual dwell time. Intraperitoneal pressure measurements give an objective measure of intraperitoneal filling, which allow for an optimized dwell volume, that is, increased dialysis efficiency without increasing the risk of hernias, leaks, and retrofiltration. We present the concept of adapted PD, that is, the combination of short dwells with low fill volume to promote ultrafiltration and long dwells with a high fill volume to improve purification within one PD session. The use of PD solutions with low glucose degradation product content is recommended in children, but unfortunately still not feasible in many countries.

Long-term control of parathyroid hormone and calcium-phosphate metabolism after parathyroidectomy in children with chronic kidney disease

BACKGROUND Hyperparathyroidism (HPT) is an essential contributor to bone disease and cardiovascular calcifications in children with chronic kidney disease (CKD). Pharmacological and dietary interventions are of limited efficacy; calcimimetics are not yet recommended in children. Parathyroidectomy (PTX) is ultimately performed if HPT becomes refractory to conservative measures; the long-term results and the impact of subsequent kidney transplantation (NTX), however, have not yet been evaluated. METHODS We analyzed the postsurgical course of 18 paediatric CKD patients with refractory HPT who underwent PTX and autotransplantation of tissue fragments. PTX was successful in all but one patient with an ectopic fifth gland; median follow-up time was 8.3 (range 2.8-19) years. RESULTS Parathyroid hormone (PTH) dropped within 1 year after PTX from 1030 +/- 108 to 98 +/- 18 pg/ml, Ca*P from 59.5 +/- 3 to 49 +/- 2 mg(2)/dl(2). Oral calcium supply transiently increased from 18.7 +/- 4.2 to 24.1 +/- 4.8 mg/kg/day within the first 6 months (all P < 0.05). Haemoglobin increased from 10.7 +/- 0.4 to 11.5 +/- 0.3 g/dl (P < 0.01), despite similar erythropoietin dose and ferritin levels. In patients on long-term dialysis, Ca*P increased again after 18 months; three patients required a second PTX after 3.8, 12 and 12.3 years. Twelve patients underwent NTX 1.8 (0.3-3.8) years after PTX, which decreased mean PTH and Ca*P into the target range throughout the entire post-NTX observation period. Postoperative complications included one transient recurrent nerve palsy, one hypocalcaemic seizure and a case of haemopericardium. At present, no patient has clinical signs of bone disease. CONCLUSIONS PTX accomplishes long-term control of HPT and calcium-phosphate metabolism in children with CKD and following PTX and may thus mitigate uraemic bone and cardiovascular disease. This has to be taken into account if alternative long-term therapy with calcimimetics (with as yet unknown effects on longitudinal growth and pubertal development) is considered.

Educational paper: Progression in chronic kidney disease and prevention strategies.

Chronic kidney disease (CKD) in children is a rare but devastating condition. Once a critical amount of nephron mass has been lost, progression of CKD is irreversible and results in end-stage renal disease (ESRD) and need of renal replacement therapy. The time course of childhood CKD is highly variable. While in children suffering from congenital anomalies of the kidneys and the urinary tract, progression of CKD in general is slow, in children with acquired glomerulopathies, disease progression can be accelerated resulting in ESRD within months. However, irrespective of the underlying kidney disease, hypertension and proteinuria are independent risk factors for progression. Thus, in order to prevent progression, the primary objective of treatment should always aim for efficient control of blood pressure and reduction of urinary protein excretion. Blockade of the renin–angiotensin–aldosterone system preserves kidney function not only by lowering blood pressure, but also by reducing proteinuria and exerting additional anti-proteinuric, anti-fibrotic, and anti-inflammatory effects. Besides, intensified blood pressure control, aiming for a target blood pressure below the 50th percentile, may exert additive renoprotective effects. Additionally, other modifiable risk factors, such as anemia, metabolic acidosis, dyslipidemia, and altered bone-mineral homeostasis may also contribute to CKD progression. In conclusion, beyond strict blood pressure control and reduction of urinary protein excretion, identification and treatment of both, renal disease-related and conventional risk factors are mandatory in children with CKD in order to prevent deterioration of kidney function.

Quantitative Histomorphometry of the Healthy Peritoneum

The peritoneum plays an essential role in preventing abdominal frictions and adhesions and can be utilized as a dialysis membrane. Its physiological ultrastructure, however, has not yet been studied systematically. 106 standardized peritoneal and 69 omental specimens were obtained from 107 patients (0.1–60 years) undergoing surgery for disease not affecting the peritoneum for automated quantitative histomorphometry and immunohistochemistry. The mesothelial cell layer morphology and protein expression pattern is similar across all age groups. Infants below one year have a thinner submesothelium; inflammation, profibrotic activity and mesothelial cell translocation is largely absent in all age groups. Peritoneal blood capillaries, lymphatics and nerve fibers locate in three distinct submesothelial layers. Blood vessel density and endothelial surface area follow a U-shaped curve with highest values in infants below one year and lowest values in children aged 7–12 years. Lymphatic vessel density is much lower, and again highest in infants. Omental blood capillary density correlates with parietal peritoneal findings, whereas only few lymphatic vessels are present. The healthy peritoneum exhibits major thus far unknown particularities, pertaining to functionally relevant structures, and subject to substantial changes with age. The reference ranges established here provide a framework for future histomorphometric analyses and peritoneal transport modeling approaches.

Are Current Peritoneal Dialysis Solutions Adequate for Pediatric Use

Peritoneal dialysis (PD) is the treatment modality of choice in pediatric CKD5D patients awaiting renal transplantation. Facing many decades of renal replacement therapy long term preservation of peritoneal membrane function is of particular importance in this patient group. Whereas conventional PD fluids induce severe morphological and functional alterations of the peritoneal membrane within a few years, reduction of glucose degradation product content by multichamber systems, replacement of glucose by icodextrin and amino acids, and of lactate by bicarbonate at a neutral to physiological pH are expected to preserve peritoneal membrane integrity. Based on numerous in vitro, experimental and clinical studies, the European Pediatric Dialysis Working Group recommended the use of low glucose degradation product solutions whenever possible. Icodextrin is considered a useful option, in particular in children with sodium and water overload, even though infants may absorb higher amounts of icodextrin and achieve less ultrafiltration. The concept of amino acid-based PD fluids is intriguing, but pediatric benefits are insufficiently described and cannot replace tube feeding in malnourished children. Bicarbonate-based PD fluids better control metabolic acidosis and have been recommended in children with acute kidney injury and impaired lactate metabolism. This review discusses the scientific evidence and potential advantages of PD solutions with an improved biocompatibility profile, with a particular focus on pediatric studies.

Neutral pH and low–glucose degradation product dialysis fluids induce major early alterations of the peritoneal membrane in children on peritoneal dialysis

The effect of peritoneal dialysates with low-glucose degradation products on peritoneal membrane morphology is largely unknown, with functional relevancy predominantly derived from experimental studies. To investigate this, we performed automated quantitative histomorphometry and molecular analyses on 256 standardized peritoneal and 172 omental specimens from 56 children with normal renal function, 90 children with end-stage kidney disease at time of catheter insertion, and 82 children undergoing peritoneal dialysis using dialysates with low-glucose degradation products. Follow-up biopsies were obtained from 24 children after a median peritoneal dialysis of 13 months. Prior to dialysis, mild parietal peritoneal inflammation, epithelial-mesenchymal transition and vasculopathy were present. After up to six and 12 months of peritoneal dialysis, blood microvessel density was 110 and 93% higher, endothelial surface area per peritoneal volume 137 and 95% greater, and submesothelial thickness 23 and 58% greater, respectively. Subsequent peritoneal changes were less pronounced. Mesothelial cell coverage was lower and vasculopathy advanced, whereas lymphatic vessel density was unchanged. Morphological changes were accompanied by early fibroblast activation, leukocyte and macrophage infiltration, diffuse podoplanin presence, epithelial mesenchymal transdifferentiation, and by increased proangiogenic and profibrotic cytokine abundance. These transformative changes were confirmed by intraindividual comparisons. Peritoneal microvascular density correlated with peritoneal small-molecular transport function by uni- and multivariate analysis. Thus, in children on peritoneal dialysis neutral pH dialysates containing low-glucose degradation products induce early peritoneal inflammation, fibroblast activation, epithelial-mesenchymal transition and marked angiogenesis, which determines the PD membrane transport function.

Complement Activation in Peritoneal Dialysis–Induced Arteriolopathy

Cardiovascular disease (CVD) is the leading cause of increased mortality in patients with CKD and is further aggravated by peritoneal dialysis (PD). Children are devoid of preexisting CVD and provide unique insight into specific uremia- and PD-induced pathomechanisms of CVD. We obtained peritoneal specimens from children with stage 5 CKD at time of PD catheter insertion (CKD5 group), children with established PD (PD group), and age-matched nonuremic controls (n=6/group). We microdissected omental arterioles from tissue layers not directly exposed to PD fluid and used adjacent sections of four arterioles per patient for transcriptomic and proteomic analyses. Findings were validated in omental and parietal arterioles from independent pediatric control (n=5), CKD5 (n=15), and PD (n=15) cohorts. Transcriptomic analysis revealed differential gene expression in control versus CKD5 arterioles and in CKD5 versus PD arterioles. Gene ontology analyses revealed activation of metabolic processes in CKD5 arterioles and of inflammatory, immunologic, and stress-response cascades in PD arterioles. PD arterioles exhibited particular upregulation of the complement system and respective regulatory pathways, with concordant findings at the proteomic level. In the validation cohorts, PD specimens had the highest abundance of omental and parietal arteriolar C1q, C3d, terminal complement complex, and phosphorylated SMAD2/3, a downstream effector of TGF-β Furthermore, in the PD parietal arterioles, C1q and terminal complement complex abundance correlated with the level of dialytic glucose exposure, abundance of phosphorylated SMAD2/3, and degree of vasculopathy. We conclude that PD fluids activate arteriolar complement and TGF-β signaling, which quantitatively correlate with the severity of arteriolar vasculopathy.