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ORIGINAL CONTRIBUTIONS

Received: March 14^th 2015

Accepted: May 15^th 2015

End stage renal disease lymphopenia; characterization and clinical correlation

José Luis Lepe-Zúñiga,^a Pedro Morales-Molina,^b Gabriela Alejandra García-Nandayapa^c

^aSubdirección de Servicios Clínicos, Hospital de Especialidades Pediátricas

^bUniversidad Autónoma de Chiapas

^cServicio de Medicina Interna, Hospital “Rafael Pascasio Gamboa”

Tuxtla Gutiérrez, Chiapas, México

Communication with: José Luis Lepe-Zúñiga

Telephone: (961) 132 5788

Email: joselepe36@hotmail.com

Background: Patients with End Stage Renal Disease (ESRD), defined as those in Stage 5 of the Kidney Disease Outcome Quality Initiative (KDOQI) classification, have a number of acquired immune deficiencies secondary to the uremic stage, among them lymphopenia. In the present report, we retrospectively characterized the peripheral blood lymphocyte counts in a group of patients with ESRD and we related lymphopenia to their biochemical parameters and to the presence or absence of infections.

Methods: Medical records from 190 patients in ESRD were selected from 282 medical records of patients being treated between February 2008 and November 2012 for kidney failure at different stages. A number of variables, including lymphocyte counts, biochemical parameters and infections, were analyzed at two different time points: Before and during dialysis.

Results: ESRD patients analyzed had a well defined peripheral blood hematological pattern, characterized by severe chronic anemia, normal or elevated leukocyte count and normal or below normal lymphocyte count. The degree of hematological changes correlated with the depth of renal dysfunction and improved with dialysis along with the improvement of urea and creatinine values.

Conclusions: Lymphopenia was present in around half ESRD patients and was associated with increased infections, but they were of the same type as those present in ESRD patients without lymphopenia. Infections were different as those commonly associated with other immune deficiency lymphopenias. The implications of these findings are discussed.

Keywords: Lymphopenia; Uremia; Chronic kidney failure; Chronic renal insufficiency

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Patients with end-stage renal disease (ESRD), as long as they do not receive a successful kidney transplant, require permanent replacement therapy in the form of dialysis, which, in all its variants, involves invasive procedures that expose them to intercurrent infections. On the other hand, these patients have various immunity disorders associated with renal failure itself, or associated diseases or causes that also contribute to infectious complications. Among these disorders are those affecting the lymphocytes.

In this context, during the daily review of the evolution of a group of patients with ESRD treated at Hospital Regional "Dr. Rafael Pascasio Gamboa" in the city of Tuxtla Gutierrez, Chiapas, it was observed that some of them had moderate to severe lymphopenia, so it was decided to retrospectively investigate its incidence, correlation with other clinical and laboratory parameters, and possible clinical significance, specifically in relation to infections presented by these patients.

Methods

The clinical records were reviewed for 282 patients who attended Hospital Regional "Dr. Rafael Pascacio Gamboa" in the city of Tuxtla Gutierrez, from February 2008 to November 2012, with the established diagnosis of renal failure. Of these, 190 cases were selected that met the inclusion criteria for ESRD (stage 5 chronic kidney disease according to the KDOQI (Kidney Disease Outcome Quality Initiative) classification of the US National Kidney Foundation (National Kidney Foundation).¹ General clinical data, related diagnoses, infectious and other complications, and data of hematological and biochemical parameters at diagnosis were collected from records and, if necessary, immediately before the first dialysis procedure and during subsequent follow-up.  

Mean values, standard deviation, minimum, and maximum were obtained for each laboratory parameter, determining the percentages of abnormal values of each, and obtaining, among other things, the percentage of patients with lymphopenia. In addition, the absolute values ​​of each parameter were correlated with each other, at diagnosis, at the start of dialysis treatment, and during follow-up, using the method of Pearson’s r coefficient. The significance of the correlations was obtained by Student's t statistic. The values ​​of laboratory parameters of the same patients at initial diagnosis, before dialysis, and at follow-up were also compared using Student’s t-test for paired samples. Cases with and without lymphopenia were correlated with observed clinical parameters using Chi-squared test.

The IBM electronic program SPSS Statistics v.15, IBM Corp., and statistical options with Microsoft Excel were used for statistical calculations.

Results

Table I shows the general characteristics of the study population, annotating diagnoses associated with ESRD and their distribution according to patient sex. With the exception of cases associated with obstructive uropathy, there were no significant differences in the distribution of diagnoses. The obstructive uropathy group in men includes cases of prostate cancer (4), obstructive postinflammatory uropathy (10), benign prostatic hypertrophy (11), and urinary tract lithiasis (12 cases). The latter predominated clearly over cases of lithiasis in women (12 versus 3).

Table II shows the mean values, standard deviation, minimum, and maximum for each of the relevant parameters of blood count and blood chemistry upon admission. All patients except one with 14.2 g/dL, had moderate to severe anemia; only 6/190 (3%) had leukopenia (< 4000/uL), while 61/190 (32%) had leukocytosis (> 11,000/uL), and 123/190 (65%) had leukocytes within normal ranges. Regarding lymphocytes, 89/190 (47%) had lymphopenia (< 1000/uL) and 23 (12%) had lymphopenia < 500/uL. All creatinine values ​​were above normal and only one patient had normal urea figures (20 mg/dL); in the rest it was elevated. In 82/147 patients (56%), albumin was below 3.0 g/dL; in the rest, this was reported within normal values.

Significant negative correlation was found between absolute values ​​of lymphocytes and urea and creatinine values ​​(p < 0.05). Hemoglobin also negatively correlated with urea and creatinine (p < 0.01). Total leukocytes correlated with the urea count and both this number and creatinine strongly correlated with each other (p < 0.01). On the other hand, there was no significant association of lymphopenia with patient gender (Chi-squared = 3.9; p > 0.05) or with one particular primary diagnosis of those associated with ESRD (Chi-squared = 3.8; p > 0.05. Table III).

Of the initial 190 patients, 75 were admitted for stabilization and eventual dialysis. Medical treatment consisted initially, as appropriate, of a low-protein, low sodium diet, correction of electrolyte abnormalities, diabetes control (insulin, glyburide, metformin), antibiotics (ceftriaxone, cefotaxime, ciprofloxacin, levofloxacin), antihypertensive medications (losartan, telmisartan, amlodipine, captopril, metoprolol), diuretics (furosemide and spironolactone), omeprazole, ranitidine, folic acid, ferrous fumarate, calcium gluconate, calcitriol, calcium, erythropoietin, salbutamol, paracetamol, and others.

The comparison of both hematological disorders and initial biochemical disorders in hospitalized patients, with the same parameters just before starting dialysis an average of 24 days later, showed comparable hemoglobin, leukocytes, urea, and creatinine in all patients (paired t). Moreover, albumin decreased significantly from 2.9 g/dL (95% CI: 2.7-3.0) to 2.5 g/dL (95% CI 2.3-2.8; p < 0.01), and lymphocytes also declined significantly from 1276/uL (95% CI: 1121-1430) to 990/uL (95% CI: 857-1124; p < 0.001), even though the total number of leukocytes remained virtually unchanged. The number of cases with lymphopenia (< 1000/uL) in this subpopulation went from 30/75 (40%) to 43/75 (57%) (Chi-squared, 4.510; p < 0.05).  

All of them were offered dialysis. However, only 59 of them were given at least one dialysis treatment; the remaining 16 requested discharge before the planned initiation of dialysis.

Table IV shows the values ​​resulting from the comparison of laboratory tests performed just before and during dialysis treatment in 41 to 59 patients for whom paired data were obtained. The values ​​shown for dialysis patients represent the average of tests made during follow-up.

The dialysis therapy was initially intensively managed or managed as continuous ambulatory peritoneal dialysis (CAPD), depending on the general clinical characteristics and the specific requirements of patients resulting from the stage of the disease, intercurrent infections, other complications, etc. Treatment was generally not optimal, resulting from administrative factors (timely availability of supplies) and/or medical factors (peritoneal catheter infection, etc.). Patients also variously received the above medications for inpatients.

Follow-up time of the 59 patients under dialysis treatment averaged 186 days (2-271 days). The number of laboratory controls under treatment ranged from 1 to 7 analyses. The results generally show improvement in all the parameters studied despite the irregularity of treatment. In particular, it is noteworthy that urea decreased from an average of 232 mg/dL to 147 mg/dL, also that this decrease is accompanied by creatinine decreasing from 15.8 to 11.7 mg/dL on average, accompanied by the recovery of the lymphocyte count despite the decreased leukocyte count and the average elevation of hemoglobin. In discrete terms, despite the significant drop in levels of urea and creatinine, no case in dialysis recovers normal values. The same can be said of the hemoglobin, which while it rises significantly, does not reach normal values ​​in almost any patient, except one (13.2 g/dL), despite virtually all cases receiving erythropoietin as part of treatment during dialysis.  

In the case of leukocyte counts, in addition to dropping significantly from 11095 down to 8633/uL on average, the number of cases with more than 11,000 cells/uL (upper reference value) fell significantly from 20/57 to 8/57 (Chi-squared 6.817; p < 0.001) and, paradoxically, the number of patients with normal lymphocytes rose from 26/58 to 40/58 (Chi-squared 6.889; p < 0.001), decreasing proportionally with the number of cases with lymphopenia from 32/58 (55%) to 18/58 (31%). Persistent lymphopenia (< 500/uL) was observed only in 6 of these cases.

During follow-up, the 59 dialysis patients had between 95 and 142 different laboratory determinations taken. The correlation of all analyses taken over an average of 186 days of follow-up showed significant negative correlations between lymphocytes and urea (p < 0.01) and between hemoglobin and urea (p < 0.01) and creatinine (p < 0.05), and positive correlation between urea and creatinine (p < 0.01).

Comparing the type and frequency of infections in the patient population studied before and during replacement therapy, it was seen that infections significantly increased during the latter, from 13 to 54 infectious episodes in 59 patients (p < 0.01). However, the increase was due almost exclusively to 30 episodes of peritonitis associated with the use of peritoneal catheter (Tenckhoff) for the dialysis procedure.

In order to study the possible clinical significance of the lymphopenia observed, the number of infectious episodes during dialysis was correlated with the presence of lymphopenia at the time of infection, compared with infections at the time of hematological study without lymphopenia. Table V shows the results of this correlation. As shown, the presence of infection correlates significantly with lymphopenia.

The risk of infection in the presence of lymphopenia is 54%, and 20% in the absence lymphopenia. The relative risk (RR) is 2.644 (95% CI = 1682-4158) times the risk of infection in the absence of lymphopenia. The odds ratio (OR) is 4.57 (95% CI = 2950-7087).

The average lymphocyte value in the 54 studies associated with infection was 962/uL (95% CI: 791-1134), compared to the average value obtained in 107 tests not associated with infection, which was 1507 (95% CI: 1376-1639); the difference between these two groups is significant (Student’s t-test for independent samples = 4.82; p < 0.0001)

However, comparison of the types of infections that occurred during dialysis with both normal lymphocytes and lymphopenia reveals no significant difference in their relative distribution. It is noteworthy that seven events of pneumonia occurred among patients with lymphopenia; this infectious process was absent in the group with normal lymphocytes. However, this difference did not reach significant levels between the two groups using the Chi-squared test. Pneumonic processes are also distributed between nosocomial pneumonia (3) and community-acquired pneumonia (4).

No differences were found between the germs isolated in these infectious processes based on whether or not they had lymphopenia, nor was association found between lymphopenia and any particular drug of the many taken by these patients.

Finally, Table VI shows the general characteristics of six patients who had persistent lymphopenia of less than 400 lymphocytes/uL during dialysis, two of whom had figures of less than 200 lymphocytes/uL. While all of these patients had some associated infection, there was no particular relationship of extreme lymphopenia with a particular type of primary diagnosis, or with any germ or infectious process.

Discussion

The group of patients with ESRD studied is similar to those that have been reported by other authors in adults in the country² or abroad,³ in which patients with diabetes mellitus with or without hypertension and patients with essential hypertension predominate, followed by patients with chronic obstructive uropathy as primary diagnoses associated with ESRD.

Patients studied also have biochemical characteristics similar to those reported in other hematological studies: moderate anemia, leukocytosis, uremia, elevated creatinine, low albumin, and lymphopenia.^3-5 Within these parameters and in accordance with the objectives of this study, it was confirmed that patients with ESRD (Stage 5, KDOQI) often present lymphopenia, which was characterized properly. In our series, lymphopenia with less than 1000 lymphocytes/uL was observed in 47% of the 190 patients at the time of diagnosis, and the initial lymphopenia was less than 500/uL in 12%. Paradoxically, lymphopenia in these patients is presented although 32% of patients had leukocytosis of over 11,000/uL. The number of lymphocytes observed inversely correlated with the increase in urea and creatinine, as did the hemoglobin value. In the initial 190 ESRD patients, lymphopenia was not found associated with the primary diagnosis or sex of the patient, which presupposes a common pathophysiology of lymphopenia in all patients with ESRD independent of primary diagnosis. 

It is noteworthy that once the patient is admitted to the hospital environment, and having initiated general care measures, infection control, and a special diet, lymphopenia became more evident and the number of patients with it significantly increased, reaching 57%. At the same time the percentage of patients with lymphopenia of less than 500/uL also increased from 12 to 24%. In contrast, hemoglobin and total leukocytes remained stable, like the biochemical parameters related to ESRD before dialysis, except albumin which decreased significantly from 2.9 to 2.5 g/dL on average, relative to the low-protein therapeutic diet.

Once the patient underwent some form of dialysis, significant changes were observed in all averages of hematologic and biochemical parameters; hemoglobin improved from 7.7 to 8.5 g/dL, total leukocytes decreased from 11095 to 8633/uL, urea dropped from 232 to 147 mg/dL, creatinine also fell from 15.8 to 11.7 mg/dL and, in contrast, lymphocyte count increased from 1011 to 1346/uL. Similarly, in the 59 patients that were followed, the number of cases with normal lymphocytes rose from 26 (45%) to 40 (70%). Again a significant inverse correlation was observed between the number of lymphocytes and urea levels, as well as with hemoglobin and urea.

Together, these data provide a solid image of blood symptomatology of the ESRD patient both before and during replacement therapy, which is characterized by moderate to severe anemia (99%), normal or elevated leukocytes (at the expense of granulocytes, 97%), and lymphopenia (47%), which tend to be corrected with replacement therapy.

As is widely known, patients with ESRD develop moderate to severe anemia due to poor erythropoietin production by the kidney, decreased red blood cell survival, disruption of iron metabolism, and additional "toxic" and deficiency factors acting on hematopoietic precursors.^6-8 Thus, all patients studied, except one, had anemia at admission with an average value of 8.0 g/dL, and those who moved on to dialysis experienced a slight but significant improvement. In general, an improvement in hemoglobin up to about 12 g/dL is expected. The lack of substantial improvement in this group was due to the irregular use of dialysis, inconsistent administration of erythropoietin, and the difficulties in obtaining donated blood for these patients.

Less known and more difficult to interpret are the changes that occur in the target formula in ESRD. As was said previously, the patients studied had normal or elevated leukocytes at the expense of granulocytes and, paradoxically, about 50% of patients present lymphopenia of less than 1000/uL, and 12% lymphopenia of less than 500/uL. It is noteworthy that the total value of leukocytes correlates directly with the urea value, while circulating lymphocytes correlate inversely with nitrogen values, especially with urea, which implies a direct relationship between them in both cases. On one hand, the elevation of neutrophils could be a result of stimulation of production similar to a state of "acute inflammation" resulting from cytotoxic action of urea or other elements that rise in tandem with urea (but are not normally measured) on non-hematological cells and lymphocytes, similar to what happens with the erythropoietin line.^7-9 However, it is very likely that the effect of retention of some substances in the uremic state on circulating leukocytes is complex and indirect, as lymphocyte cultures with the serum of patients with ESRD and similar experiments have not shown a direct cytotoxic effect on them.^10,11

The leukocyte disorders observed in our study are similar to those previously observed in cases of ESRD undergoing hemodialysis.^4,5 To explain these, Papadimitriou et al.⁴ speculated that removal of toxic factors derived from uremia may be related to changes observed in lymphocytes, and that neutrophil adherence to the dialysis membrane may be contributing to the lower count after the procedure. The patients in our series showed the same changes and did not receive hemodialysis, so the post-dialysis decrease in neutrophils cannot be related only to factors of adherence to a dialysis membrane. On the other hand, in the study and follow-up of a cohort of 267 patients with ESRD, Agarwal and Light5 observed eosinophilia and lymphopenia and were able to correlate sharp increases in leukocyte count with the prognosis of progression to end-stage renal disease and death. Lymphopenia alone, on the other hand, has been correlated with the mortality of patients with ESRD.^3,5,12,13 Mortality was not analyzed in our study.

Although most patients had normal or elevated leukocytes, which in theory would be sufficient for the defense of infections, the facts that in the present work lymphopenia is found associated with infections, and that the relative risk of infection in the presence of lymphopenia is 2.64 times the risk without lymphopenia, suggest that regardless of the values ​​of neutrophil leucocytes, lymphopenia is a direct contributor to the increase in infections in this population. Therefore, regardless of their intimate cause, lymphopenia is a marker for the possibility of infections in patients with ESRD and can serve as a basis for prophylactic infection protocols in these cases.

Other authors have also observed functional changes in lymphocytes, disorders in the distribution of circulating lymphocyte subpopulations, and disorders in other components of the innate and adaptive immune systems,^14-19 which together contribute to these patients’ susceptibility to infections. In the future it will be necessary to carry out immune function and especially lymphocyte studies in relation to the primary diagnosis in order to clearly determine the functional disorders that correspond to the primary process and those corresponding to the retention of nitrogen and other substances.

It is also interesting to note that despite lymphopenia, which in several cases was comparable to what is seen in advanced stages of acquired immunodeficiency, the type of infections presented by these patients is similar to that observed in patients without lymphopenia (except, perhaps, regarding pneumonia). This behavior distinguishes lymphopenia in ESRD from that seen in hereditary or acquired immunodeficiency involving lymphocytes, because in those the infections tend to be of a specific type, different from those observed in patients without lymphocyte abnormalities, for example: candidiasis, cryptococcosis, Pneumocystis carinii pneumonia, etc. These infections are not observed in our patients.^20-23

This observation leads necessarily to reasonable doubt about whether the current lymphopenia observed is the result of the decrease in the total number of lymphocytes or whether it is just a product of the redistribution of lymphocyte pools only affecting circulating lymphocytes and not the total body lymphocyte mass (factitious lymphopenia), a fact that should be studied in the future.

Finally, it is important to note that recently several authors have defined a background phenomenon in ESRD characterized by malnutrition, chronic inflammation, and atherosclerosis associated with death from heart failure.^24-26 In this context, the central phenomenon in ESRD is chronic inflammation related to oxidative stress, and it is defined by elevated acute phase reactants, circulating proinflammatory lymphokines, and hematological disorders similar to those found in the present work, which together correlate with mortality. This concept allows the possibility of understanding the leukocyte disorders observed and controlling the inflammatory phenomenon in ESRD, thus being able to influence the future of their mortality.²⁷

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