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How to cite this article: Robles-Vázquez ND, Aguilar-Kitsu MA, Mendoza-Guevara L, Miranda-Novales MG. Infectious complications in children with end-stage renal disease on replacement therapy. Rev Med Inst Mex Seguro Soc. 2015;53 Suppl 3:S246-52..

PubMed: http://www.ncbi.nlm.nih.gov/pubmed/26509300

ORIGINAL CONTRIBUTIONS

Received: August 14^th 2014

Accepted: September 1^st 2015

Infectious complications in children with end-stage renal disease on replacement therapy

Néstor Daniel Robles-Vázquez,^a María Alejandra Aguilar-Kitsu,^b Leticia Mendoza-Guevara,^c María Guadalupe Miranda-Novales^d

^aHospital de Pediatría

^bJefatura de Nefrología, Hospital de Pediatría

^cDivisión de Especialidades, Hospital de Pediatría

^dUnidad de Investigación en Epidemiología Hospitalaria, Coordinación de Investigación en Salud

Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Distrito Federal, México

Communication with: María Guadalupe Miranda-Novales

Telephone: (55) 5627 6900, extensión 22507

Email: guadalumiranda@terra.com.mx

Background: Annually, 5000 children younger than 20 years of age and 200 younger than two-years require treatment for chronic kidney disease (CKD). The objective was to estimate the incidence rate of infectious complications in children requiring renal replacement therapy.

Methods: Retrospective cohort. Patients with a minimum of three months of follow-up in programs of peritoneal dialysis and hemodyalisis were included. The incidence rate for infections associated to replacement therapy was calculated.

Results: 67 patients were analysed. In 88 %, initial therapy for CKD was peritoneal dialysis. A total of 52 episodes of peritonitis occured, with an incidence rate of 0.63 episodes/patient-year. Thirty children (48 %) never had an episode of peritonits during the folow-up. At six months, 90 % of the children had the same peritoneal dialysis catheter, decreasing to 84, 74 and 50 % at 12, 18 and 24 months, respectively. Forty-five children were on hemodialysis, 82 % preceded by peritoneal dialysis. Dialysis treatment time in 25 % of them was longer than 19 months. Twenty-two episodes of catheter-related bacteremia occurred, with an incidence rate of 1 episode/1000 catheter-days or 2.5/1000 hemodyalisis sesions. Twenty-nine patients received a transplant (43 %); two of them died. Median waiting time to transplant was 15 months.

Conclusions: Incidence rate of infectious complications was similar to the rates reported in the literature by other centers. At 20 months, half of the patients had at least one infectious complication.

Keywords: Chronic kidney failure, Peritoneal dialysis, Dialysis.

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In 2002, the National Kidney Foundation in the United States (Kidney Disease Outcomes Quality Initiative) published guidelines for the evaluation, classification, and stratification of chronic kidney disease (CKD).¹ The classification system identifies five stages of CKD, based on glomerular filtration rate (GFR). CKD is defined by the presence of renal lesion for a time ≥ three months, or glomerular filtration rate < 60 ml/min/1.73 m² for a time ≥ 3 months. Although this classification is widely used, it has its limitations for pediatric patients in whom estimating GFR is a challenge, especially in early stages of renal lesion. Moreover, the classification cannot be used before the two years of age.² The classic term chronic renal failure in this classification corresponds to GFR values ​​between 15 and 60 mL/min/1.73 m² (stages 3 and 4), and end-stage renal disease (ESRD) to GFR values ​​below 15 mL/min/1.73 m² (stage 5); this is accompanied, in most cases, by the signs and symptoms of uremia or the need to initiate renal replacement therapy in its various forms (hemodialysis, peritoneal dialysis, or renal transplantation).

In the US registry (US Renal Data System), ESRD patients under 20 years of age constitute a small proportion, but represent a challenge due to the variety of extrarenal manifestations and the need for a multidisciplinary approach. The main causes are hereditary and congenital, which contribute 36% of cases, while 23% are due to glomerular disease and 11% to glomerulonephritis, including vasculitis. About 40% receive transplants during the first year of treatment and only 4% die. During 2007-2011, the rate of ESRD was 15.2 per million.³ In other countries the information is different: Europe has a reported rate of 11 to 20 per million people under age 20,⁴ Latin America has from 2.8 to 15.8 per million people under age 18, and Asia has 38 to 300 per million inhabitants of pediatric age.²

Mortality among children and adults in chronic dialysis therapy is higher than that of the general population. For years it has been assumed that peritoneal dialysis (PD) is the safest mode of treatment in terms of cardiovascular risk. However, recently it has been found that cardiovascular risk and mortality in general are at least the same or greater in adults in PD than in hemodialysis (HD).⁵ Pediatric dialysis centers treat a relatively small number of children and adolescents, so most of the observations concerning the survival and causes of death of patients in replacement therapy are derived from national or international reports from developed countries. Mortality rates are lower compared to adults. However, an assessment of causes of death reflects the excess risk of heart and vascular disease and high prevalence of left ventricular hypertrophy and dyslipidemia in children treated with renal replacement therapy.⁶ Infants and young children on dialysis have a higher mortality rate than older children, which is due in part to comorbidities.⁷ Despite clear improvement in the long-term survival of children and adolescents with ESRD over the last 40 years, ten-year survival is estimated at 80% for children with ESRD.⁸ In Mexico, the national survey conducted in 1992 in the Instituto Mexicano del Seguro Social (IMSS) registered a rate of 200 patients per million beneficiaries receiving peritoneal dialysis.⁹ However, subsequent studies indicated higher figures and the need for more resources for the care of patients with ESRD.¹⁰  

Infection is the second leading cause of death among dialysis patients. Hospitalization rates due to sepsis are higher in patients in HD.¹¹ The risk of bacteremia is seven times higher when HD is performed through a vascular catheter instead of with an arteriovenous fistula. The overall incidence of bacteremia is 1.2 episodes per 1,000 days or 2.9 per 1000 hemodialysis sessions.¹² Up to 50% of PD patients have to switch to HD within 4 or 5 years due to failure of the technique.¹³ The incidence of episodes of peritonitis in our area is reported from 1 every 4.5 months/patient, to one every 14 months/patient. There are also factors that increase the risk for recurrent peritonitis.¹⁴

Mexico has no national registry of patients on replacement therapy, and in particular there is a lack of data on complications in the pediatric population. Therefore, the present study aimed to determine the frequency of infectious complications in pediatric patients with end stage renal disease in replacement therapy.

Methods

A retrospective cohort study was conducted at the Departamento de Nefrología of the Unidad Médica de Alta Especialidad, Hospital de Pediatría of the Centro Médico Nacional Siglo XXI, from January 2005 to December 2008. Patients younger than 17 years were included, with ESRD, in replacement therapy with a minimum time of dialysis of three months. Patients with incomplete files were excluded as were those not available due to transfer to another medical unit. The outcome variables recorded were infectious complications related to the use of PD catheter and HD catheter. Demographic data, diagnosis, time of progression and monitoring, type of dialysis therapy, subsequent therapies, reason for change of therapy, and complications were all obtained from medical records. If the patient had an infectious complication, the isolation, identification, and sensitivity of the microorganism were confirmed in the bacteriology section.

Infections were classified as follows: a) peritonitis, with suggestive symptoms (abdominal pain and cloudy peritoneal fluid) or peritoneal fluid cytology with more than 100 cells/mm³ or peritoneal fluid culture with microbiological growth; b) bacteremia, defined by positive blood culture with the microorganism sample obtained from the catheter and the peripheral vein; c) infection of the catheter exit site, defined as drainage, redness, or pain at the exit site; d) tunnel infection, defined as inflammation or pain with or without erythema in the catheter tunnel.

For statistical analysis, descriptive statistics and Kaplan-Meier survival curves were made with which the duration of peritoneal dialysis catheter was calculated. Infection rates were calculated by dividing the total number of infections by total time in PD or HD.

The study was approved by the IMSS Comisión Nacional de Investigación Científica with the number 2009-785-033.

Results

During the study period, 80 patients met the inclusion criteria, and 13 were discarded for not having complete clinical files. Data from 67 patients were analyzed. The total months of peritoneal dialysis was 981 months and for hemodialysis 668 months, with a median of 15 and 9 months for PD and HD, respectively. The minimum and maximum time was three to 41 months and three to 70 months for PD and HD, respectively.

The general characteristics of the study population are shown in Table I. Males predominated by 58%. In 53.7% of the population the age at chronic kidney disease diagnosis was 10 to 14 years. The median age was 11.4 years, with a range from one month to 15 years and three months. The predominant etiology of CKD was glomerulopathies with 52%, urinary tract malformations in second place with 37%, and the rest were due to hereditary diseases and indeterminate causes.

Of patients, 88% (n = 59) had peritoneal dialysis as their first renal replacement therapy.

Peritoneal dialysis

During the course of their disease, 62 children were in PD at some point. The maximum duration of this was 41 months, with a median of 15 months. In 34 cases (55%) it was necessary change to dialysis therapy to HD: 18 due to peritonitis unresponsive to treatment, and 16 due to peritoneal membrane failure. Of these, only six (17.6%) returned to PD (four had resolved peritonitis, one had HD catheter colonization, and one due to resolution of the PD catheter dysfunction).

A total of 52 peritonitis events were presented in 62 children with PD. The incidence density for peritonitis was 0.63 episodes/patient per year. Thirty children (48%) never had an episode of peritonitis, 17 (27%) had peritonitis once, 13 (21%) twice, and two (3%) three times. In these two patients with three peritonitis events, catheter removal and changing dialysis therapy to HD was temporarily necessary, which resolved the infection in both cases: in one of them two different strains of Candida sp. were isolated, and in the other case methicillin-resistant Staphylococcus epidermidis. 

The most common etiology of the peritonitis events was due to Staphylococcus aureus and Staphylococcus epidermidis. In 24 cases (46%) it was not possible to determine the causative agent, and the remainder were Gram negative microorganisms and fungi (Table II).

Seventeen cases of infection were presented at the peritoneal dialysis catheter exit site, 15 of them in the first catheter placed. Removal was necessary in only one case due to granuloma and exit site infection. The incidence density of exit site infection in PD dialysis was 0.20 episodes/patient per year. 

84 Tenchkoff catheters were used. The median catheter duration was 24 months. At 6 months follow-up, 90% of children still had the same catheter, which decreased to 84, 74, and 50% at 12, 18 and 24 months, respectively. The maximum duration was 41 months (Figure 1).

Hemodialysis

Forty-five children were in HD. Eight (18%) were initially admitted to HD and the rest (82%) had been in PD before. Of the eight children who initially underwent HD, six had abdominal surgery for urinary tract malformation, and two of them were due to emergency dialysis (one for hemolytic uremic syndrome and another for hyperkalemia).

Children requiring HD were maintained with the same therapy for a maximum period of 70 months, with a median of nine months. Time in hemodialysis was over 19 months in 25% of the population and less than four months in 25%. 105 vascular accesses were used: 32 Permacath catheters, 55 Mahurkar, and 18 arteriovenous fistulas.

Regarding infectious complications, there were 22 HD catheter-related bacteremia events, one of them after acute rejection of renal transplant with reinitiation of HD. The incidence density for bacteremia related to HD catheter colonization was 1 episode/1000 catheter-days or 2.5/1000 hemodialysis sessions (one case in 30 months). 

In bacteremia, three-quarters of the microorganisms were Gram positive cocci and the rest were Gram negative (Table III). Regarding HD catheter exit site infections, 11 cases were recorded in 45 patients. The incidence density was 0.5/1000 catheter-days (one case in 60 months).

Kidney transplant

Twenty-nine children received transplants (43%) (33 transplants: 28 from living related donor and five cadaveric donor). Two children were transplanted twice and one thrice. 60% of those who received kidney transplants were female. 63% had glomerulopathy as the etiology, followed by 26% with urinary tract malformation. 11 transplant graft rejections were presented: three acute and eight chronic. Of the patients with rejection, five were readmitted to HD, two died, three were transplanted a second time, and one received two more transplants. The minimum waiting time for kidney transplantation was four months and maximum was 79 months, with a median of 13 months.

Deaths

Two deaths occurred in this group of patients: an 8-year-old patient with urinary tract malformation diagnosed at birth and with renal replacement therapy (PD and HD) in the last two years prior to death. He died 15 days after cadaveric donor kidney transplant of acute graft rejection and septic shock. The second death was of a 17-year-old patient diagnosed with urinary tract malformation and receiving HD since age eight; she received a living related donor kidney transplant at age 10 with chronic graft rejection and readmission to HD at age 16. She died at 17 from septic shock.

Discussion

The etiology of ESRD in this study contrasts with that recorded in other countries. In our population the most common cause is glomerulopathies, while in the United States and European countries, the main etiology corresponds to cystic and hereditary causes.¹⁵

PD is still the most common form of replacement therapy initially prescribed to children with chronic kidney disease throughout the world.¹⁶ The North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) reports that 63% of patients under 21 years receive PD and 37% HD.¹⁷ For patients included in this study, we found that overall 58% were in PD and 42% in HD, although the initial therapy for most of them was PD. Patients’ time with PD (with a median of 15 months) was similar to that recorded in the pediatric cohort in North America, in which half of the patients in PD and HP change therapy at 12 months, and virtually none remain in their initial mode at 36 months. However, as in other developed countries, most of those who change therapy receive a transplant. The percentage of children who received transplants in 2011 in the US was 69%,¹⁸ compared with 43% at our center.  

Longer time in either of the two modes increases the exposure to peritoneal dialysis and hemodialysis catheters, the handling required, and therefore a greater chance of complications. In the eighties, peritonitis associated with dialysis catheters was the main complication that forced change from PD to HD.¹⁴ By developing safer dialysis systems, this complication decreased markedly, and other factors such as patient comorbidities and being a nasopharyngeal carrier of some microorganisms, including Staphylococcus aureus,¹⁹ have greater weight for the presentation of peritonitis. Currently, the frequency of peritonitis episodes is similar to that reported in reports from Europe and the United States,^2,20 corresponding to less than one episode per year. Almost half of patients remain free of peritonitis while awaiting transplantation; the percentage in the hospital was slightly higher compared with that reported by Schaefer et al. (48% versus 40%).²¹ The microorganisms that most commonly cause infections are Staphylococcus, both aureus and coagulase-negative. Bradley et al., in a retrospective cohort study including records from 47 pediatric centers in 14 countries in Europe, America, and Asia, found that Gram positive organisms were isolated in 44%, Gram negative in 25%, and 31% had negative cultures.²² Three cases of Candida infection were presented, who, due to needing the catheter removed in order to heal, remained in HD until the end of treatment. Of the patients who developed peritonitis, 46% had no isolation of the causative organism, making it difficult to choose the best treatment. One limitation for recovering the etiologic agent is the relatively low count of bacteria per mL of dialysate fluid, which can be improved if concentration methods are used; however, the possibility of these methods is not available 24 hours, so the patient begins treatment once the cytochemical results are corroborated, and when the sample is sent for culture, the bacterial count is even lower, and no development is obtained.

Regarding catheter-related bacteremia events in hemodialysis patients, the incidence was similar to adult studies,²³ even in units where strict protocols have been implemented to reduce infections.²⁴ It should be noted that the microorganisms other than Staphylococcus spp., isolated in both PD and HD patients, are diverse and come mainly from the atmosphere, suggesting that emphasis should be placed in the care of catheters, both in the hospital and at home.²⁵

Conclusion

Although the incidence rates of complications associated with replacement therapy are low and similar to those reported in the literature by other centers, half of the patients at 20 months of follow-up had at least one infectious complication, and at 40 months none of them continued in the same dialysis therapy with which they had begun. The ideal treatment option for pediatric patients is kidney transplant; unfortunately, however, most patients do not receive a transplant, and for those who do, the waiting time is longer than one year. According to data recorded by the Centro Nacional de Trasplantes of the Secretaría de Salud as of July 2, 2014, there were 10,917 patients waiting for a kidney transplant in Mexico, with average waiting times ranging from 24 to 30 months. It is essential to promote the culture of organ donation for the social reintegration of patients with end-stage renal disease.

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