How to cite this article: Munguía-Miranda C, Ventura-García MJ, Ávila-Díaz M, Orihuela-Rodríguez O, Paniagua-Sierra R. Factors related to residual renal function loss in patients in peritoneal dialysis. Rev Med Inst Mex Seguro Soc. 2015;53(5):578-83.
Received: November 3th 2014
Accepted: April 16th 2015
Catarina Munguía-Miranda,a María de Jesús Ventura-García,a Marcela Ávila-Díaz,a Oscar Orihuela-Rodríguez,b Ramón Paniagua-Sierraa
aUnidad de Investigación Médica en Enfermedades Nefrológicas
bServicio de Cardiología
Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Distrito Federal, México
Communication with: Catarina Munguía-Miranda
Telephone: 5627 6900, extensión 21371
Background: Residual renal function (RRF) contributes to the quality of life of patients on dialysis. The preservation of RRF is associated with higher patient survival in peritoneal dialysis (PD), and is now accepted that RRF and peritoneal clearance are not of equal value in patient survival. The aim of this study is to know the factors related to RRF loss in prevalent patients in continuous ambulatory peritoneal dialysis (CAPD).
Methods: This is an analysis of secondary outcomes. Forty-three adult patients with type 2 diabetes were included. They had RRF preserved. Clinical and laboratory assessments were done in each visit during a year.
Results: The male gender (p = 0.042), systolic (p = 0.009) and diastolic (p = 0.006) blood pressure (BP), hemoglobin (p = 0.008), peritoneal creatinine clearance (p = 0.014), peritoneal ultrafiltration (p = 0.017) and levels of tumor necrosis factor-alpha (TNF-alpha) in plasma (p = 0.022) and dialysate (p = 0.008) were related with RRF loss.
Conclusions: It is important to understand the factors associated with RRF loss in our patients to prevent the gradual loss and its implications on the mortality and quality of life.
Keywords: Kidney diseases, Peritoneal dialysis, Renal insufficiency
RRF is defined generally as the glomerular filtration rate (GFR) residual in patients with chronic end-stage kidney disease (ESKD). In patients with chronic kidney disease (CKD) in stage V on dialysis programs, it is common to observe a progressive decrease in RRF due to loss of functional renal parenchyma.
Potential mechanisms to achieve better results in the preservation of the RRF include the optimal removal of fluids and adequate control of blood pressure, the efficient clearance of low molecular weight toxins and inflammatory mediators, preservation of erythropoietin synthesis in hypoxia response, an increase in the synthesis of vitamin D and decreased the rate of peritonitis. Additionally, preservation of RRF is a measure of decrease in the advance of ESKD, suggesting that patients who preserve RRF have less comorbidity and better overall health and quality of life.1 RRF loss, especially in patients on peritoneal dialysis (PD) is a powerful predictor of mortality,2-8 and its prevalence has been shown to influence the increased survival of patients, establishing that it is this, and not peritoneal clearance, which has predictive power in PD patient mortality.9-11
RRF loss is related to demographic factors such as age, gender, and ethnic group.12-15 Current literature suggests that the etiology of ESKD does not favor a better effect on the preservation of RRF,12 but there has been a rapid and progressive loss of diuresis in patients with proteinuria severa.13-15 Other risk factors for RRF loss in adults are diabetes12,14 and cardiovascular disease.12,15
In Mexico, a study was published recently whose objective was to determine the influence of inflammation and myocardial damage markers on RRF loss in PD patients. Their results indicate that age and serum albumin, C-reactive protein and pro-BNP natriuretic peptide were risk factors for RRF loss.16
However, in our country, diabetes is a major public health problem, and CKD is a common complication for this condition, which generates great social and economic costs. Both entities have motivated prominent studies, however, except for the aforementioned, there is no information to evaluate the mechanisms involved in their reduction or loss. The aim of this study was to determine the factors associated with RRF loss in a group of Mexican diabetic patients, enrolled in CAPD.
This is an analysis of secondary outcomes in an open, controlled, randomized trial. This study was approved by the Local Research Committees of the participating hospitals and the Comisión Nacional de Investigación Científica of the Instituto Mexicano del Seguro Social (registration number: FIS/IMSS/PROT/G09/747).
The patients in the study signed a letter of informed consent. All were recruited from 4 general hospitals belonging to the Instituto Mexicano del Seguro Social, located in the metropolitan area of Mexico City (Hospitales Generales de Zona numbers 8, 25, 27 and 47). Adult subjects with type 2 diabetes, enrolled in PD programs, in whom diabetic nephropathy was the cause of ESKD were included. Participants preserved RRF, presenting urinary volume above 100 mL in 24 hours. During the screening, a simplified test for peritoneal balance (PB) was done and only patients with high peritoneal transport rates and high average were included. Subjects who were seropositive for hepatitis B or HIV were not included, nor were those with one or more episodes of peritonitis during the month preceding the assessment. All patients received three parts of 2 liters of solution containing 1.5% dextrose (Dianeal, Baxter) during the day, and at night, a replacement solution with 2 liters of 2.5% dextrose (Dianeal, Baxter).
Clinical and biochemical evaluation
The patients received weekly visits during the first month and then every month for a year. At each visit clinical evaluations (anthropometry and body composition analysis) were performed. Laboratory studies were performed at baseline and monthly, these included: hemoglobin, hematocrit, serum albumin, glycated hemoglobin and cytokines (CRP, IL-6, TNF-alpha) as well as levels of glucose, serum urea and creatinine, urine and peritoneal liquid. Biochemical analyses were performed using standard methods (Synchron CX-5 analyzer, Beckman, Brea, CA, USA). Serum albumin and glycated hemoglobin were measured by nephelometry (Array, Beckman) and cytokines using immunoephelometric methods. The body composition analysis was done by multi-frequency spectroscopic bioimpedance (Biodynamics, Seattle, WA, USA).
Additional information included measurements of blood pressure, use of medications (anti-hypertensives, diuretics, cholesterol lowering, erythropoietin); peritonitis episodes, presentation time, causative organism, dose and duration of antibiotic treatment were also recorded.
Measuring dialysis adequacy
Dialysis adequacy was evaluated using ADEQUEST software (Baxter Healthcare Corp., Deerfield, IL, USA). The kidney and peritoneal clearance of urea and creatinine were measured in urine and dialysate 24 hours, simultaneously determinations of serum urea and creatinine were obtained. The PET was performed during the adequacy study using standard methodology.
RRF was calculated as the average of creatinine and urea clearance in the collection of urine at 24 hours. RRF measurements were corrected for body surface area of 1.73 m2, which was calculated using the Du Bois formula and dry body weight. All subjects had at least two RRF measurements at 6 month intervals. The outcome measure in the study was the presence of anuria, which was determined by calculating the residual GFR over time. Anuria was defined as the 24-hour urine volume of less than 100 mL or creatinine clearance less than 1 mL/min on two consecutive occasions.
Blood pressure was measured in office with mercury sphygmomanometer and with a device for ambulatory blood pressure monitoring for 24 hours (Oscar-2 24 h ABP, Suntech Medical Instruments, Raleigh, NC, USA, and AccuWinPro v2.4 software system). Dimensional and Doppler echocardiography were performed using a Toshiba Sonolayer ultrasound system (Toshiba Corporation, Tochigi-Ken, Japan) with standard image translators with frequencies from 2.5 to 3.5 MHz. The parameters studied were: Left ventricular mass, left ventricular diastolic diameter, ejection fraction, shortening fraction, thickness of interventricular septum and posterior wall. All studies were performed by the same cardiologist and measurements were made following the recommendations of the American Association of Echocardiography. 24-hour electrocardiographic monitoring (Holter ECG, Medilog FD5, Oxford Medical Instruments, Old Woking, Surrey, UK) was also performed.
Statistical analysis was done using SPSS version 18 (SPSS, Inc., Chicago, IL, USA). Continuous variables are reported as mean and standard deviation. ANOVA was conducted one-way to identify the significant variables and then Cox multiple regression multivariate analysis was done to determine the influence of demographic, clinical, biochemical, dose, and dialysis adequacy, on RRF loss.
The demographic, clinical, biochemical, dose, and dialysis adequacy data are shown in Table I. We included 43 patients with a mean age of 60.82 ± 8.50 years, with average time on CAPD 12.18 ± 8.69 months. The male to female ratio was 22:20. Table II shows parameters related to dose and dialysis adequacy. The average total weekly Kt/V and the Kt/V of PD were 1.87 ± 0.37 and 1.82 ± 0.33, respectively. The total average weekly creatinine clearance was 55.40 ± 10.45 L/week per 1.73 m2, and the residual GFR was 0.22 ± 0.21 mL/min per 1.73m2. The study duration was 12 months. The variables associated with loss of RRF are shown in Tables I and II, and include: male gender (p = 0.042), systolic (p = 0.009) and diastolic blood pressure (p = 0.006), hemoglobin (p = 0.008), TNF-alpha (tumor necrosis factor alpha) in plasma (p = 0.022) and dialysate (p = 0.008), peritoneal creatinine clearance (p = 0.014) and peritoneal ultrafiltration (p = 0.017).
|Table I Demographic data and clinical and biochemical measurements of study population|
|Age (years)||60.82 ± 8.50||0.529|
|Sex (male/female) ᵃ||22/20||0.042 *|
|Time in peritoneal dialysis (months)||12.18 8.69 ±||0.918|
|Frequency of peritonitis (events)||0.59 ± 0.70||0.718|
|Weight (kg)||66.08 ± 11.46||0.209|
|Waist (cm)||158.73 11.43 ±||0. 107|
|BMI (kg/m2)||26.26 ± 4.09||0.892|
|Waist/hip ratio||0.97 ± 0.06||0.656|
|Total body water (% of body weight)||34.81 ± 6.66||0.310|
|Extracellular fluid (% of body weight)||16.16 ± 2.69||0.198|
|Systolic blood pressure (mmHg)||134 ± 26||0.009 *|
|Diastolic blood pressure (mmHg)||77 ± 14||0.006 *|
|Hemoglobin (g/dL)||1019 ± 2.28||0.008 *|
|Hematocrit (%)||29.80 6.57 ±||0.014 *|
|Serum glucose (mg/dL)||174.20 ± 136.89||0.086|
|Serum albumin (g/dL)||2.68 ± 0.36||0.195|
|HbA1c (%)||7.58 ± 4.2||0.984|
|CRP (mg/L)||0.661 ± 0.573||0.112|
|IL-6 in plasma (pg/ml)||6.35 ± 2.57||0.256|
|IL-6 in dialysate (pg/ml)||10.24 ± 1.67||0.769|
|TNF-alpha in plasma (pg/ml)||5. 91± 3.31||0.022 *|
|TNF-alpha in dialysate (pg/ml)||4.59 ± 3.65||0.008 *|
|to= Frequency;BMI = body mass index;CRP = C-reactive protein;IL-6 = Interleukin-6;TNF -Alpha= tumor necrosis factor alpha.The data are expressed in mean±CI;c= p value based onCox multivariate multiple regression analysis|
|Table II Kidney function measurements in group of studied patients|
|Test of peritoneal balance (PET 4 hours)||0.79 ± 0.08||0.582|
|Peritoneal clearance of Cr (L/week)||52.55 ± 10.79||0.014 *|
|Renal clearance of Cr (L/week)||2.85±2.61||0.256|
|Peritoneal Kt/V||1.82 ± 0.33||0.108|
|Total clearance of Cr (L/week)||55.40 ± 10.45||0.557|
|Total Kt/V||1.87 ± 0.37||0.234|
|Residual GFR (mL/min)||0.22 ± 0.21||0.369|
|Volume of urine (mL/24 h)||353 ± 242||0.060|
|Peritoneal ultrafiltration (mL/24 h)||1337 ± 490||0.017 *|
|PET 4 hours = d/p Cr 4 hours.GFR = glomerular filtration rate.The data are expressed in mean± SD;c= p-values are based on Cox multivariate multiple regression analysis|
The parameters of Doppler echocardiography, ambulatory electrocardiographic monitoring and pharmaceutical consumption were not associated with RRF loss (data not shown).
The gradual deterioration of RRF in patients with ESKD on PD therapy does not depend on a simple mechanism, there are multiple factors operating simultaneously. The preservation of RRF is an important goal in the management of patients with this disease, even after the start of dialysis therapy. Many studies have shown that patients treated with PD have a lower risk of RRF loss compared with hemodialysis patients. However, the results of the factors related to the decrease or loss of RRF are unclear.
Our data, like reports by other authors14,17,18 indicate that the male gender is associated with the loss of RRF. This is related to the finding that female gender does not predict a more rapid loss of RRF, information consistent with observations in animals, showing that, with aging, male rats developed spontaneous proteinuria and glomerulosclerosis; while females, males treated with estrogen and orchidectomized male rats, are relatively resistant to these abnormalities.19,20 However, some authors suggest that gender, race, and the presence of diabetes do not contribute to the decline in RRF in PD patients.12,15
Moreover, the association between blood pressure and RRF loss has also been documented by Hidaka et al.,13 who showed that one of the factors related to the rapid decline in GFR was blood pressure higher than 110 mmHg; contrary to these results, Singhal et al.17 found no significant association between blood pressure level and the rate of decrease in residual GFR, however, they found that patients who were not receiving medication to control blood pressure had a rapid decrease in residual GFR compared with those that did, suggesting that patients without treatment have more elevated blood pressure and increased involvement of the remaining nephrons.
As regards the association between serum hemoglobin (Hb) levels and the RRF, we now know that the cause of anemia in patients with CKD is associated with decreased functional renal tissue and its inability to produce adequate quantities of erythropoietin in response to renal hypoxia. Among the studies showing association between Hb levels and renal function is the report of the Canadian Multicentre Study in Early Renal Disease,21 which showed a hemoglobin level of 14.3 g/dL among patients referred to a nephrology clinic with a creatinine clearance above 50 mL/min, compared to 12.8 g/dL among patients with creatinine clearance 25-50 mL/min and 11.7 g/dL in those with lower clearance (p <0.001). Another important study, the Third National Health and Nutrition Examination Survey (NHANES III), which examined more than 15,000 people from the general population in the United States between 1988 and 1994, found an inverse relationship between GFR <60 ml/min/1.73 m2 and the prevalence of anemia. Using an estimated GFR, the rate of anemia increased 1% in patients with a GFR of 60 ml/min/1.73 m2 and 9% in the case of GFR in the range of 30 ml/min/1.73 m2 and 33% in men and 67% in women with a GFR of 15 ml/min/1.73 m2.22
As for the finding of association between peritoneal creatinine clearance and RRF loss, Davies et al.23 found that high transport of peritoneal solutes in CAPD patients is an independent marker of poor performance and that changes observed in the urea kinetic are produced by RRF loss. Similarly, the study by Chung et al.24 showed that peritoneal transport rate during the first year of PD is associated with inflammation and decreased RRF according to which it is possible that inflammation causes increased rate of peritoneal transport and decrease in RRF, or that decreased RRF aggravates inflammation due to less efficient removal of cytokines.
In the present study, we found a clear association between the concentrations of TNF-alpha in urine and dialysate and RRF loss. As is known, in patients with CKD, circulating levels of cytokines and other inflammatory markers are considerably higher, which can be caused by increased formation, decreased elimination or both. Some studies25,26 show that plasma levels of TNF-alpha and interleukins are higher in patients with low levels of renal function, also that inflammation and RRF decrease are identified as independent factors determining the rate of peritoneal transport. Inflammation may cause increased peritoneal filtration rate and reduced RRF, and with that the clearance of cytokines by both mechanisms.24
Finally, this study also demonstrated association between the ultrafiltration volume and RRF loss. It is well known that ultrafiltration and sodium removal rate produced by PD may have a deleterious effect on RRF,27 because aggressive ultrafiltration induces alterations in the volume of extracellular and intracellular fluid, causing acute changes in blood pressure and secondly, reduction of renal blood flow and impaired function.28,29 It has also been identified that CAPD patients that present a high rate of solute transport often have ultrafiltration problems due to faster absorption of glucose and loss of driving force for osmotic liquid transport through the peritoneal membrane.30
RRF is very important from a clinical point of view. It not only adds to the clearance achieved by dialysis technique, but also is of better quality and helps greatly in maintaining the balance of sodium and water. Unfortunately, RRF tends to decrease over time and eventually disappears. This loss is influenced by factors related to both the patient and the dialysis technique itself. It is of paramount importance to understand the factors involved in order to make the necessary strategies for its preservation.
Conflict of interest statement: The authors have completed and submitted the form translated into Spanish for the declaration of potential conflicts of interest of the International Committee of Medical Journal Editors, and none were reported in relation to this article.