peritoneal membrane ultrafiltration failure ( uff ) is a relevant long - term complication menacing peritoneal dialysis ( pd ) . it has been reported to lead to technique failure in a rate of 1.7%   to 13.7% . peritoneal morphological changes seem to be related to dialysis solutions , bioincompatibility , and to infections . uremic milieu per se may also contribute to peritoneal changes since both submesothelial fibrosis and vascular changes are already present in uremic patients , before dialysis induction . the median thickness of the submesothelial compact collagenous zone was 50  micron for normal subjects , but was 140  micron for uremic predialysis patients , 150  micron for patients undergoing hemodialysis , and 270  micron for patients undergoing pd . honda et al . concluded that the average peritoneal thickness was increased in uremic patients and progressively thickened as the duration of peritoneal dialysis prolonged , while the lumen / vessel diameter ratio was lower in uremia than normal and progressively decreased as the duration of peritoneal dialysis was prolonged . thus , the effect of uremia on the baseline and time dependent profiles of peritoneal membrane function deserves further studies . it is a continuous bystander in dialysis patients only more recently introduced in pd animal models , but often excluded from uff analysis . currently , the determinants of small solutes , proteins , and water transport across the peritoneal membrane , as well as their evolution during pd therapy , are still a matter of debate . recently , some mechanisms involved in acquired uff have been identified but less is known about the role of previous renal replacement therapy time in this issue . moreover , early uff is still an unexplained phenomenon . a fast transport status is the primary mechanism of uff and it is sometimes documented as an inherent condition whose clinical impact has been debated [ 811 ] but early uff still remains often unexplained [ 7 , 12 ] .   later during pd , loss of glucose osmotic conductance might add to the process of acquired uff , with a disproportionally more severe compromise of free water transport . additionally , it is known that peritoneal fibrosis is induced by pd solutions but uraemia per se is also a fibrogenic factor . residual renal function and precious renal replacement therapy time at pd start are clinical variables that reflect the cumulative uremia stage . we aim to identify relevant clinical determinants of early and acquired uff , focusing on the independent impact of previous renal replacement therapy time and residual renal function at start of pd . its eventual independent impact may strengthen pd prescription as a first renal replacement therapy option . we prospectively studied 123 consecutive peritoneal dialysis incident patients enrolled at hospital santo antnio pd unit since 1st january 2001 . standard prescription included low - gdps solutions ; median glucose concentration exposure was 1.65% ( range 1.36%2.27% ) and 40% used icodextrin . age , diabetes , previous renal replacement therapy time ( rrt ) , baseline residual renal function ( rrf ) quantified as glomerular filtration rate ( gfr ml / min/1.73  m)based on   24  hrs urine collections with determinations of creatinine and urea , davies comorbidity score , automated pd , and peritonitis events were investigated as possible determinants of baseline or late uff . all patients performed baseline and yearly 3.86%-peritoneal equilibration tests ( pets ) , being followed for median 26 ( 4105 ) months : d / p creatinine , d / d0 glucose , sodium sieving , and peritoneal ultrafiltration ( uf ) were analyzed , and uf failure was defined as a net uf lower than 400  ml after a 4-hour dwell with 3.86% . pet ; ca125 appearance rate was also   calculated after 4 hours of pet dwell . the time course of pet parameters was explored by repeated measurements mixed linear model analysis with spss software . clinical and laboratory parameters considered to be possible determinants of uff were investigated and its impact on uff - free survival was studied by using cox multivariate analysis . investigation was made both in the whole cohort and in the subgroup after excluding patients admitted after renal graft failure . the investigated patients had a mean age of 48  15 ( 2082 ) years and female predominance ( 62% ) . twenty - three patients ( 18.7% ) were diabetic , thirty ( 24.4% ) were anuric and the majority of them ( 59% ) were on apd . fifty - four patients ( 43.9% ) had been on previous renal replacement therapy ( rrt ) for a median time of 63 months ( 2410 ) : 30.9% after hemodialysis ( hd ) and 13.0% after renal transplant failure ( rt ) .   by repeated measurements mixed model analysis , it was shown that small solute , uf , and sodium - sieving parameters remained essentially stable during the followup . a u - shaped curve of d / p creatinine was documented , but this variation with time did not attain significance ( figure 1 ) . ca125 decreased progressively ( p = 0.009 ) ( figure 2 ) , mainly in late uff patients . the same profile was documented in the subgroup of patients after excluding those admitted after renal graft failure ( d / p creatinine u - shaped curve though p = ns ; for ca125 parameter p = 0.015 ) . uff was documented in 15 patients : eight patients ( 6.5% ) showed baseline ultrafiltration failure ( uff ) while seven patients ( 5.7% ) developed acquired uff . sex , age , diabetes , comorbidity score , baseline rrf , and previous rrt did not differ significantly between baseline uff group and the other patients ( table 1 ) .   d / p creatinine of inherent uff group and other patients was similar ( 0.74  0.11 versus 0.75  0.13 , p = 0.74 ) . also sodium sieving did not differ significantly between the groups ( d / p na60 0.90  0.038 versus 0.87  0.034 , p = 0.057 ) , although a trend was noticed .   on the other hand , the acquired uff group presented type i uff profile with clearly compromised sodium sieving ( d / p creatinine was 0.83  0.10 versus 0.72  0.12 , p = 0.035 and d / pna60 0.92  0.028 versus 0.87  0.034 , p = 0.010 ) ( table 2 ) . they had significantly lower baseline rrf ( p = 0.009 ) and longer previous rrt time ( p = 0.003 ) ( figure 3 ) . baseline lower rrf and longer previous rrt were independently associated with lower uff - free survival by cox multivariate analysis ( table 3 ) . sex , age , diabetes , apd modality , and peritonitis did not significantly impact on uff - free survival . after excluding patients admitted   after   graft failure ( n = 13 ) , rrt time   remained independently associated with uff ( b 0.023 exp(b ) 1.023 ( 1.0071.040 ) p = 0.006 ) as also baseline gfr ( ml / min ) ( b-0.447 exp(b ) 0.64 ( 0.4120.993 ) p = 0.047 ) . our study highlights that residual renal function and previous cumulative renal replacement therapy time , in a contemporary pd population - free of hypertonic 3.86% glucose solutions exposition , independently impact on ultrafiltration - failure - free survival . this study therefore adds a new argument for a pd - first policy as a strategy to improve technique survival . measuring peritoneal transport characteristics is an approach which gives objective and reproducible information on peritoneal performance and possible etiological factors of uff . a fast transport status however , either alone or in combination with other alterations in membrane function , remains the most common underlying mechanism of uff . we indeed showed that acquired uff group presented type i uff profile with compromised sodium sieving . uff in long - term pd is most often due to a combination of a rapid disappearance of the osmotic gradient , together with an impairment of transcellular water transport ( tcwt ) . but the activity of water channels is dependent and limited by the crystalloid osmotic pressure   which our methodology did not allow to be calculated , being a limitation for characterization of the late stage uff . in spite of that we were able to document free water transport compromise by the indirect sign of decreased sodium sieving . for this reason , we are now measuring the actual uf and effluent sodium after 60  min dwell followed by effluent reinfusion and completion of standardized 4-hour 3.86% pet which allows    evaluation of both free water and standardized small solute transport .   finally , back filtration of fluid through the capillaries and fluid reabsorption from the peritoneal cavity into tissues and lymphatics is a recognized mechanism of uf failure and accounts for approximately 25% of the cases of uf dysfunction , but only investigational methods with tracer macromolecules hard to apply in a clinical ward are able to evaluate this . more relevant to our study was to highlight that baseline uff is prevalent but often transitory and not predicted by baseline clinical variables according to previous investigations [ 712 ] . while lymphatic absorption can not be excluded as a cause of early uff , the evolution of patients recovering ultrafiltration capacity does not support such etiology . we can speculate that although no significant changes were documented in small solute transport at baseline between the groups with and without uff , membrane structural changes induced by uremia per se namely interstitium fibrosis might justify the marginal compromise of sodium sieving . this indeed gives   lumped information and is not only dependent on an increase of diffusive mass transport coefficients   for small solutes , but also on a decrease of the glucose osmotic conductance ( number and function of aquaporins , number and diameter of   small pores ) and on reduction of ultrafiltration coefficient of the peritoneal membrane ( role for the interstitium changes ) . interestingly , we found a u - shaped curve of d / p creatinine in the followup , already previously reported by our group and others [ 8 , 13 , 18 ] though not attaining statistical   significance in this contemporary cohort . the early phase of d / p creatinine normalisation may express an adaptive process whose mechanisms are unclear but may include early recruitment or vasodilation of vessels mediated by vasoactive mediators , many of them secreted by mesothelial cells . therefore , in some of our patients a transitory fast transport status may explain the inherent uff . in other patients , the causes of such baseline uff are not clear , pointing to the complexity of peritoneal membrane time - dependent functional changes . the risk phase with clinical impact may be documented by the late increasing side of the u - shaped curve , with decreasing mesothelial cell mass as a marker of structural changes that go along with uff and sodium sieving compromise . again we highlight the importance of routine membrane monitorization also including an accessible and affordable structural marker ca125 effluent appearance rate .   however , our global population presented stability in the transport rates for small molecules and sodium sieving over time . this is in accordance with previous publications where small - solute transport parameters were found to be increased only in long - term patients , but happily , in disagreement with the gloomier reports of sustained and inexorable increase of d / p creatinine over time , already from the start . on the other hand , uremia and baseline gfr as its surrogate , is indeed an important bystander not usually taken into account in peritoneal membrane changes investigation . we identified it here as a clinical variable that independently impacts on uff - free survival . this clue deserves further investigation but suggests that uremia may be crucial to explain acquired peritoneal membrane changes , and although it has not been associated with baseline transport characteristics may modulate membrane time - dependent profile [ 46 ] .    as a limitation of our study , we did not control for a panel of   pharmacological agents shown experimentally to modulate membrane structure , namely , renin angiotensine system inhibitors and erythropoiesis stimulating agents [ 22 , 23 ] . however , since the use of these agents is massive in our pd patients , it is not presumed to change our results .   in spite of some controversy , our study also showed that the influence of peritonitis on the development of uff seems to be limited . it has been found that patients with a history of peritonitis were not different from patients without a previous peritonitis episode in terms of d / p ratio and mass transfer area coefficient of low molecular weight solutes , lymphatic absorption rate , transcapillary ultrafiltration , and net ultrafiltration . only clusters of peritonitis or peritonitis episodes that occur later in pd have been described as causing a decrease in uf . some papers document that systemic inflammation associated with comorbid diseases and elevated interleukin- ( il- )   6 level may induce vasodilation and neoangiogenesis in peritoneal membrane . we did not find any association between morbidity and higher transport rates , like others , nor comorbidity score was predictive of uff . as a structural marker , effluent cancer antigen 125 can be used reflecting mesothelial cell mass and cell turnover in stable , noninfectious pd patients . its decrease with the duration of pd , described previously , is consistent with the reported cell loss observed in peritoneal biopsies . such profile of effluent ca125 appearance rate is therefore more likely a sign of damage to the peritoneum than a causative factor of uf by itself . it can be interpreted as an additional prognostic sign , adding to the changes of d / p creatinine and effluent il-6 .   in conclusion , this paper documents early - stage peritoneal membrane changes with transitory cases of inherent ultrafiltration capacity failure dissociated from small - solute transport , whose mechanisms remain unclear . on the other hand , lower baseline rrf and previous longer rrt were associated with acquired uff in our population . in spite of these detrimental factors , we found generally stable long - term peritoneal transport parameters with 5 years 83% cumulative uff - free survival . by highlighting the importance of previous cumulative rrt time and baseline rrf concerning peritoneal membrane function status these results support a pd - first strategy in the integrated renal replacement treatment plan .
background . 
 peritoneal membrane changes are induced by uraemia per se . 
 we hypothesise that previous renal replacement therapy ( rrt ) time and residual renal function ( rrf ) at start of peritoneal dialysis impact on ultrafiltration failure ( uff ) . 
 methods . 
 the time course of pet parameters from 123 incident patients , followed for median 26 ( 4105 ) months , was evaluated by mixed linear model . 
 glucose 3.86% solutions were not used in their standard therapy . 
 sex , age , diabetes , previous rrt time , rrf , comorbidity score , pd modality and peritonitis episodes were investigated as possible determinants of uff - free survival . 
 results . 
 pet parameters remained stable during follow up . 
 ca125 decreased significantly . 
 inherent uff was diagnosed in 8 patients , 5 spontaneously recovering . acquired uff group presented type i uff profile with compromised sodium sieving . at baseline 
 they had lower rrf and longer previous time of rrt which remained significantly associated with uff - free survival by cox multivariate analysis ( hr 0.648 ( 0.4280.980 ) , p = 0.04 ) and ( hr 1.016 ( 1.0041.028 ) , p = 0.009 , resp . ) . 
 uff free survival was 97% , 87% and 83% at 1 , 3 and 5 years , respectively . conclusions . 
 inherent uff is often unpredictable but transitory . on the other hand baseline 
 lower rrf and previous rrt time independently impact on ultrafiltration failure free survival . in spite of these detrimental factors generally stable long - term peritoneal transport parameters is achievable with a 5-year cumulative uff free survival of 83% . 
 this study adds a further argument for a pd - first policy .