Intravenous Iron Does Not Affect the Rate of Decline of Residual Renal Function in Patients on Peritoneal Dialysis

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1 Advances in Peritoneal Dialysis, Vol. 22, 2006 Hemal Shah, Ashutosh Shukla, Abirami Krishnan, Theodore Pliakogiannis, Mufazzal Ahmad, Joanne M. Bargman, Dimitrios G. Oreopoulos Intravenous Iron Does Not Affect the Rate of Decline of Residual Renal Function in Patients on Peritoneal Dialysis The preservation residual renal function (RRF) is important for adequacy of peritoneal dialysis. Oxidative stress from intravenous (IV) iron has been shown to cause renal damage. The effect of IV iron on RRF has not been studied. Here, we report our experience during April 1999 March 2005 of the effect of IV iron on RRF. The study group included 24 patients (9 men, 15 women). The mean age of the group was 61 ± 17.7 years. Diabetes mellitus and hypertension were the underlying cause of end-stage renal disease in 55% of the patients. We found serum creatinine, creatinine clearance, urea clearance, urine output, hemoglobin, transferrin saturation, and ferritin all to be statistically significantly different before and after administration of IV iron to the patients. However, the rate at which the glomerular filtration rate (GFR) declined over time did not change significantly when calculated for the period before and after the iron infusion, suggesting that the changes we observed after IV iron infusion were the result of the declining RRF the rate of that decline being unaffected by the IV iron. Furthermore, the rate of GFR decline in this study was similar to that previously reported in our patients. Key words Intravenous iron toxicity, residual renal function, oxidative stress Introduction The importance of preservation of residual renal function (RRF) in peritoneal dialysis (PD) patients was From: The University Health Network and the University of Toronto, Toronto, Ontario, Canada. well documented by the CANUSA and the NECOSAD studies (1 3). Management of anemia in chronic kidney disease patients involves treatment with erythropoietin and oral or intravenous (IV) iron (4). The National Kidney Foundation Dialysis Outcomes Quality Initiative guideline recommends oral iron for all patients on erythropoietin and intravenous iron for patients with a ferritin level below 100 µg/l and a transferrin saturation below 20%. Using these interventions to maintain hematocrit between 33% and 36% has been associated with a reduction of cardiovascular risk and has improved the quality of life of patients on dialysis (5). In vivo and in vitro studies have shown that IV iron increases oxidative stress (6), and increased oxidative stress is associated with progression of renal failure (7). The rapid development of oxidative stress because of free iron has been reported to cause transient renal injury (8). The effect of this oxidative stress on RRF in patients on PD has not been examined. We therefore conducted a study to evaluate the effect of IV iron on RRF in patients on PD. Patients and methods All patients on PD at our center come to the clinic every 4 8 weeks for a follow-up visit. During each visit, patients undergo a clinical examination and laboratory investigations, including complete blood count, serum creatinine, creatinine and urea clearance from a 24-hour urine collection, electrolytes, serum protein, and albumin. Serum iron studies are carried out every 4 months (or twice monthly when relevant). All patients with a ferritin level below 100 µg/l and a transferrin saturation below 20% receive IV iron saccharate 500 mg weekly for 2 weeks. All patients are on erythropoietin, with the dose being adjusted

2 100 Shah et al. according to a target hemoglobin level of g/l in iron-replete patients. All patients on PD for more than 6 months at our center were eligible for the study. All patients included in the study had 3 regular twice-monthly follow-up visits before and after receiving IV iron. Anuric patients were excluded from the study. Demographic data such as age, sex, original disease, comorbidities, date of initiation onto PD, type of PD, and medications were noted, as were the laboratory data obtained during the 6 clinic visits. Episodes of infection, hospitalization, change in medication, and use of IV contrast media were also recorded. Statistics Continuous measures are expressed as mean ± standard deviation, and categorical measures are expressed as number and percentage. To determine whether the slopes of the measurements were significantly different pre- and post-treatment, a series of paired t-tests was performed. Results The study group included 24 patients (9 men, 15 women). Mean age of the group was 61 ± 17.7 years. Diabetes mellitus and hypertension were the cause of end-stage renal disease in 55% of the patients (Table I). None of the patients had peritonitis during the study period, and no additional changes were made to medications. Table II shows the mean change in the various parameters before and after administration of IV iron. Table III shows changes in mean creatinine and urea clearances and glomerular filtration rate (GFR) as measured by the slope of the reciprocal of serum creatinine. Figure 1 illustrates the rate of decline of RRF before and after IV iron. Mean serum creatinine, creatinine clearance, urea clearance, and urine output were significantly worse after IV iron infusion. This difference probably represents the natural loss of RRF on dialysis. That hypothesis was confirmed by our observation that the rate of GFR decline, as estimated by the slope of the reciprocal of serum creatinine, and clearance of creatinine and urea before and after iron infusion were not significantly different. Our observations suggest that IV iron infusion did not worsen the rate of RRF decline. A transient deterioration in the rate of decline immediately after the infusion was noted TABLE I Demographic data for the study patients (n = 24) Mean age (years) 61±17.7 Sex [n (%)] Women 15 (62.5) Men 9 (37.5) Underlying renal disease [n (%)] Alport syndrome 1 (4.2) Amyloid 1 (4.2) Chronic glomerulonephritis 2 (8.3) Diabetes mellitus 7 (29.2) Hypertensive nephrosclerosis 6 (25.0) Immunoglobulin A 1 (4.2) Lupus erythematosus 4 (16.7) Polycystic kidney disease 1 (4.2) Unknown 1 (4.2) Mean duration on PD (months) 23.5±5.2 Modality [n (%)] CAPD 12 (50.0) CCPD 12 (50.0) PD = peritoneal dialysis; CAPD = continuous ambulatory peritoneal dialysis; CCPD = continuous cycling peritoneal dialysis. TABLE II Renal and hematologic parameters of the patients before and after intravenous (IV) iron infusion Before After IV iron IV iron Measure (6 mo.) (6 mo.) Serum creatinine (µmol/l) 666.6± ±331.0 a Urea (mmol/l) 19.1± ±4.7 CCr (ml/min/m 2 ) 6.3± ±3.2 a CUr (ml/min/m 2 ) 3.1± ±1.7 a Mean GFR b (ml/min/m 2 ) 4.7± ±2.4 a Urine volume (ml/24 h) 757.5± ±384.2 a Hemoglobin (g/l) 109.6± ±19.2 a Transferrin saturation (%) 0.18± ±0.4 Ferritin (µg/l) 234.5± ±223.0 a a p < b Calculated as CCr + CUr / 2. CCr = creatinine clearance; CUr = urea clearance; GFR = glomerular filtration rate. (Figure 1); however, that decline was not found to be statistically significant. As expected, hemoglobin and ferritin levels were significantly higher after iron infusion. Transferrin saturation improved after iron infusion. Discussion The rise in mean serum creatinine and the decline in mean creatinine clearance, urea clearance, and GFR

3 IV Iron and Residual Renal Function 101 TABLE III Change in the slopes of renal function parameters before and after intravenous (IV) iron infusion Difference Measure Before IV iron After IV iron (after before) p Value 1 / serum Cr ±3.1 8±1.7 6± Monthly CCr (ml/min/m 2 ) 0.12± ± ± Monthly CUr (ml/min/m 2 ) 0.35± ± ± Monthly GFR (ml/min/m 2 ) 0.09± ± ± Cr = creatinine; CCr = creatinine clearance; CUr = urea clearance; GFR = glomerular filtration rate. FIGURE 1 Rate of decline of glomerular filtration rate (GFR). IV = intravenous. after IV iron infusion were found to be statistically significant. However, the rate of GFR decline calculated as the slope of creatinine clearance and the reciprocal of serum creatinine was not found to be significantly different. In a previous study, we reported the rate of RRF decline in 242 patients starting chronic PD between January 1994 and December We found that rate to be 0.14 ± 0.20 ml/min per month (9). Of our patients from that study, 40% became anuric after 20 months on PD. In the present study, we observed a rate of RRF decline of 0.12 ml/min per month before the administration of IV iron, which was not significantly different from the rate of 0.15 ml/min per month after the infusion. The rate of GFR decline was similar to the rate of decline seen in the previous study. In the earlier study, we had observed that male sex, high body mass index, presence of diabetes, higher 24-hour proteinuria, increased severity of congestive heart failure, and increased rate of peritonitis with aminoglycoside use were related to a faster RRF decline. We had not included IV iron in that analysis. Only recently has the role of iron in the progression of renal disease been studied in more detail. The role of RRF in patient survival on PD has been established (1 3). Various interventions to prevent the loss of RRF for example, use of angiotensin converting enzyme inhibitors or angiotensin type II receptor blockers, avoidance of nephrotoxic medications such as aminoglycosides, IV contrast, and non steroidal anti-inflammatory drugs are universally practiced. What hasn t been considered, however, is that oxidative stress has a well-established role in the progression of renal failure (6,7) and can be extrapolated to a role in accelerating the loss of RRF. Oxidative stress can be viewed as a disturbance in the balance between oxidant production and antioxidant defense. An imbalance in favor of pro-oxidants can lead to oxidation of macromolecules, resulting in tissue injury (10,11). Iron has the unique ability to reversibly alternate between the ferric and the ferrous state. In doing so, it serves as a carrier of oxygen and electrons and a catalyst for oxygenation, hydroxylation, and other metabolic processes. These processes in turn lead to generation of powerful and potentially hazardous reactive oxygen species when hydroxyl radicals are created by the Haber Weiss reaction (7). The reactive oxygen species thus generated play a major role in the initiation and propagation of lipid peroxidation and lipid oxidation. This process is prevented when iron binds to transport proteins such as transferrin and storage proteins such as ferritin. However, this antioxidant mechanism is easily overcome by rapid saturation of the binding sites for these proteins in situations such as an IV infusion of iron (8). Iron as a source of reactive oxidant species is associated with cardiovascular disease, infections, and renal injury (12,13). The role of oxidants in the

4 102 Shah et al. progression of renal failure is also well established (6,7). Intravenous iron is associated with renal injury in animal and human studies: animal studies (14 16) have shown a correlation between iron accumulation and loss of renal function, and similar results have been noted in human studies (8,17). Agarwal et al. (8) studied the relationships between IV iron, oxidative stress, and renal injury. In 20 subjects with stage 3 or 4 chronic kidney disease, they compared the oxidative stress induced by IV administration of 100 mg iron sucrose over 5 minutes and prevention of that stress with N-acetylcysteine. They concluded that IV iron produces oxidative stress that is associated with transient proteinuria and tubular damage. None of the foregoing studies has addressed longterm effect on GFR, however. Our study is the only study that has attempted to address the issue by looking at the rate of GFR decline in PD patients. In our study, we observed no effect of IV iron on rate of GFR decline. That finding suggests that oxidative stress induced by IV iron may cause transient injury without permanent damage. Our patients received IV iron as an infusion over 6 hours. That method of administration was significantly slower than the 100 mg infused over 5 minutes in the Agarwal study (8). Earlier, we reported the clinical advantage of slow iron infusion (18). Slow infusion may prevent the rapid saturation of iron binding sites, thus reducing oxidative stress. We are aware of the limitations of our study: its retrospective nature; the small number of patients, with an average pre-iron GFR of less than 5 ml/min/1.73 m 2 ; and the 23-month mean time on PD. Earlier, we showed that most patients become anuric after 18 months on PD. Also, 24-hour urine collection for estimation of GFR has its limitations, and our estimations were carried out 4 8 weeks before and after the IV iron. Because of that timing, transient changes in GFR may not be accurately reflected. Conclusions The present study is the first to look at the effect of IV iron on the rate of RRF decline in PD. The importance of RRF preservation cannot be overemphasized. We found no change in the rate of RRF decline, and we therefore conclude that IV iron did not affect RRF. The results of this study need to be confirmed in a prospective study with larger numbers of new patients starting PD. References 1 Bargman JM, Thorpe KE, Churchill DN, for the CANUSA Peritoneal Dialysis Study Group. Relative contribution of residual renal function and peritoneal clearance to adequacy of dialysis: a reanalysis of the CANUSA study. J Am Soc Nephrol 2001; 12: Merkus MP, Jager KJ, Dekker FW, de Haan RJ, Boeschoten EW, Krediet RT. Predictors of poor outcome in chronic dialysis patients: the Netherlands Cooperative Study on the Adequacy of Dialysis. Am J Kidney Dis 2000; 35: Chung SH, Heimbürger O, Stenvinkel P, Qureshi AR, Lindholm B. Association between residual renal function, inflammation and patient survival in new peritoneal dialysis patients. Nephrol Dial Transplant 2003; 18: National Kidney Foundation. IV. NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: update Am J Kidney Dis 2001; 37(Suppl 1):S Ma JZ, Ebben J, Xia H, Collins AJ. Hematocrit level and associated mortality in hemodialysis patients. J Am Soc Nephrol 1999; 10: Nath KA, Fischereder M, Hostetter TH. The role of oxidants in progressive renal injury. Kidney Int 1994; 45(Suppl 45):S Shah S. Role of iron in progressive renal disease. Am J Kidney Dis 2001; 37(Suppl 2):S Agarwal R, Vasavada N, Sachs NG, Chase S, Richard L. Oxidative stress and renal injury with intravenous iron in chronic kidney disease. Kidney Int 2004; 65: Singhal MK, Bhaskaran S, Vidgen E, Bargman JM, Vas SI, Oreopoulos DG. Rate of decline of residual renal function in patients on continuous peritoneal dialysis and factors affecting it. Perit Dial Int 2000; 20: Himmelfarb J, Stenvinkel P, Ikizler TA, Hakim R. The elephant in uremia: reflections on oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int 2002; 62: Himmelfarb J, Hakim RM. Oxidative stress in uremia. Curr Opin Nephrol Hypertens 2003; 12: Feldman HI, Santanna J, Guo W, et al. Iron administration and clinical outcomes in hemodialysis patients. J Am Soc Nephrol 2002; 13: Drueke T, Witko Sarsat V, Massy Z, et al. Iron therapy, advanced oxidation protein products, and carotid artery intima-media thickness in end-stage renal disease. Circulation 2002; 106: Harris DC, Tay C, Nankivell BJ. Lysosomal iron accumulation and tubular damage in rat puromycin nephrosis and ageing. Clin Exp Pharmacol Physiol 1994; 21:73 81.

5 IV Iron and Residual Renal Function Alfrey AC, Froment DH, Hammond WS. Role of iron in the tubulointerstitial injury in nephrotoxic serum nephritis. Kidney Int 1989; 36: Zager RA, Johnson AC, Hanson SY. Parenteral iron nephrotoxicity: potential mechanisms and consequences. Kidney Int 2004; 66: Nankivell BJ, Boadle RA, Harris DC. Iron accumulation in human chronic renal disease. Am J Kidney Dis 1992; 20: Aggarwal HK, Tziviskou E, Bellizzi V, et al. Prolonged administration over six hours of large doses of intravenous iron saccharate (500 mg) prevents severe adverse reactions in peritoneal dialysis patients. Perit Dial Int 2002; 22: Corresponding author: Dimitrios G. Oreopoulos, MD, Toronto Western Hospital, 399 Bathurst Street, Ontario M5T 2S8 Canada. dgo@teleglobal.ca

PART ONE. Peritoneal Kinetics and Anatomy

PART ONE. Peritoneal Kinetics and Anatomy PART ONE Peritoneal Kinetics and Anatomy Advances in Peritoneal Dialysis, Vol. 22, 2006 Paul A. Fein, Irfan Fazil, Muhammad A. Rafiq, Teresa Schloth, Betty Matza, Jyotiprakas Chattopadhyay, Morrell M.