International Journal of Innovative Pharmaceutical Sciences and Research www.ijipsr.com THE EFFECT OF N-ACETYL CYSTEINE THERAPY IN THE MANAGEMENT OF INFECTIONS ON PATIENTS WITH CHRONIC KIDNEY DISEASE 1 Mathew George, 2 Lincy Joseph, 3 Deepthi Mathew, 4 Merin Jincy Joseph * 1 Department of Pharmacology, Pushpagiri College of Pharmacy, Tiruvalla, Kerala, INDIA 2 Department of Pharmaceutical Chemistry, Pushpagiri College of Phamacy, Tiruvalla, Kerala, INDIA 3 Department of Pharmaceutics, Pushpagiri College of Pharmacy, Tiruvalla, Kerala, INDIA 4 PG Student, Department of Pharmacy Practice, Pushpagiri College of Pharmacy, Tiruvalla, Kerala, INDIA Abstract Chronic kidney disease is a very common long standing disease of the kidneys leading to renal failure. People with kidney disease can be more prone to infection because of related conditions such as uremia, diabetes, inadequate calorie and protein intake, and the access site can be vulnerable to infection. N- acetyl cysteine is a slightly modified version of sulphur-containing amino acid cysteine. N-acetyl cysteine is prescribed for chronic kidney disease patients as a supplement to prevent infections. N- acetyl cysteine has been used successfully to treat glutathione deficiency in a wide range of infections, genetic defects and metabolic disorders. The aim of the study was to determine the effect of N-acetyl cysteine on prevention of infections, by measuring C- reactive protein, in patients with chronic kidney disease. In this study we also analysed the effect of N-acetyl cysteine in retarding the progression of Chronic Kidney Disease. N-acetyl cysteine improves kidney functions and also reduces the occurrence of infections. Keywords: Chronic kidney disease, Infection, N-acetyl cysteine, Glutathione. Corresponding Author: Merin Jincy Joseph Department of Pharmacy Practice, Pushpagiri College of Pharmacy, Tiruvalla, Kerala, INDIA E-mail: merinjincyjoseph@gmail.com Phone: +91-9061296683 Available online: www.ijipsr.com July Issue 10
INTRODUCTION Chronic kidney disease (CKD) also called chronic renal insufficiency (CRI) is defined as a progressive loss of kidney function occurring over several months to years, and is characterized by the gradual replacement of normal kidney architecture with interstitial fibrosis [1]. The symptoms of worsening kidney function are not specific, and might include feeling generally unwell and experiencing a reduced appetite. Often, chronic kidney disease is diagnosed as a result of screening of people known to be at risk of kidney problems, such as those with high blood pressure or diabetes and those with a bloodline relative with CKD. This disease may also be identified when it leads to one of its recognized complications, such as cardiovascular disease, anemia, pericarditis or renal osteodystrophy. Chronic kidney disease is identified by a blood test for creatinine, which is a breakdown product of muscle metabolism. Higher levels of creatinine indicate a lower glomerular filtration rate and as a result a decreased capability of the kidneys to excrete waste products. It is a reciprocal relationship (the higher the creatinine, the lower the GFR). All individuals with a glomerular filtration rate (GFR) <60 ml/min/1.73 m 2 for 3 months are classified as having chronic kidney disease [1]. The CKD population is predisposed to adverse infectious events because of overwhelming uremia, which is associated with alterations in primary host defense mechanisms and increases the risk of bacterial infections [2]. Neutrophils exhibit impaired chemotaxis, oxidative metabolism, phagocytic activity, degranulation, intracellular killing and dysregulated programmed cell death. Factors contributing to neutrophil dysfunction include malnutrition, trace element deficiencies, iron overload, impaired glucose metabolism, hyperparathyroidism, dialysis and uremic retention solutes [2]. N-acetyl cysteine (NAC), the acetylated variant of the amino acid L-cysteine. NAC is an excellent source of sulfhydryl (SH) groups, and is converted in the body into metabolites capable of stimulating glutathione (GSH) synthesis, promoting detoxification, and acting directly as free radical scavengers. Administration of NAC has historically been as a mucolytic agent in a variety of respiratory illnesses. NAC is a powerful antioxidant and potential therapeutic agent in the treatment of cancer, heart disease, HIV infection, heavy metal toxicity, and other diseases characterised by oxidative damage [3]. The mechanism for the anti-bacterial effect of NAC may be that it acts by competitively inhibiting amino acid (cysteine) utilization or; by virtue of possessing a sulfhydral group, may react with bacterial cell proteins [6]. NAC s powerful health benefits derive from its ability to restore intracellular levels of glutathione.glutathione is a very Available online: www.ijipsr.com July Issue 11
important compound because it s our body s own powerful antioxidant and detoxifier. It is the most important cellular defense that allows the body to prevent and fight infections and disease. Glutathione is the protector of the immune cell and allows newly formed immune cells to proliferate to attack germs and viruses. Glutathione feeds, protects and strengthens our immune system. Glutathione boosts WBC production to fight infection, particularly the T-cells, which are called lymphocytes. T-cells are at the core of our immunity, and tailor the body s immune response to pathogens, viral and bacterial infections. NAC is the precursor of glutathione and is the most effective way of raising levels in the body. NAC is also very beneficial for the kidneys and can help to protect them from damage. NAC neutralizes toxins and pollutants including heavy metals that accumulate in the liver, kidneys, brain and fatty parts of the body. Restoring glutathione levels with NAC supplements makes liver cells more able to protect themselves from on-going damage caused by fatty accumulation (fatty liver) viral infections, drug induced damage, alcohol excess or autoimmune inflammation. The main problem is that glutathione is not well absorbed from the gut, as it is broken down by digestive enzymes before it has a chance to be absorbed. For this reason it is far more effective to take its precursor (building block) [4]. N-acetyl cysteine supplementation supported by scientific evidence include prevention of chronic obstructive pulmonary disease exacerbation, prevention of contrast induced kidney damage during imaging procedures, attenuation of illness from the influenza when started before infection, treatment of pulmonary fibrosis. N-acetyl cysteine is a safe and well-tolerated antioxidant with a well-defined mechanism of action [5]. The aim of the study is to determine the effect of N-acetyl cysteine therapy in the management of infections on patients with chronic kidney disease. Objectives include: 1. To analyze the effect of N-acetyl cysteine on infections by measuring biochemical (C-reactive protein) and hematological parameters. 2. To analyze the effect of N-acetyl cysteine in egfr of a chronic kidney disease patients. 3. To evaluate the role of N-acetyl cysteine in retarding progression of chronic kidney disease. MATERIALS AND METHODS STUDY DESIGN: A prospective experimental study. SAMPLE SIZE: 60 STUDY POPULATION: Patients receiving N- acetyl cysteine (TEST) Available online: www.ijipsr.com July Issue 12
Patients not receiving N- acetyl cysteine (CONTROL) STUDY SETTING Nephrology Department of Pushpagiri Medical College Hospital, Thiruvalla. Pushpagiri College of Pharmacy, Thiruvalla. STUDY PERIOD: 6 months STUDY CRITERIA INCLUSION CRITERIA: CKD patients with egfr less than 60mL/min. Patients on age group 18-75 years. IP/ OP patients. EXCLUSION CRITERIA Patients with age group less than 18 years. Patients with age group greater than 75 years. Patients not willing to participate. BRIEF PROCEDURE OF THE STUDY A prospective experimental study on the topic The effect of N-acetyl cysteine therapy in the management of infections on patients with chronic kidney disease was conducted at Pushpagiri Medical College Hospital, Thiruvalla. The study was conducted after getting approval from Institutional Ethics Committee. Informed consent of the patients was taken before the study. Patient data collection form was used for recording the demographic details of the patient. It was a 6 months study in which patients were recruited based on inclusion and exclusion criteria. A total of 60 patients, age 18 to 75 years with chronic kidney disease (estimated GFR (egfr) <60mL/min per 1.73m 2 were prospectively enrolled in the study, in which 30 patients are taken as test group (N- acetyl cysteine receiving group) and 30 patients are taken as control group (N- acetyl cysteine not receiving group).dose of N-acetyl cysteine on test group is 600mg once daily for 6 months. Six months follow up was used in the study. The outcome was measured by comparing the baseline and follow up values of CRP, Serum creatinine, egfr, WBC, ESR. The study was also analyze the effect of N- acetyl cysteine on retarding the progression of CKD. The level of creatinine, WBC, ESR was recorded from Medical Records. For the determination of C reactive protein, serum was collected from the laboratory and determined by using semiautomated clinical chemistry analyzer. Medication adherence was evaluated by using MMAS 4 scale. Estimated Glomerular Filtration Rate (egfr) is calculated by using CKD-EPI Creatinine Available online: www.ijipsr.com July Issue 13
Equation (2009).Developed in 2009 by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). Analysis of data was done using SPSS VERSION 20.00 statistical software. Data are expressed as the mean ± standard deviations. The differences in parameter (CRP, Serum creatinine ESR, WBC) levels before (baseline) and after (follow up) were analyzed with the unpaired t test. The significant levels were determined by P value. P values of <0.05 were considered statistically significant. RESULTS AND DISCUSSION Fig. 1: DISTRIBUTION OF PATIENTS BASED ON AGE GROUP In this study people of 61-70 age groups (48.3%) were found to be higher. Fig.2: DISTRIBUTION OF PATIENTS BASED ON GENDER In this study there is a higher incidence of chronic kidney disease in male population (80%) followed by female population (20%). Available online: www.ijipsr.com July Issue 14
Fig.3: DISTRIBUTION OF PATIENTS BASED ON SOCIAL HABITS In this study patients have social habits. Fig.4: DISTRIBUTION OF PATIENTS BASED ON ECONOMIC STATUS In this study population, test groups were high and medium economic status. Fig.5: DISTRIBUTION OF PATIENTS BASED ON OCCURRENCE OF INFECTIONS It was found that infections are less in test group than in control group Available online: www.ijipsr.com July Issue 15
Fig.6: COMPARISON OF CRP IN TEST AND CONTROL From the fig 6. It was found that mean serum CRP level of test (N- acetyl cysteine receiving group) is decreased more than control (N- acetyl cysteine not receiving group). At baseline there is no significance difference in the CRP value (P=0.133) but after follow up there is significance (P<0.001). Fig.7: COMPARISON OF SERUM CREATININE IN TEST AND CONTROL From the Fig 7 it was found that mean serum creatinine level of test (N-acetyl cysteine receiving group) is decreased more than control (N-acetyl cysteine not receiving group). At baseline there is no significance difference in the serum creatinine value (P=0.418) but after follow up there is significance (P<0.05). Fig.8: COMPARISON OF egfr IN TEST AND CONTROL Available online: www.ijipsr.com July Issue 16
From the Fig.8 it was found that mean egfr level of test (N-acetyl cysteine receiving group) is increased more than control (N-acetyl cysteine not receiving group). At baseline there is no significance difference in the egfr value (P=0.696) but after follow up there is significance (P<0.05). Fig.9: COMPARISON OF ESR IN TEST AND CONTROL From the Fig 9 it was found that mean ESR level of test (N- acetyl cysteine receiving group) is decreased more than control (N acetyl cysteine not receiving group). At baseline there is no significance difference in the ESR value (P=0.206) but after follow up there is significance (P<0.001). Fig.10: COMPARISON OF WBC VALUES IN TEST AND CONTROL From the Fig 10 it was found that mean WBC level of test (N- acetyl cysteine receiving group) is decreased more than control (N- acetyl cysteine not receiving group). At baseline there is no significance difference in the WBC value (P=0.812) but after follow up there is significance (P<0.001). CONCLUSION Chronic kidney disease (CKD) is fast emerging as a major public health problem in the 21st century. Kidney diseases are among the leading causes of death around the globe. Any malfunctioning of the kidney leads to the accumulation of waste materials and metabolites resulting in kidney failure. The CKD population is predisposed to adverse infectious events Available online: www.ijipsr.com July Issue 17
because of overwhelming uremia, which is associated with alterations in primary host defense mechanisms and increases the risk of bacterial infections. N-acetyl cysteine is a modified form of L-cysteine, an amino acid that is a precursor to reduced glutathione. It is known to be a potent antioxidant that scavenges oxygen-free radicals in the body. N-acetyl cysteine is considered a non- antibiotic drug that has anti-bacterial properties. The mechanism for the anti-bacterial effect of NAC may be that it acts by competitively inhibiting amino acid (cysteine) utilization or, by virtue of possessing a sulfhydral group, may react with bacterial cell proteins. N-acetyl cysteine is prescribed for chronic kidney disease patients as a supplement to prevent infections. Use of NAC may be a new strategy for the treatment of infections. From the study The Effect of N-acetyl cysteine Therapy in the Management of Infections on Patients with Chronic Kidney Disease it has been concluded that N-acetyl cysteine reduces the occurrence of infections. It has also been suggested that NAC significantly decreases the amount of CRP, Serum creatinine, ESR, WBC. NAC also improves Estimated Glomerular Filtration Rate (egfr); thereby it has a role in retarding the progression of CKD. ACKNOWLEDGEMENTS I would like to thank Dr. Manu G. Krishnan, Nephrologist, Pushpagiri Medical College Hospital, Tiruvalla for his immense support and guidance for the success of the thesis work and also all the members of Pushpagiri College of Pharmacy. REFERENCES 1. Harsh Mohan. Textbook of pathology ;( 6); 649-650. 2. Sakina B. Naqvi and Allan J. Collins. Infectious complications in chronic kidney disease. Advances in Chronic Kidney Disease, vol 13, No 3(July), 2006: 199-204. 3. Julius Goepp. The overlooked compound that saves lives. Life Extension Magazine May 2010/5/-n- acetyl cysteine. 4. http:// www.liver doctor.com/n-acetyl-cysteine-can-help-to-protect-your-liver-andkidneys/. 5. Stey C, Steurer J, Bachmann S, Medici TC,Tramer MR. The effect of oral N- acetyl cysteine in chronic bronchitis: a quantitative systematic review.eur Respir J. 2000;16(2):253-262. 6. Tiemei Zhao and Youning Liu. N acetyl cysteine inhibits biofilms produced by Pseudomonas aeruginosa.biomedcentral Microbiology 2010; 10:140. Available online: www.ijipsr.com July Issue 18