Glucose Derivative Induced Vasculopathy in Children on Chronic Peritoneal Dialysis.

[Figure: see text].

Peritoneal transformation shortly after kidney transplantation in pediatric patients with preceding chronic peritoneal dialysis.

BACKGROUND: The unphysiological composition of peritoneal dialysis (PD) fluids induces progressive peritoneal fibrosis, hypervascularization and vasculopathy. Information on these alterations after kidney transplantation (KTx) is scant. METHODS: Parietal peritoneal tissues were obtained from 81 pediatric patients with chronic kidney disease stage 5 (CKD5), 72 children on PD with low glucose degradation product (GDP) PD fluids, and from 20 children 4-8 weeks after KTx and preceding low-GDP PD. Tissues were analyzed by digital histomorphometry and quantitative immunohistochemistry. RESULTS: While chronic PD was associated with peritoneal hypervascularization, after KTx vascularization was comparable to CKD5 level. Submesothelial CD45 counts were 40% lower compared with PD, and in multivariable analyses independently associated with microvessel density. In contrast, peritoneal mesothelial denudation, submesothelial thickness and fibrin abundance, number of activated, submesothelial fibroblasts and of mesothelial-mesenchymal transitioned cells were similar after KTx. Diffuse peritoneal podoplanin positivity was present in 40% of the transplanted patients. In subgroups matched for age, PD vintage, dialytic glucose exposure and peritonitis incidence, submesothelial hypoxia-inducible factor 1-alpha abundance and angiopoietin 1/2 ratio were lower after KTx, reflecting vessel maturation, while arteriolar and microvessel p16 and cleaved Casp3 were higher. Submesothelial mast cell count and interleukin-6 were lower, whereas transforming growth factor-beta induced pSMAD2/3 was similar as compared with children on PD. CONCLUSIONS: Peritoneal membrane damage induced with chronic administration of low-GDP PD fluids was less severe after KTx. While peritoneal microvessel density, primarily defining PD transport and ultrafiltration capacity, was normal after KTx and peritoneal inflammation less pronounced, diffuse podoplanin positivity and profibrotic activity were prevalent.

Inactivation of Osteoblast PKC Signaling Reduces Cortical Bone Mass and Density and Aggravates Renal Osteodystrophy in Mice with Chronic Kidney Disease on High Phosphate Diet.

Chronic kidney disease (CKD) frequently leads to hyperphosphatemia and hyperparathyroidism, mineral bone disorder (CKD-MBD), ectopic calcifications and cardiovascular mortality. PTH activates the osteoanabolic Gαs/PKA and the Gαq/11/PKC pathways in osteoblasts, the specific impact of the latter in CKD-MBD is unknown. We generated osteoblast specific Gαq/11 knockout (KO) mice and established CKD-MBD by subtotal nephrectomy and dietary phosphate load. Bone morphology was assessed by micro-CT, osteoblast function by bone planar scintigraphy at week 10 and 22 and by histomorphometry. Osteoblasts isolated from Gαq/11 KO mice increased cAMP but not IP3 in response to PTH 1-34, demonstrating the specific KO of the PKC signaling pathway. Osteoblast specific Gαq/11 KO mice exhibited increased serum calcium and reduced bone cortical thickness and mineral density at 24 weeks. CKD Gαq/11 KO mice had similar bone morphology compared to WT, while CKD Gαq/11-KO on high phosphate diet developed decreased metaphyseal and diaphyseal cortical thickness and area, as well as a reduction in trabecular number. Gαq/11-KO increased bone scintigraphic tracer uptake at week 10 and mitigated tracer uptake in CKD mice at week 22. Histological bone parameters indicated similar trends. Gαq/11-KO in osteoblast modulates calcium homeostasis, bone formation rate, bone morphometry, and bone mineral density. In CKD and high dietary phosphate intake, osteoblast Gαq/11/PKC KO further aggravates mineral bone disease.

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-ß 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-ß signaling, which quantitatively correlate with the severity of arteriolar vasculopathy.

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.

miR-21 Promotes Fibrogenesis in Peritoneal Dialysis.

Peritoneal dialysis (PD) is a life-saving form of renal replacement therapy for those with end-stage kidney disease. Mesothelial cells (MCs) line the peritoneal cavity and help define peritoneal response to treatment-associated injury, a major reason for treatment failure. miRNAs are important regulators, but their roles in peritoneal fibrosis are largely unknown. In this study, miR-21 was one of the most abundant miRNAs in primary MCs, and was up-regulated by the profibrotic cytokine transforming growth factor-ß1 and in PD effluent-derived MCs exhibiting mesenchymal phenotypic change. Increased miR-21 was found in peritoneal membrane biopsy specimens from PD patients compared to healthy controls (PD biocompatible, 5.86×, P = 0.0001; PD conventional, 7.09×, P < 0.0001, n = 11 per group). In PD effluent from a cohort of 230 patients, miR-21 was higher in those receiving the therapy long-term compared to new starters (n = 230, miR-21 3.26×, P = 0.001) and associated with icodextrin use (R = 0.52; 95% CI, 0.20-0.84), peritonitis count (R = 0.16; 95% CI, 0.03-0.29), and dialysate cytokines. miR-21 down-regulated programmed cell death 4 and programmed cell death 4 protein was decreased in peritoneal membrane biopsy specimens from PD patients compared to healthy controls. New miR-21 targets were identified that may be important during PD fibrogenesis. These data identify miR-21 as an important effector of fibrosis in the peritoneal membrane, and a promising biomarker in the dialysis effluent for membrane change in patients receiving PD.

Should sodium removal in peritoneal dialysis be estimated from the ultrafiltration volume?

In peritoneal dialysis (PD), ultrafiltration (UF) volume is the sum of solute-free- and solute-coupled-water removal, a dynamic process throughout the entire dwell exerted via aquaporin-1 (AQP1) and small pores, respectively. Determination of sodium sieving is used as a parameter for AQP1 function analysis, while coupled water removal is essential for adequate sodium and water balance and thus blood pressure control. The diffusive capacity of glucose via the small pores determines the dynamic crystalloid osmotic gradient. The osmotic conductance, i.e., milliliter of UF per gram of glucose absorbed, quantifies cooperation between small-pores and AQP1 channels. In continuous ambulatory peritoneal dialysis, with dwell times beyond glucose-induced sodium-sieving effects, approximate dialytic sodium removal (DSR) may be estimated from the UF volume (in average 100 mmol Na/L UF), while DSR is lower, with shorter cycle times, in automated PD (APD); therefore, effluent sodium concentrations should be measured. Applying dialysis mechanics, i.e., varying dwell time and dwell volume-as proposed in adapted APD to the PD prescription-may provide unmatched high DSR relative to UF volume, findings which are not sufficiently explained by the three-pore model of PD. Overall DSR should therefore be measured rather than estimated from UF volume.

Body composition monitoring-derived urea distribution volume in children on chronic hemodialysis.

BACKGROUND: Modern hemodialysis (HD) machines are able to measure ionic dialysance online and thereby continuously monitor Kt/V. The accuracy of measurement depends on the input of the correct urea distribution volume (V), available from anthropometric equations and body composition monitoring (BCM). The latter method, however, has not been validated in children. METHODS: We compared V determined by BCM to that calculated using four different anthropometric formulas (Morgenstern, Mellits and Cheek, Hume-Weyers and Watson equations) in 23 pediatric HD patients. We also compared online Kt/V using BCM-derived V with the Kt/V calculated from pre- and post-dialytic urea concentrations using the single-pool second-generation Daugirdas equation. RESULTS: The V calculated by the Morgenstern equation was similar to that derived by BCM, with a mean difference of -0.7% (95% limits of agreement -11.7 to 10.3%). In contrast, the V calculated by the other equations was 5.4, 6.2 and 18%, respectively higher than the BCM-derived V. The mean difference between Kt/V calculated using the Daugirdas equation and online Kt/V determination based on BCM-derived V data was 0.10 (95% limits of agreement -0.50 to 0.70%). CONCLUSIONS: In our pediatric HD patients the V measured by BCM was in agreement with that calculated using the Morgenstern equation, which is the only equation which has been validated to date in children on dialysis. Online determination of Kt/V using a BCM-derived V largely agreed with that calculated by the Daugirdas equation. We therefore conclude that the former approach is suitable for frequent online assessment of dialytic small solute clearance.

Indications, technique, and outcome of therapeutic apheresis in European pediatric nephrology units.

BACKGROUND: Few observations on apheresis in pediatric nephrology units have been published. METHODS: This retrospective study involved children ≤18 years undergoing plasma exchange (PE), immunoadsorption (IA), or double filtration plasmapheresis (DFPP) in 12 European pediatric nephrology units during 2012. RESULTS: Sixty-seven children underwent PE, ten IA, and three DFPP, for a total of 738 PE and 349 IA/DFPP sessions; 67.2 % of PE and 69.2 % of IA/DFPP patients were treated for renal diseases, in particular focal segmental glomerulosclerosis (FSGS), hemolytic-uremic syndrome (HUS), and human leukocyte antigen (HLA) desensitization prior to renal transplantation; 20.9 % of PE and 23.1 % of IA/DFPP patients had neurological diseases. Membrane filtration was the most common technique, albumin the most frequently used substitution fluid, and heparin the preferred anticoagulant. PE achieved full disease remission in 25 patients (37.3 %), partial remission in 22 (32.8 %), and had no effect in 20 (29.9 %). The response to IA/DFPP was complete in seven patients (53.8 %), partial in five (38.5 %), and absent in one (7.7 %). Minor adverse events occurred during 6.9 % of PE and 9.7 % of IA/DFPP sessions. CONCLUSIONS: PE, IA, and DFPP are safe apheresis methods in children. Efficacy is high in pediatric patients with recurrent focal segmental glomerulosclerosis (FSGS), atypical hemolytic uremic syndrome (HUS), human leukocyte antigen (HLA) sensitization, and neurological autoimmune diseases.

Pleuro-peritoneal or pericardio-peritoneal leak in children on chronic peritoneal dialysis-A survey from the European Paediatric Dialysis Working Group.

BACKGROUND: Pleural or pericardial effusions secondary to pleuro-peritoneal fistula (PPF) and pericardio-peritoneal fistula (PcPF) are rare but serious complications of peritoneal dialysis (PD). METHODS: We conducted a 10-year survey across all participating centres in the European Paediatric Dialysis Working Group to review the incidence, diagnostic techniques, therapeutic options and outcome of children on chronic PD with PPF and/or PcPF. RESULTS: Of 1506 children on PD there were ten cases (8 of PPF, 1 each of PcPF and PPF + PcPF), with a prevalence of 0.66%. The median age at presentation was 1.5 [inter-quartile range (IQR) 0.4-2.4] years, and nine children were <3 years. The time on PD before onset of symptoms was 4.3 (IQR 1.3-19.8) months. Eight children had herniae and seven had abdominal surgery in the preceding 4 weeks. Symptoms at presentation were respiratory distress, reduced ultrafiltration and tachycardia. PD was stopped in all children; three were managed conservatively and thoracocentesis was performed in seven (with pleurodesis in 3). PD was restarted in only three children, in two of them with success. CONCLUSION: In conclusion, PPF and PcPF are rare in children on chronic PD, but are associated with significant morbidity, requiring a change of dialysis modality in all cases. Risk factors for PPF development include age of <3 years, herniae and recent abdominal surgery.

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.

Adapted automated peritoneal dialysis.

Conventional automated peritoneal dialysis (APD) is prescribed as a repetition of the same dwell time and the same fill volume delivered by the cycler during the dialysis session. Nevertheless, it is well recognized that a cycle with a short dwell time and a small fill volume favors ultrafiltration (UF), while a cycle with a long dwell time and a large fill volume favors uremic toxin removal. The use of varied dwell times and dwell volumes, called adapted APD, allows for an optimized peritoneal dialysis prescription with better volume control--that is, both an increased UF volume at a lower metabolic cost [UF per gram of glucose absorbed (mL/g)] and increased dialytic sodium removal resulting in improved removal of uremic toxins (urea, creatinine, phosphate) during dialysis.

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.

Late recovery of renal function by rituximab in a patient with Wegener's granulomatosis.

BACKGROUND: Rituximab has proven effective in the treatment of complicated granulomatosis with polyangiitis (Wegener's, GPA). Two controlled trials in adults demonstrated beneficial effects of rituximab compared to cyclophosphamide in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis to induce remission and to treat relapses. Pediatric experience with rituximab in GPA is limited; the impact on renal function is unknown. CASE-DIAGNOSIS/TREATMENT: We report a female adolescent with GPA and necrotizing glomerulonephritis that lead to end-stage renal disease (ESRD). After 22 months of peritoneal dialysis, she still experienced relapses and major treatment-associated adverse effects. After a single dose of rituximab, she rapidly achieved clinical remission and, unexpectedly, steadily recovered glomerular filtration rate, plateauing at 25 ml/min/1.73 m(2). Peritoneal dialysis could be discontinued for 16 months. CONCLUSIONS: This case documents a potent beneficial effect of rituximab on renal manifestation of GPA even in long-established ESRD.

Bleeding complications in pediatric ABO-incompatible kidney transplantation.

BACKGROUND: ABO-incompatible renal transplantation (ABOi-RTx) following preconditioning with immunoadsorption (IA) and rituximab is a promising approach to facilitate living-related RTx. However, clinical experience is limited in pediatric patients. METHODS: Three patients underwent living-related ABOi-RTx in our center. Preoperative IA was performed six, ten and 11 times in patient one, two and three, respectively, to achieve isoagglutinin titers of ≤1:8 on the day of transplantation; rituximab was administered once. The immunosuppressive regimen further comprised tacrolimus, mycophenolate, methylprednisolone and basiliximab; immunoglobulin G (IgG) was infused on the day of ABOi-RTx. RESULTS: All three patients achieved normal renal function within 2-6 days post-RTx. Major postoperative bleeding occurred in two patients, with one requiring repeated blood transfusions and the other a surgical revision 4 h after RTx, despite local citrate anticoagulation use during the preoperative IA procedures in the latter patient. A pyelonephritis-associated increase of the isoagglutinin IgG/IgM titers to 1:64/1:128 led to a biopsy-proven acute humoral rejection in the third patient, which was treated successfully with plasma exchange and methylprednisolone pulses. The estimated glomerular filtration rate at 18, 8 and 23 months post-RTx was 96, 52 and 74 ml/min/1.73 m(2), respectively. CONCLUSIONS: ABOi-RTx can successfully be performed in pediatric patients after preconditioning with quadruple immunosuppression, rituximab and IA. Caution is required regarding bleeding complications, which are most likely due to the unspecific binding of coagulation factors during repeated IA.

Hydration measurement by bioimpedance spectroscopy and blood pressure management in children on hemodialysis.

BACKGROUND: Hypertension is frequent in chronic hemodialyzed patients and usually treated by reducing extracellular fluid. Probing dry weight only based on a clinical evaluation may be hazardous, especially in case of volume independent hypertension. METHODS: We performed a 1-year retrospective study in three pediatric centers to define the relation between blood pressure (BP) and hydration status, assessed by whole-body bioimpedance spectroscopy (BIS). We analyzed 463 concomitant measurements of BP, relative overhydration (rel.OH), and plasma sodium (Napl) in 23 children (mean age 13.9 ± 5.1 years). RESULTS: Pre-dialytic under-hydration (rel.OH < -7%) was present in 5.4% of the sessions, out of which 24% showed hypertension. Normohydration (rel.OH -7 - +7%) was observed in 62.4% of the sessions, 45.3% of them revealed hypertension. Moderate OH (rel.OH +7 - +15%) was present in 21% of the sessions, 47.4% of them showed normal BP. In 11.2% of the sessions, severe overhydration (rel.OH > +15%) was assessed, however, the majority (73%) showed normal BP. Patient-specific Napl setpoint could not be described. Mean dialysate sodium concentration was higher than mean Napl. CONCLUSIONS: Hypertension is not always related to overhydration. Therefore, BIS should restrict the practice of "probing dry weight" in hypertensive children. Moreover, sodium dialytic balance needs to be considered to improve BP management.

Human peritoneal tight junction, transporter and channel expression in health and kidney failure, and associated solute transport.

Next to the skin, the peritoneum is the largest human organ, essentially involved in abdominal health and disease states, but information on peritoneal paracellular tight junctions and transcellular channels and transporters relative to peritoneal transmembrane transport is scant. We studied their peritoneal localization and quantity by immunohistochemistry and confocal microscopy in health, in chronic kidney disease (CKD) and on peritoneal dialysis (PD), with the latter allowing for functional characterizations, in a total of 93 individuals (0-75 years). Claudin-1 to -5, and -15, zonula occludens-1, occludin and tricellulin, SGLT1, PiT1/SLC20A1 and ENaC were consistently detected in mesothelial and arteriolar endothelial cells, with age dependent differences for mesothelial claudin-1 and arteriolar claudin-2/3. In CKD mesothelial claudin-1 and arteriolar claudin-2 and -3 were more abundant. Peritonea from PD patients exhibited increased mesothelial and arteriolar claudin-1 and mesothelial claudin-2 abundance and reduced mesothelial and arteriolar claudin-3 and arteriolar ENaC. Transperitoneal creatinine and glucose transport correlated with pore forming arteriolar claudin-2 and mesothelial claudin-4/-15, and creatinine transport with mesothelial sodium/phosphate cotransporter PiT1/SLC20A1. In multivariable analysis, claudin-2 independently predicted the peritoneal transport rates. In conclusion, tight junction, transcellular transporter and channel proteins are consistently expressed in peritoneal mesothelial and endothelial cells with minor variations across age groups, specific modifications by CKD and PD and distinct associations with transperitoneal creatinine and glucose transport rates. The latter deserve experimental studies to demonstrate mechanistic links.Clinical Trial registration: The study was performed according to the Declaration of Helsinki and is registered at www.clinicaltrials.gov (NCT01893710).

Cardiac magnetic resonance imaging in children with chronic kidney disease and renal transplantation.

CV disease is the major cause of death in patients with CKD. Recently, CMR imaging emerges as a complementary method providing advantages in cardiac assessment; however, data on CMR in pediatric CKD are scarce. We performed CMR in 15 children: two with CKD, six on peritoneal dialysis, seven on hemodialysis, and in 18 children 5.1 (0.4-15.4) yr after kidney Tx. Eight children underwent CMR six months before and after Tx. Results are presented as mean z score ± SD. LV EF was higher and in the normal range in Tx patients compared with CKD (-0.3 ± 1 vs. -2.1 ± 1.6, respectively, p < 0.05), whereas RV EF was similar (-0.9 ± 1.4 vs. -0.9 ± 1.8, p = n.s.). End-diastolic and end-systolic LV volume index (0 ± 1.7 vs. 2.1 ± 3.1; 0.2 ± 1.2 vs. 3.1 ± 3.7, both p < 0.05) and LV mass index (1.4 ± 1.5 vs. 3.4 ± 2.9, p < 0.05) were lower in Tx children. All parameters improved in the eight children after Tx. In conclusion, our CMR analysis suggests marked improvement of cardiac function and morphology in children after kidney Tx. CMR might be an appropriate complementary method for measuring detailed cardiac status in children with CKD.

Molecular Adsorbents Recirculating System dialysis in children with cholestatic pruritus.

BACKGROUND: Cholestatic pruritus may severely compromise quality of life. The Molecular Adsorbents Recirculating System (MARS) allows removal of pruritogenic substances without exposure to foreign proteins. Pediatric data, however, are scant. METHODS: We retrospectively analyzed the efficacy of MARS in three boys with severe cholestatic pruritus. They received a total of 135 MARS sessions during 8, 4, and 13 months prior to liver transplantation. Total serum bilirubin and bile acids were monitored, and pruritus was assessed by a numerical rating scale (NRS 0 = no pruritus, 10 = maximal pruritus). RESULTS: MARS sessions were initially performed three times weekly at a mean duration of 6.3 ± 1.4 h. Sessions could be reduced to once weekly and once every other week in two patients. Pre-MARS plasma bile acid concentrations averaged 207 ± 67 µmol/l. They declined to 67 ± 9%, 48 ± 3%, 38 ± 14%, and 37 ± 5% of baseline within 2, 4, 6 and 8 h of therapy, respectively (all p < 0.05). The average interdialytic increase of plasma bile acids was 34 ± 33 µmol/l per day. Mean NRS score decreased from 6.5 ± 2.3 to 3.3 ± 2.9 (p < 0.01). Skin lesions from itching disappeared. All MARS treatments were well tolerated. CONCLUSION: MARS dialysis substantially reduces cholestatic pruritus in children refractory to pharmacological treatment.

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.