Effects of Spironolactone on Residual Renal Function and Peritoneal Function in Peritoneal Dialysis Patients

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1 Advances in Peritoneal Dialysis, Vol. 30, 2014 Berna Yelken, 1 Numan Gorgulu, 1 Meltem Gursu, 2 Halil Yazici, 1 Yasar Caliskan, 1 Aysegul Telci, 3 Savas Ozturk, 2 Rumeyza Kazancioglu, 4 Tevfik Ecder, 1 Semra Bozfakioglu 1 Effects of Spironolactone on Residual Renal Function and Peritoneal Function in Peritoneal Dialysis Patients There is increasing evidence that long-term peritoneal dialysis (PD) is associated with structural changes in the peritoneal membrane. Inhibition of the renin angiotensin system has been demonstrated to lessen peritoneal injury and to slow the decline in residual renal function. Whether spironolactone affects residual renal function in addition to the peritoneal membrane is unknown. We evaluated 23 patients (13 women) with a glomerular filtration rate of 2 ml/min/1.73 m 2 or more who were receiving PD. Patients with an active infection or peritonitis episode were excluded. Baseline measurements were obtained for serum high-sensitivity C-reactive protein (hs-crp), vascular endothelial growth factor (VEGF), transforming growth factor β (TGF-β), and connective tissue growth factor (CTGF); for daily ultrafiltration (in milliliters); for end-to-initial dialysate concentration of glucose (D 4 glucose), Kt/V, and peritoneal transport status; and for dialysate cancer antigen 125 (CA125). Spironolactone therapy (25 mg) was given daily for 6 months, after which all measurements were repeated. Mean age of the patients was 46 ± 13 years. Duration of PD was 15 ± 21 months (range: 2 88 months). After spironolactone therapy, mean dialysate CA125 was significantly increased compared with baseline (20.52 ± U/mL vs ± U/mL, p = 0.028). Serum hs-crp, VEGF, TGF-β, CTGF, daily ultrafiltration, D 4 glucose, Kt/V, and peritoneal From: 1 Division of Nephrology, Department of Internal Medicine, Istanbul Faculty of Medicine; 2 Division of Nephrology, Department of Internal Medicine, Haseki Education and Research Hospital; 3 Department of Biochemistry, Faculty of Medicine, Istanbul University; and 4 Division of Nephrology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey. transport status were similar at both times. At the end of the study period, residual glomerular filtration rate in the patients was lower. In PD patients, treatment with spironolactone seems to slow the decline of peritoneal function, suppress the elevation of profibrotic markers, and increase mesothelial cell mass. Key words Spironolactone, residual renal function, peritoneal function Introduction Long-term peritoneal dialysis (PD) is accompanied by alterations in the peritoneal membrane (1 3) because of continuous exposure to bioincompatible components of dialysis solution and repeated episodes of peritonitis (4). The characteristic feature of peritoneal damage in PD is declining ultrafiltration (UF) capacity, associated with submesothelial fibrosis, accumulation of extracellular matrix, and neoangiogenesis (5). Activation of the renin angiotensin aldosterone system (RAAS) initiates a process mediated by the cytokine transforming growth factor β (TGF-β), which ends with tissue repair (6 8). Angiotensin converting-enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have been shown to prevent peritoneal membrane damage (9 11). Clinical and experimental data support the hypothesis that mineralocorticoid receptor antagonists might improve the prognosis of patients with kidney injury (12,13). In an experimental study, irbesartan, spironolactone, and irbesartan plus spironolactone were found to moderate peritoneal fibrosis in rats with bacterial peritonitis compared with uninfected control rats (14). However, whether aldosterone blockade is useful in preventing peritoneal fibrosis and preserving peritoneal function in patients on PD is not yet completely understood.

2 6 Spironolactone, RRF, and Peritoneal Function in PD Residual renal function (RRF) is the major determinant of morbidity and mortality in patients on PD (15,16). It contributes to measures of dialysis adequacy and creatinine clearance (17,18) and accounts for most of the variability in the requirement for dialysis (19). Although ACEIs and ARBs have been shown to slow the decline in RRF (20,21), the usefulness of aldosterone blockade in preserving RRF in patients on PD is unknown. In the present study, we aimed to evaluate the protective effects of spironolactone on peritoneal function and RRF in PD patients. Methods Patients Our study enrolled 30 adult patients between 18 and 70 years of age who had been on PD for at least 3 months, who had a glomerular filtration rate (GFR) of 2 ml/min/1.73 m 2 or more, and who had no history of taking an ACEI or ARB for at least 6 months. Patients were excluded from the study if they had an underlying medical condition (such as congestive heart failure) that mandates therapy with an ACEI or ARB, hyperpotassemia (serum potassium > 5.5 mmol/l), or an active infection or a peritonitis episode within the preceding month. Information on age, sex, body mass index, blood pressure, cause of end-stage renal failure, and time spent on PD were gathered from patient records. Spironolactone therapy (25 mg) was given daily for 6 months. Patients were evaluated in the outpatient PD clinic every month. During the study, no major alterations were made in medications (for example, phosphate binders, erythropoietin, vitamin D preparations) or dialysis modalities of the patients except that patients who required antihypertensive medication were allowed to take agents other than ACEIs and ARBs. Doses were adjusted appropriately to achieve and maintain the target blood pressure of 135/85 mmhg or to avoid symptomatic hypotension. A regular diet containing g/kg protein daily and limited sodium was recommended throughout the follow-up period. Laboratory data Fasting serum samples for biochemical analysis were obtained between 0800 h and 0900 h. A complete blood cell count was performed, and serum levels of glucose, blood urea nitrogen, creatinine, sodium, potassium, calcium, phosphorus, total protein, albumin, triglycerides, total cholesterol, and low-density and very-low-density lipoprotein cholesterol were measured by standard enzymatic methods. Highsensitivity C-reactive protein (hs-crp) was measured by the nephelometric method (Dade Behring, Deerfield, IL, U.S.A.). For measurements of serum vascular endothelial growth factor (VEGF), TGF-β, and connective tissue growth factor (CTGF), blood samples were centrifuged at 4000 cycles per second for 5 minutes. The supernatant was stored at 80 C until determinations were made by enzyme-linked immunosorbent assay using a commercial kit (Invitrogen, Camarillo, CA, U.S.A.). Renal and peritoneal urea and creatinine clearances were measured in 24-hour urine and dialysate collections. Simultaneous serum urea and creatinine determinations were obtained during the collection period. Residual GFR was defined as the average of the 24-hour urinary urea and creatinine clearances (18). Weekly Kt/V was used to estimate the dialysis dose. Peritoneal function including daily UF (in milliliters) and glucose transport [(4-hour) end-toinitial dialysate ratio of glucose (D 4 glucose)] were examined in a standard peritoneal equilibration test using dialysate containing 2.5% glucose. The cancer antigen 125 (CA125) concentration in the 24-hour peritoneal effluent collection was measured by electrochemiluminescence assay (Elecys CA125 II kit with an Elecsys 2010 immunoassay analyzer: Roche Diagnostics, Mannheim, Germany). After 6 months, all measurements were repeated. Patient examinations conformed to good medical and laboratory practices and to the recommendations of the Declaration of Helsinki on biomedical research involving human subjects. The Istanbul School of Medicine Clinical Studies Board approved the study. Statistical analysis The statistical analysis was carried out using the Statistical Package for Social Sciences (version 15.0 for Windows: SPSS, Chicago, IL, U.S.A.). Numerical variables are presented as mean ± standard deviation. Variables were compared using the paired-samples t-test, and p < 0.05 was accepted as significant. Results Of the 30 enrolled patients, 7 were eventually excluded (1 because of sterile peritonitis, 1 because of

3 Yelken et al. 7 dialysis inadequacy leading to a switch to hemodialysis, and 5 because they stopped spironolactone treatment). The final study group included 13 women and 10 men, with a mean age of 46 ± 13 years (range: years) and a PD duration of 15 ± 21 months (range: 3 88 months). Table I shows the causes of end-stage renal disease in the patients. The PD modality was continuous ambulatory PD in 20 patients and continuous cycling PD in 3. Mean blood pressure was 141 ± 27 mmhg systolic and 89 ± 15 mmhg diastolic. Table II shows the demographic features of the patients and the results of their peritoneal functional tests at the end of the study period. Body mass index and systolic and diastolic blood pressure were all similar in both periods (Table II). No decline in peritoneal membrane function (UF, D 4 glucose, Kt/V urea) was observed at the end of the 6 months. Peritoneal transport characteristics at the baseline and final (after 6 months of spironolactone therapy) evaluations were divided as follows: high, 2 at baseline, 3 at 6 months; high average, 11 at baseline, 12 at 6 months; low average, 8 at baseline, 6 at 6 months; and low, 2 at baseline, 2 at 6 months. Residual GFR had significantly declined by the end of the study period compared with baseline (5.20 ± 3.10 ml/min vs ± 3.22 ml/min, p = 0.006). Table II shows biochemical results such as glucose, blood urea nitrogen, creatinine, sodium, potassium, calcium, phosphorus, albumin, cholesterol readings, hs-crp, and hemoglobin at both evaluations. We observed no statistically significant differences in the values at the end of 6 months compared with baseline values. At 6 months, mean dialysate CA125 had significantly increased compared with baseline (20.52 ± U/mL vs ± U/mL, p = 0.028). Serum profibrotic markers such as VEGF, TGF-β, and CTGF were similar in the two evaluations (Table III). Discussion Long-term PD is associated with structural changes in the peritoneal membrane. The importance of local angiotensinogen II in the loss of peritoneal function and of RAAS blockage leading to regression of that loss has previously been established (10). In an experimental study, treatment with ACEI reduced peritoneal thickness and increased UF volume in rats (9). In human studies, ARB not only preserved RRF, but also increased peritoneal creatinine clearance 1 table i Causes of end-stage renal disease in the study patients Cause Patients [n (%)] Glomerulonephritis 5 (21.7) ADPKD 4 (17.4) Pyelonephritis 2 (8.7) Primary nephrosclerosis 2 (8.7) Unknown or others 10 (43.5) TOTAL 23 ADPKD = autosomal-dominant polycystic kidney disease. table ii Patient parameters at baseline and 6 months Parameter Value a p Value Baseline 6 Months Blood pressure (mmhg) Systolic 141±27 136± Diastolic 89±15 86± Body mass index (kg/m 2 ) 27±5.1 27± Glucose (mg/dl) 111±42 125± BUN (mg/dl) 55±16 65± Creatinine (mg/dl) 7.1± ± Sodium (mmol/l) 138±3 136± Potassium (mmol/l) 4.3± ± Ca P 40.2± ± Albumin (g/dl) 3.75± ± Triglycerides (mg/dl) 155±80 162± Cholesterol (mg/dl) Total 194±37 192± LDL 121±39 115± hs-crp (mg/l) 10.2± ± Hemoglobin (g/dl) 11.1± ± Total Kt/V urea 2.7± ± Ultrafiltration (ml/day) 689± ± D 4 glucose 0.46± ± Residual GFR (ml/min) 5.2± ± a Mean ± standard error of the mean. BUN = blood urea nitrogen; Ca P = calcium phosphorus product; LDL = low-density lipoprotein; hs-crp = high-sensitivity C-reactive protein; D 4 = 4-hour to initial dialysate concentration ratio; GFR = glomerular filtration rate. year after PD initiation (21). The foregoing studies indicate that the RAAS plays a role in the progression of peritoneal fibrosis, deterioration of UF, and maintenance of RRF. However, little is known about the role of mineralocorticoid receptor antagonists in

4 8 Spironolactone, RRF, and Peritoneal Function in PD table iii Levels of profibrotic markers and cancer antigen 125 (CA125) Parameter Value a p Value Baseline 6 Months In serum VEGF (pg/ml) 325±48 365± TGF-β (pg/ml) 10047± ± CTGF (pg/ml) 3583± ± In dialysate CA125 (U/mL) 20.5± ± a Mean ± standard error of the mean. VEGF = vascular endothelial growth factor; TGF-β = transforming growth factor β; CTGF = connective tissue growth factor. preventing peritoneal fibrosis and maintaining peritoneal function in PD patients. To our knowledge, the present trial is the first in humans on PD to examine the effect of spironolactone on peritoneal function and RRF. After 6 months of spironolactone treatment, no significant difference was observed in profibrotic markers or in parameters of peritoneal membrane function (UF, Kt/V, D 4 glucose), and dialysate levels of CA125, a useful marker of mesothelial cell mass, increased. In a study conducted in rats, peritoneal functions including UF, glucose transport, albumin leakage, and peritoneal thickening were significantly improved by spironolactone in 14 days of administration (22). Although our study detected no improvement in parameters of peritoneal function such as UF, Kt/V, and D 4 glucose, no significant decline in those parameters occurred after 6 months of spironolactone treatment either. Spironolactone treatment did not prevent decline in residual GFR. Because no control group was used in our study, it is difficult to evaluate the effect of spironolactone on residual GFR and its clinical consequences. An in vitro study that exposed a mesothelial cell culture to high concentrations of glucose determined that increased RAAS activation and angiotensinogen II led to an elevation in TGF-β. Evidence from more than one study has suggested that TGF-β is the key mediator in the development of fibrosis (6,23). Our analysis of molecules that might be involved in peritoneal damage found that spironolactone suppressed inflammatory and fibrotic processes (24). No significant difference was found in the levels of serum profibrotic markers (VEGF, TGF-β, CTGF) after 6 months of spironolactone treatment, although such profibrotic markers are usually expected to increase during the 6-month period after PD start. Note that all markers were examined in serum; the results might have been different had the analyses been made in effluent and tissue samples. Long-term PD is known to cause alterations in the peritoneal membrane. Loss of mesothelial cells is one of those alterations. Dialysate CA125 is a useful marker indicating loss of mesothelial cell mass, at least with respect to the effect of the cell mass on mesothelium (25 27). Peritoneal mesothelial cells are the most likely source for local CA125 release within the peritoneum because CA125 is almost undetectable in lymphocytes, monocytes, granulocytes, and fibroblasts (28). Three different studies have found a relationship between the number of mesothelial cells in peritoneal effluent from PD patients and effluent CA125 concentration. In addition, a decline in the appearance rate of CA125 has been established during longitudinal analysis (29 31), and low CA125 values have been found in patients with peritoneal sclerosis (32,33). A significant elevation in effluent CA125 was observed after 6 months of spironolactone treatment in the present study. Hence, spironolactone treatment seems to be associated with an increase in mesothelial cell mass. Our study has some limitations. First, no control group was used, and the number of participating patients was small. We used 25 mg of spironolactone daily in the study, but higher doses might produce different results with respect to RRF and profibrotic markers. Conclusions Spironolactone treatment seems to slow the loss of peritoneal function, suppress the expected elevation in profibrotic markers, and increase mesothelial cell mass in PD patients. However, we were unable to show a positive effect of spironolactone on RRF. Disclosures No financial conflict of interest exists. References 1 Davies SJ. Longitudinal relationship between solute transport and ultra-filtration capacity in peritoneal dialysis patients. Kidney Int 2004;66:

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6 10 Spironolactone, RRF, and Peritoneal Function in PD 30 Ho-dac-Pannekeet MM, Hiralall JK, Strujik DG, Krediet RT. Markers of peritoneal mesothelial cells during treatment with peritoneal dialysis. Adv Perit Dial 1997;13: İleri T, Söylemezoğlu O, Sindel S, et al. The predictive value of cancer antigen 125 (CA125), collagen III, plasminogen activator inhibitor type-1 (PAI-1), basic fibroblast growth factor (bfgf) on peritoneal fibrosis in chronic peritoneal dialysis [abstract]. Nephrol Dial Transplant 2000;15:A Burkhart J, Stallard R. Result of peritoneal membrane (PM) resting (R) on dialysate (d) CA125 levels and PET results [abstract]. Perit Dial Int 1997;17(suppl 1):S5. 33 Moriishi M, Sakikubo E, Asakimori Y, et al. CA125 appearance rate is useful marker for peritoneal sclerosis in long-term CAPD patients [abstract]. Perit Dial Int 1998;18(suppl 2):S90. Corresponding author: Savas Ozturk, md, Haseki Training and Research Hospital, Department of Nephrology, Istanbul, Turkey.