registry studies suggest that the overall survival of children in whom chronic dialysis was initiated during the neonatal period is similar to those who commenced at a later stage . however , neurological complications remain a therapeutic challenge in this group of patients and significantly increase the risk of death . currently , published data lack information on the type of neurological complications presented in infants undergoing chronic peritoneal dialysis ( pd ) or on the underlying pathogenic mechanisms . we describe four infants treated with chronic pd since the neonatal period , displaying consistently low blood pressure ( bp ) values and who suffered symptomatic cerebral ischaemia . a recent publication demonstrated that haemodialysis significantly lowers levels of stable nitric oxide ( no ) metabolites nitrate and nitrite , which may increase the risk of cardiovascular events . therefore , we investigated whether pd may have interfered with no - generating systems , i.e. the classical l - arginine - dependent no synthase ( nos ) or the nitrate  nitrite  no pathway . this retrospective observational cohort study of infants who commenced chronic pd during the neonatal period ( age 1 month ) at our department since 2005 was approved by the hospital ethics board ( protocol number 2014/1631 - 31 ) . informed consent was waived in all but two patients who underwent additional blood and dialysate testing . one patient developed cerebral atrophy of unknown cause , another patient suffered cerebral hypoxic lesions due to a severe pulmonary disease and the other four patients experienced symptomatic cerebral ischaemia . in the latter patient group , the primary renal diagnosis was congenital abnormalities of the kidney and urinary tract in three patients ( case 1 , 2 and 3 ) and autosomal recessive polycystic kidney disease in the other patient ( case 4 ) . dialysis dose was individualized and regarded clinically adequate if it allowed the patient to achieve a proper nutrition , to correct acid  base and electrolytic imbalances and to improve plasma creatinine and urea levels . in all patients , nutrition was provided enterally using either nasogastric tubes ( case 1 , case 3 and case 4 ) or gastrostomy ( case 2 ) . the ischaemic event was documented at the age of 5 months ( case 1 ) , 4.5 months ( case 2 ) , 2.5 months ( case 3 ) and 2 months ( case 4 ) , respectively . neurological symptoms at presentation were ocular flutter ( case 1 ) , deviation of gaze ( case 2 ) and seizures ( case 1 , 3 and 4 ) . at the time , the duration of daily pd session was 14 h in case 1 ( 26 ml / kg fill volume and 30-min dwell time ) , 20 h in case 2 ( 17 ml / kg fill volume and 20- to 45-min dwell time ) , 16 h in case 3 ( 26 ml / kg fill volume and 20- to 40-min dwell time ) and 16 h in case 4 ( 20 ml / kg fill volume and 20-min dwell time ) . in all patients , physioneal 40 glucose 2.27% w / v ( baxter ) was the standard pd solution used . manual pd , i.e. the fluid exchanges were performed manually with the active participation of a nurse , was the pd procedure used in case 2 , case 3 and case 4 , whereas case 1 underwent automated pd ( baxter homechoice ) . figure  1 shows representative neuroimages of either computed tomography scanning or magnetic resonance imaging performed after symptom onset . at presentation , none of these patients was on antihypertensive therapy . since low systolic bp ( sbp ) has been associated with increased mortality in paediatric victims of traumatic brain injury , presumably due to cerebral hypoperfusion , we calculated the median of all documented oscillometric sbp values recorded in each patient during the 10 days previous to the first occurrence of neurological symptoms . the number of sbp measurements per patient was 24 ( case 1 ) , 28 ( case 2 ) , 146 ( case 3 ) and 22 ( case 4 ) . median ( range ) sbp values were consistently far under the 50th distribution adjusted age- and sex - related percentile in all the patients : case 1 , 53 ( 40118 ) mmhg ; case 2 , 72.5 ( 52102 ) mmhg ; case 3 , 69 ( 26119 ) mmhg ; case 4 , 56 ( 40126 ) mmhg . fig .  1.native computed tomography ( cases 1 and 3 ) and diffusion - weighted ( dw ) magnetic resonance imaging ( cases 2 and 4 ) of the head showing ischaemic lesions ( arrows ) . dw magnetic resonance imaging of the chest and the abdomen performed in case 4 ( e ) showing extensive vascular thrombosis and collateral circulation ( arrows ) . in parentheses ( pictures a , b , c , d , and e ) are depicted patient 's date at symptomatic cerebral ischaemic event ( month / year ) . native computed tomography ( cases 1 and 3 ) and diffusion - weighted ( dw ) magnetic resonance imaging ( cases 2 and 4 ) of the head showing ischaemic lesions ( arrows ) . dw magnetic resonance imaging of the chest and the abdomen performed in case 4 ( e ) showing extensive vascular thrombosis and collateral circulation ( arrows ) . in parentheses ( pictures a , b , c , d , and e ) are depicted patient 's date at symptomatic cerebral ischaemic event ( month / year ) . two patients ( cases 1 and 4 ) died after 6 and 1 month following the diagnosis of brain injury . at the time of writing , the other patients ( cases 2 and 3 ) , aged 2 and 1 year , respectively , are still on pd and none have any measurable neurologic deficit . in cases 3 and 4 , we investigated whether pd may have impaired no bioavailability . plasma samples were obtained on three separate pd sessions , both at the beginning and end of each daily pd session . as previously described , a dedicated hplc system was used to measure nitrate and nitrite content , and mass spectrometry method for analyzing amino acids linked to nos function . in both patients , reductions in plasma nitrate and nitrite levels were consistently observed at the end of the pd sessions ( figure  2a and b ) , whereas figure  2c and d illustrate the increase of these inorganic anions in the total spent dialysate volume , i.e. dialysate plus ultrafiltrate per pd session . plasma levels of arginine and citrulline remained unchanged , whereas ornithine levels decreased at the end of the pd sessions ( figure  2e ) . plasma citrulline - to - arginine ratios , a surrogate of endothelial nos activity , were similar at the beginning ( 0.43  0.03 ) and at the end of the pd sessions ( 0.57  0.09 ) . on the other hand , plasma ornithine - to - citrulline ratios were reduced at the end of the pd sessions ( 2.22  0.19 versus 1.48  0.15 ) , which could indicate a lower arginase activity . we also investigated plasma levels of the asymmetric dimethylarginine ( adma ) and symmetric dimethylarginine ( sdma ) , which are known endogenous inhibitors of nos - dependent no generation . we observed a reduction of both plasma adma and sdma levels at the end of the pd sessions ( figure  2e ) . 2.analysis of nitrate and nitrite content in plasma , both at the beginning ( before ) and end ( after ) of each daily pd session ( a and b , respectively ) and in total spent dialysate volume ( dialysis solution ) per daily pd session ( c and d , respectively ) . measurements were conducted on three separate daily pd sessions both in case 3 ( closed circles ) and in case 4 ( open circles ) . measurement of amino acids , relevant for nos function , was determined in a similar way and presented as mean  sem for plasma ( e ) and total spent dialysate volume ( f ) . analysis of nitrate and nitrite content in plasma , both at the beginning ( before ) and end ( after ) of each daily pd session ( a and b , respectively ) and in total spent dialysate volume ( dialysis solution ) per daily pd session ( c and d , respectively ) . measurements were conducted on three separate daily pd sessions both in case 3 ( closed circles ) and in case 4 ( open circles ) . measurement of amino acids , relevant for nos function , was determined in a similar way and presented as mean  sem for plasma ( e ) and total spent dialysate volume ( f ) . in the face of fluctuations in bp , the cerebral vessels possess the ability to maintain an adequate perfusion pressure . if the autoregulatory property of the cerebral vessels is intact , a decrease in bp leads to dilatation of the cerebral resistance vessels to preserve an adequate cerebral blood flow , while an increase in bp results in the opposite effect . this autoregulatory property is modulated by the endothelium through the release of various vasorelaxing ( e.g. no ) or vasoconstrictor ( e.g. thromboxane a2 and endothelin ) agents . collectively , our results suggest no major effect of pd on nos function , but rather emphasize that removal of nitrate and nitrite by pd could have limited the nitrate - nitrite - no pathway . we speculate that in our patients , sustained low sbp , in the context of reduced no bioavailability , might have predisposed to episodes of silent cerebral hypoperfusion until becoming symptomatic . several lines of evidence indicate that no deficiency is associated with thrombotic disorders . in case 4 , with the extensive vascular thrombosis , a routine workup ruled out identifiable causes of hypercoagulable states ( data not shown ) . to what extent pd - mediated removal of plasma nitrate and nitrite , as observed in this patient , may have contributed to thrombus formation remains to be elucidated . in conclusion , our observations suggest that infants undergoing pd may benefit from treating low sbp levels and from preventing a decrease in the bioavailability of no . the latter could readily be achieved by supplementing the pd solutions and/or enteral feeding with physiological levels of inorganic nitrate and nitrite .
the underlying pathogenic mechanisms of neurological complications in infants undergoing peritoneal dialysis ( pd ) are poorly understood . 
 we report on four male infants treated with pd who developed symptomatic cerebral ischaemia . 
 blood pressure ( bp ) levels were low both before the event and at presentation . in two patients 
 , we observed that the removal of nitrate and nitrite by pd could have impaired the nitrate / nitrite-nitrite oxide ( no ) pathway , a system that generates no independently of no synthase . 
 our observation suggests that low bp and reduced no bioavailability puts infants treated with pd at risk for impaired cerebral blood flow and consequently for brain ischaemia .