Adverse Drug Reaction and Kidney

Adverse Drug Reaction (ADR) is defined as any unintended and undesired effect of a duly prescribed drug which occurs at a dose used in humans for prophylactic, therapeutic or diagnostic purposes. All drugs taken externally or internally produce some undesirable effects along with their beneficial effects. Adverse events that occur as a result of drug use may range from local reaction, respiratory distress, renal lesions/damage or liver function impairment to serious life threatening condition. The liver and kidney are the organs which bear the brunt of majority of adverse drug reactions (ADRs) as these are associated with the drug metabolism and clearing from the body. The nature of the beneficial effects of a drug is predictable, but the nature of adverse reaction could be predictable to some extent otherwise unpredictable. The term drug here means any substance or product used to modify or explore physiological system and pathological states for the benefit of the patient/recipient. The health products considered to be drugs include vaccines, food supplements, blood and blood products, herbals, traditional or complementary medicines, pace maker devices and implants. Mismatched blood would cause transfusion reaction with life threatening implications. Blood products like platelet rich plasma (PRP) which is normally infused in patients suffering from Dengue virus infection may lead to the development of antibodies against human leukocyte antigens (HLAs) as platelets carry Major Histocompatibilty Complex, class-I (MHC class-I) antigens i.e. HLA-A, HLA-B, & HLA-C antigens at their surface and these antibodies may lead to lyses of platelets and thrombocytopenia (decreased platelet count) at a later stage.

Regulatory approval to market drug is usually based on the results of controlled clinical trials, as such, these short term studies in a specific population may not be sufficient to explore the ill effects of a particular drug. The ADR monitoring begins with the earliest administration of a drug to man and continues throughout, as long as a drug is on prescription list of clinicians.

Long term surveillance studies are also being undertaken to evaluate effectiveness and safety of a drug in various subpopulations such as, children, elderly patients and patients with associated ailments like impaired liver function, kidney disease and diabetes. In order to highlight the ADR events, the pharmacovigilance is important. The ADR events include the events due to non-compliance, drug interactions with co-administered drugs and drug over dosages and adverse effect of the drug per se. As per the data available to-date, about 6% of Emergency visits are related to ADRs and about 0.1% of these could be life threatening.

Can We Prevent Adverse Drug Reactions: Yes, a lot of these ADRs are preventable, most probably those resulting from mere ignorance of route of administration or non-compliance. There are ADR cases wherein patients have swallowed the tablets prescribed for intra vaginal infection.

How and Whom to Report ADR: Independent reporting can be undertaken by any one who is prescribing a drug, administering a drug or consuming a duly prescribed drug. This type of reporting is called Voluntary Reporting or Spontaneous Reporting. One should be ready with the following information while reporting ADR: Patient"s short name, age, sex, height, weight, trade name of drug, manufacturer, date of manufacture, date of expiry, mode of administration, type of reaction, duration of administration, route of use, date of reaction, date of recovery and associated medication etc. Adverse Drug Reaction should be reported to the Pharmacovigilance Center. There are National, Zonal, Regional and Peripheral Pharmacovigilance Centers in all the countries. The matter can also be reported to the Drug Controller General of the Country or reported directly to the United States FDA. For reporting the ADR or adverse events to International Regulatory Authority like US FDA one can use online reporting facility at the  website http://www.fda.gov/medwatch/ .  Go to the FDA-Medwatch website and visit the link-Medical Product Reporting for reporting adverse drug reaction or adverse events.

Pulse and Pulse Pressure

Pulse and pulse pressure are two wonderful parameters of circulatory system in association with cardiac cycle. Anybody and everybody can feel pulse, but there are very few who could recognize pulse and diagnose ailments in the light of pulse characteristics. Arterial pulse is a wave of increased pressure which is felt in the arteries when blood is pumped out by the heart. It may conveniently be felt at a point where an artery lies superficially over a bone. The most common is the radial artery at the front of the wrist. Pulse may also be felt at the temporal artery over the temporal bone or the dorsalis pedis artery at the bend of ankle. Pulse is the pressure transmitted from the aorta which travels faster than the blood. The pulse rate is directly associated with the cardiac cycle. The pumping rate of the heart varies in a normal person with reference to age and emotional state. Pulse rate may also vary in a person in relation to activity of the body like walking, running, sleeping or after taking food. If the pulse count is 72 per minute, the cardiac cycle would have occurred 72 times per minute.

The Cardiac Cycle: The pumping events which take place in the heart during handling of blood for the circulation to various organs and tissues of the body, are called cardiac cycle. As we know, the action of heart is controlled by sino-atrial-node (S.A.) and is described in two parts, systole or contraction and diastole or relaxation. Contraction of atria (upper chambers of heart) is called atrial systole and their relaxation is called atrial diastole. It is worth mentioning here that the left and right atria contract or relax simultaneously. The contraction and relaxation of ventricles (lower chambers of heart) is called ventricular systole and ventricular diastole respectively. It is pertinent to add that the ventricular contraction lasts 0.3 seconds and the relaxation phase is about 0.5 seconds. The only time, the cardiac muscle gets rest is during the periods of ventricular diastole. The heart keeps on beating continuously the day and night during the life.

Normal Pulse Rate in Relation to Age or Stage of Life

Stage of Life	Pulse: Beats/minute
New Born	135-140
During the first year of life	115-120
During the second year of life	105-110
At the age of 5 to 10 years	95-100
At the age of 11 to 18 years	80-90
Adults	60-80

Blood Pressure and Pulse Pressure: Arterial Blood Pressure is the force of pressure, which the blood exerts against the walls of blood vessels during circulation. The blood pressure varies during thecardiac cycle. The cardiac cycle has been discussed above. The blood pressure recorded as upper or systolic blood pressure and lower or diastolic blood pressure. During the ventricular systole, when the left ventricle forces the blood into the aorta, the pressure rises to a peak and is called systolic blood pressure. During the diastole the pressure falls and the lowest value it reaches is called diastolic blood pressure. The range of systolic blood pressure in an adult is 105 to 130 mm Hg (millimeters of Mercury) and the range of diastolic blood pressure is 60 to 80 mm Hg. As the age advances the range of systolic blood pressure increases as 130 to 150 mm Hg and diastolic blood pressure ranging from 80 to 90 mm Hg is considered normal. In women the blood pressure is 5 to 10 mm Hg less than in men. The difference in systolic anddiastolic blood pressure is called the pulse pressure and normally it should be around 30 to 50 mm Hg.

Renal Function in Infants

We know that the main function of kidneys is their ability to produce the glomerular filtrate and thereby concentrating the urine by way of absorption of water from the glomerular filtrate. The ability to concentrate urine is not well developed in infants. Indeed the ability to concentrate urine is partially developed after three months of life and fully developed renal function is acquired by the end of first year of life. The lack of concentrating urine is because the kidneys are not adapted to the action of antidiuretic hormone (ADH) of pituitary gland. The kidneys gradually start responding to the ADH and acquire full ability within one year. If the infants are not given sufficient fluids during the first five days of life they are sure to loose 10% of their body weight. Adults with well developed renal function are capable of conserving fluid by reabsorption. The lack of concentrating power in the kidneys of infants is probably due to imperfect development of loop of Henle. In infants the tubular function is lower than the glomerular filtration rate (GFR). The reabsorption of water in infants is 70% to 80% less than the adults. An infant, therefore, has a narrow margin of defense against the factors which decrease body fluids. The renalfunction in infants is helpless to regulate water balance when water is lost by any reason like fever, vomiting or diarrhea and leads to clinical implications. Infants need special care during fever, vomiting or diarrhea to offset any dehydration.

Renal Transplantation & BK Virus Nephropathy in Allograft Recipients

Renal transplantation is the ultimate surgical treatment to save the life of a patient with irreversible renal failure. As we do blood grouping and cross matching before blood transfusion likewise we have to do tissue typing and cross matching to check the histocompatibility between the kidney donor and kidney recipient (the patient). Like the blood group antigens the other genetic system is 'human leukocyte antigens' (HLA) system controlling the histocompatibility. The success of the organ transplantation is related mainly to these two genetic systems as the immune response of an individual is controlled by the genes linked to the major histocompatibility complex (MHC). Renal transplantation is generally carried out after testing the histocompatibility even then there are chances of rejection of transplanted kidney as the immune system of the recipient recognizes it as foreign material. To avoid the transplant rejection the allograft recipient is put on immunosuppressive therapy. The survival and adaptation of transplanted kidney could only be achieved through non-nephrotoxic immunosuppression. The adverse effect of immunosuppression is that it promotes viral infections. BK virus nephritis (BKN) in recipients of renal allograft has been on the rise. Despite increased incidence, therapeutic options remain limited and progression of disease often leads to allograft failure (transplanted kidney failure). BK virus (BKV) replication in kidney transplant recipients may progress from asymptomatic viruria (viruses in urine) to progressive allograft dysfunction leading to allograft failure. BK virus infection may also lead to systemic infection and bladder cancer. The diagnosis of BKN could be achieved on the histology examination of the allograft biopsy by specific immunohistochemical (IHC) staining for BKV. The clinical and functional parameters often correlate with the duration and histological progression (stage) of nephropathy. Over or intense immunosuppression leads to complications. In the absence of specificantiviral therapy, the treatment of choice is to reduce the dose of maintenance immunosuppressive therapy. Non-nephrotoxic immunosuppressive drugs are the need of the hour for effective immunosuppression and renal allograft survival.

Tags: allograft failure, allograft recipient, antiviral therapy, histocompatibility, immunosuppressive therapy, kidney donor, kidney recipient, non-nephrotoxic immunosuppression, transplant rejection

Internal Environment & Renal Physiology

Internal Environment: The body is made up of organs and tissues each composed of cells and fibers that constitute their histology. Water with its solvents needed for the health of the cells is termed as body fluid and this fluid is partly inside and partly outside the cells. Water constitutes about 70 per cent of fat free body weight. Water is the fabric of everything that lives. The body of a baby contains mostly water, whilst the old man or woman shrivels up like a wilted plant. We are completely immersed in water during the first nine months of life in the mother's womb. Water is involved in the health, disease and death. Loss of water leads to dehydration and may cause death if not corrected. Retention of water leads to edema and may cause death if remedial action is not taken. For each cell in the body the same conditions prevail as for the single-celled creatures fixed on the bed of a flowing stream which brings their food and oxygen and carries away their waste material. In our body water or the body fluid is controlled in the two major compartments: (1) intracellular compartment for intracellular fluid (2) extracellular compartment for extracellular fluid. The extracellular fluid is of two subtype (1) interstitial fluid (2) blood plasma. Intracellular fluid makes up about 40 to 50 per cent of the body weight and bulk of it being contained in muscles. Extracellular fluid represents about 20 per cent of the body weight, of which 15 per cent is interstitial fluid including lymph and 5 per cent constitute the blood plasma. The interstitial fluid constitutes the real internal environment. It is the adjustable segment in the total water content of the body. Its volume and solutes are regulated by the kidneys, lungs, endocrine glands, and are influenced by sweat glands and gastrointestinal tract. The blood plasma is in equilibrium with the interstitial fluid. Both the vascular and intracellular compartments contain a lot of protein. The normal intake of water in an adult is about 2500 ml. About 2100-2200 ml of this is taken by mouth as food and pure water and rest is the endogenous water from cellular oxidation. Renal Physiology: The word renal pertains to kidney in medical terminology. Water regulation in our body is achieved by water loss through four routes: (1) intestine (2) lungs (3) skin and (4) kidneys. Kidneys play a major role in water regulation as these excrete 50 to 70 per cent of excess water. Major functions of kidneys are: (a) excretion/elimination of excess water from body (b) excretion/elimination of waste products of metabolism e.g. urea and creatinine (c) excretion/elimination of foreign substances such as drugs (d) retention of substances necessary for normal body functions (major substances are proteins, amino acids and glucose) (e) regulation of electrolyte balance and osmotic pressure of the body fluids. Sodium ions, potassium ions, bicarbonate ions and chloride ions are major electrolytes. Urea is the main product of protein metabolism in the body. Removal of amino groups from amino-acids, from which urea is formed, takes place in the liver. Urine urea estimations are most commonly carried out as part of renal efficiency tests. A high concentration of urea in the urine shows that the kidneys possess a good concentrating power. However, in cases where there is increased blood urea due to non-renal or pre-renal factors, urine urea may be quite high. On an average concentration of urea in urine should be 2.0 per cent over the day. The total urea excretion in an adult is about 30 grams daily. At least 1500 ml of water must be excreted by kidneys daily to carry the solids which have to be eliminated. There is a pair of kidneys in our body to accomplish the above task. The kidney is the organ concerned with the regulation of the volume and composition of body fluids. Each kidney contains over 1000,000 functional units called nephrons. Each nephron consists of (a) glomerulus with its afferent and efferent arteriole (b) proximal convoluted tubule (c) loop of Henle (d) distal convoluted tubule and (e) collecting tubule. The structure of the glomerulus is that of a filtration mechanism. The afferent arteriole divides into 3 or 4 branches, which gives the lobulated appearance to the glomerular tuft. Each branch gives rise to 40 to 50 capillary loops, which probably do not anastomose with one another. The diameter of efferent arteriole is only half of that of afferent arteriole and the efferent arteriole splits up into a huge network of capillaries containing blood that is highly viscous by reason of the preceding loss of water. The viscous blood moves slowly, so raises the pressure in the glomerular tuft and thus facilitate filtration. The glomerular tuft consists of four main components: (i) the endothelium lining the capillaries (ii) the basement membrane which separates the endothelium from (iii) the epithelium and (iv) the mesangium. Mechanism of Renal Function: Every minute about 1000 ml of blood containing about 500 ml of plasma flows through the glomeruli of kidneys and about 100 ml of it is filtered out as raw-urine called glomerular filtrate. The plasma containing all the salts, glucose and other small substances is filtered in the glomerular filtrate. The cells and plasma proteins are too big to pass through the pores of the filter and stay behind in the blood stream. The glomerular filtrate then passes through the real tubules and 85% of it is absorbed automatically by the proximal tubules, where essential substances are reabsorbed. The fate of remaining 15% depends upon the degree of further reabsorption of water in the distal tubules. The reabsorption is controlled by antidiuretic hormone (ADH) released from the posterior pituitary gland (an endocrine gland). Loss of ADH results in defective reabsorption of water in the distal tubules and causes diabetes insipidus. An increase in the electrolyte osmotic pressure (osmolality) of the extracellular fluids results in an increased release of ADH with an increased water reabsorption in distal tubules. Conversely any decrease in the osmolality will lead to opposite effect. This complex controlling mechanism is termed as neurohypophysial-renal axis. Just as the electrolytic osmotic pressure of the extracellular fluid is controlled by the ADH, the volume of that fluid is controlled by aldosterone from the adrenal gland. The ADH regulates the retention or excretion of water and the aldosterone regulates the reabsorption of sodium and thus the retention of water. Thus the secretion of urine is accomplished in three steps: (a) glomerular filtration. (b) tubular reabsorption and (c) tubular secretion. By comparing the amount filtered by the glomeruli per day with the amount usually excreted in the urine we can see how selective is renal function? Daily about 150 liters of water is filtered and about 1500 ml is excreted; about 750 grams of salts are filtered and 15 grams are excreted; about 150 grams of glucose are filtered and no amount is excreted and about 50 grams of urea are filtered and about 30 grams excreted.

Human Anatomy & Physiology: Introduction

Anatomy: The study of the structure of the human body and the relationship of its constituent parts to each other or one or the other is called general anatomy. In regional anatomy, a geographical study is made and each region e.g. arms, legs, head, ears, eyes. nose, trunk, genitalia etc., is being studied in terms of its components. Different regions of human body do have some common structures such as bones muscles, nerves and blood vessels. An anatomical region performing a particular function is called a system. There are a variety of systems in human body. The systematic study of these systems is called the systematic anatomy. The functional relationship of different parts or organs of the body is called the functional anatomy. The anatomical features of our body which could be appreciated by naked eye are covered under the macroscopic anatomy and the finer structures which could be revealed with the help of a microscope are termed as microscopic anatomy. Closely allied to the anatomy are histology and cytology, the study of tissues and cells respectively. Human body is studied from the erect position with the arms by the sides and the palms of the hands facing forwards, the head erect and eyes looking straight in front. This is the universal description of anatomical position. Various parts of the body are described in relation to certain imaginary lines or planes. The median plane runs through the center of the body. Any structure which lies nearer to the median plane of the body is said to be medial to the other. For example the inner side of the thigh is described as the medial aspect and the outer as the lateral aspect. The terms internal and external are used to describe the relative distance of an organ or structure from the center of a cavity. The ribs for example have an internal and external surface. The terms superficial and deep are used to denote relative distance from the surface of the body. The terms superior and inferior are used to denote the positions relatively high or low in relation to trunk and the terms proximal and distal are employed to describe nearness to or distance from a given point particularly in relation to limbs. For example the proximal phalanges are nearer to the wrist and the distal ones are the farthest away. When three structures are running from the medial plane of the body outwards, they are described as being placed in medial, intermediate and lateral position. The terms anterior and posterior are synonymous with ventral and dorsal. These terms are only adapted to man in the erect attitude or anatomical position. For example the anterior and posterior tibial arteries lie in front and back in the leg. In describing hand the terms palmar and dorsal are used instead of anterior and posterior and in describing foot the terms plantar and dorsal are employed. Many parts of the body are symmetrically arranged. For example left and right limbs are similar. The eyes, ears lungs and kidneys too are left and right and symmetrically arranged. There is also a good deal of asymmetry in the arrangement of the body. The spleen lies entirely on the left side; the pancreas lies partly on each side and the larger part of the liver lies on the right side. Physiology: It is the study of the internal functions of the normal human body and closely linked to the study of internal functions of all the living creatures in the subject of biology. The body is made up of many tissues and organs each having its own particular function to perform. The cell is the smallest unit of the body of which all the body parts are comprised. The cells and/or organs are adapted to perform the special functions in a system. The cells of the nervous system and muscle are very specialized. Other cells such as those in the connective tissue are not so highly developed as compared to muscle and nerve cells. Bioenergetic pathways, cellular interactions and their biochemical products such as enzymes and hormones are at the core of the physiology.