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1.0 Introduction 1.1. Natural History of HIV infection.

Infection with the Human Immunodeficiency Virus type 1 (HIV-1) and type 2 (HIV-2) is the primary cause of the Acquired Immunodeficiency Syndromes (AIDS), with HIV-1 accounting for the majority of cases worldwide (1-4). The course of an infection with HIV may be divided into four distinct stages. The first phase is the incubation period, which is asymptomatic and may last 2-4 weeks. This is followed by the acute phase of infection lasting an average of 28 days characterized by high viral replication and high viral load, which may be accompanied by symptoms including lymphadenopathy, pharyngitis, skin rashes, myalgia and malaise(5). After the acute infection, there is a reduction in plasma viral load probably due to the production of Anti HIV specific antibodies and T-cells leading to the latency phase that lasts for several years (6;7). During this period there is gradual destruction of the immune system especially as a result of HIV infecting and destroying CD4+ cells including the T-helper cells. When the CD4+ cells follow below a critical number, immunity is greatly compromised leading to a wide array of infections and cancers characteristic of the last stage - AIDS. Although there are reports of survival for up to 25 years after seroconversion, the median survival is about 12 years but varies considerably between individuals and may be influenced among other things by race, geographical reasons, sex, virus type and age at seroconversion(8;9). 1.2 HIV and Organ Function A wide range of organ malfunction can be attributed to HIV infection, opportunistic infections and drug toxicities or a combination. Cases of multiple organ failure have also been reported even in the acute phase of HIV infection (10-12). The introduction of highly active antiretroviral therapy (HAART) has greatly improved the life expectancy of people living with HIV/AIDS (13;14). HAART however can cause serious metabolic disturbances such as insulin resistance, disturbances in lipid metabolism and glucose homeostasis. The metabolic disturbances result into clinical conditions e.g. metabolic syndrome, hyperlipidemia, lipodystrophy, cardiovascular disease and nephropathies further complicating the life of an HIV infected individual (15-19). 2.0 Renal Function. The kidney regulates water, electrolyte and acid-base balance and excretes drugs, toxins as well as products of protein and nucleic acid metabolism e.g. urea, creatinine, uric acid, sulphate and phosphate. The kidney also produces the hormones erythropoietin, Calcitriol (1,25 Dihydroxycholecalciferol), the active form of vitamin D and the enzyme Rennin(20). The nephron, a tube with one end closed and the other open, (fig 1) is the primary functional unit of the kidney and consists of the Glomerulus, the Bowmans capsule, proximal tubule, the loop of henle and the collecting duct. The closed end of the tube is pushed in to form a double walled chamber called the Bowmans capsule. The Bowmans capsule houses a network of capillaries called the glomerulus. Blood enterers the glomerulus trough the afferent arteriole (A in figure 1) under pressure forcing water, small molecules and ions to filter through into the Bowmans capsule as the nephric filtrate, blood then leaves through the efferent arteriole

(E in figure 1). The nephric filtrate collects with in the Bowmans capsule and flows into the proximal tubes where glucose, amino acids, uric acid and inorganic salts are reabsorbed by active transport while water follows by osmosis. The active transport of sodium in the proximal tubules is controlled by angiotensin II while the active transport of phosphate (PO43-) is controlled by the parathyroid hormone.

Figure 1:The nephron with minor modifications from (21).

E A

Although only approximately 20% of the nephritic filtrate reaches the loop of henle, reabsorption from and secretion into the filtrate continues through the distal tubules and the collecting ducts. The final reabsorption of sodium in the distal tubules is regulated chiefly by aldosterone and determines the final sodium and water balance and hence the blood pressure. Sodium reabsorption is associated with hydrogen excretion and reabsorption of chloride and bicarbonate so as to maintain electrostatic equilibrium. The antidiuretic hormone/ arginine vasopressin (ADH/AVP) produced by the posterior pituitary controls the reabsorption of water in the distal tubules and the collecting ducts. ADH is produced in response to increased osmotic pressure as occurs in dehydration and inhibited by reduced osmotic pressure as occurs after drinking large amounts of water. ADH binds V2 receptors present on cells of the distal tubules leading to increase water permeability due to insertion of aquaporin-2 channels. If the body needs more water, ADH is produced by the posterior pituitary leading to increased water reabsorption. The opposite is observed if blood is diluted. The rest of the filtrate is passed out as urine. The kidney therefore makes urine through three major processes i.e. filtering small molecules from blood, reclaiming/reabsorbing useful materials in the right amounts and excreting excess water, waste molecules and ions as urine.(20-23).

3.0 Renal Dysfunction.

Abnormalities in any of the kidney functions can lead to serious morbidities that can be fatal. For example, Erythropoietin (EPO) produced chiefly by the peritubular capillary endothelial cells of the kidney controls erythropoesis, controls the brains response to neural injury and is also involved in wound healing(24-28). Erythropoietin deficiency will therefore result in anemia as seen in chronic kidney disease, Diabetic Nephropathy and also leads to diminished wound healing (27;29;30). Calcitriol (1,25 Dihydroxycholecalciferol), the active form of vitamin D, is produced by the cells of the proximal tubule of the nephron. Calcitriol controls plasma levels of calcium and phosphorus by increasing absorption and reabsorption of calcium and phosphorous in the gut and renal tubules respectively. It therefore prevents hypocalcaemia there by promoting skeleton mineralization(31). Low plasma calcium and phosphate levels result in poor mineralization causing rickets and ostoemalacia in children and adults respectively(32). In addition to calcium and phosphorous homeostasis Vitamin D has endocrine functions... Rennin (Angiotensinogenase) secreted by the kidney from the granular cells of the juxtaglomerular apparatus catalyses the synthesis of angiotensin I by cleavage of the precursor angiotensinogen. Angiotensin I is converted to Angiotensin II a strong vasoconstrictor and angiotensin III by the angiotensin converting enzyme and aminopeptidase respectively. Angiotensin II &III bind receptors in the kidney stimulating the production of aldosterone. Aldosterone increases reabsorption of Na+, Cl and water accompanied by excretion of excretion of K+ and H+. This rennin-angiotensinaldosterone system (RAAS) therefore increases blood pressure through vasoconstriction and increased blood/plasma volume(20;33). Since the kidney acts in tandem with the heart to regulate several functions including blood pressure, dysfunction of one of the organs can cause dysfunction of the other. Cardiovascular disease is the leading cause of death in patients with end-stage renal disease(34). Despite the diverse functions of the kidney, kidney function is more often than not discussed in terms of glomerular and tubular function. 3.1 HIV and Renal Dysfunction. HIV infected individuals are at increased risk of developing renal complications resulting from several etiologies including HIV infecting renal cells, drug toxicities and disease progression and renal dysfunction increases the risk of death by 2.5 fold(35-41). HIV infected individuals may present with renal pathologies seen in none infected individuals as well as those exacerbated by side effects of some antiretroviral drugs e.g. diabetic and hypertensive nephropathy especially when drugs that cause glucose intolerance and vascular dysfunction are used which may lead to an increase in the incidence nephropathy from these conditions(42;43) acute tubular necrosis (ATN) has been associated with medications used as part of HAART or in the treatment of HIV/AIDS related opportunistic infections e.g. aminoglycoside antibiotics, pentamidine, acyclovir, foscarnet, amphotericin, tenofovir, adefovir, and cidofovir(44). Membranous nephropathy, focal segmental glomerulosclerosis, immune complex glomerulonephritis

and Fanconi syndrome are some of the other pathologies seen in HIV infected individuals that may not directly be attributed to HIV infection (45-51). On the other hand, some renal diseases e.g. HIV associated nephropathy, HIV immune complex disease are directly attributed to HIV infection(52-56) 4.0. Assessment of Renal Function Assessment of the state of renal function may be required for several reasons including establishment of renal impairment/damage, monitoring of disease progression and establishment of baseline measurements prior to starting administration of certain drugs e.g. Antiretroviral therapy. Generally speaking the prime function of the kidney is the regulation/maintenance of extracellular fluid composition and volume. It accomplishes these functions through glomerular filtration and tubular activity. It is the loss of this function that is commonly referred to as renal failure, which may be acute, characterized by rapid decline in renal function that returns to normal within three months or Chronic (CKD) that persists for more than 3 months(57). The excretion of soluble waste products such as Urea and Creatinine, foreign materials e.g. drugs and the maintenance extracellular fluid volume and composition through electrolyte, water, acid / base balance are accomplished through glomerular and tubular function. By determining how well the kidney performs each of these functions, the state of kidney function can be established. Since no single test can assess overall renal function, the choice of test to perform or analytes to measure will depend on the reason for assessing renal activity and may include the following. 4.1 Urinalysis. Physical, chemical and microscopic examination of urine can help identify substances associated with metabolic and/or kidney disorders. Such substances include: 4.1.1 Proteins greater than >20,000 Daltons are normally not filtered at the glomerulus. Low molecular weight proteins are filtered but reabsorbed. The presence of proteins in excess of 30mg/day is therefore a result of glomerular damage or failure of the tubules to adequately reabsorb normally filtered proteins and is the earliest marker of kidney damage (58-61). 4.1.2 Urinary Specific Gravity (USG) can be used to test the concentrating power of urine in states of relative dehydration. Normal USG is between 1.003 and 1.030. Lower values are associated with diuretic use, diabetes insipidus, adrenal insufficiency, aldosteronism and impaired renal function while higher values are associated with glycosuria, and the syndrome of inappropriate antidiuretic hormone(58;62). 4.1.3 Urinary PH can be affected by several factors including diet with proteins and acidic fruits causing acid urine while high citrate diets cause alkaline urine(63-65). Usually urine is acid but the PH can be anywhere between 4.5 and 8. The kidney

normally acidifies urine by balancing the secretion of H+ and the reabsorption of biocarbonate. The failure to acidify urine results in accumulation acid in the body a condition known as Renal Tubular Acidosis (RTA)(66;67). The acid load test is used to diagnose RTA due to diminished H+. It involves administration of ammonium chloride and measuring urinary PH in urine specimens over 8hours (20;68;69). The determination of urinary PH is also used in the diagnosis and management of urinary tract infections and calculi. 4.1.4 Glucose is completely reabsorbed in the renal tubules and does not appear in urine unless the blood glucose levels exceed the renal threshold. The presence of glucose in urine is termed as glycosuria. Renal glycosuria is an abnormality in which glucose is excreted in urine despite normal blood levels due tubular dysfunction. Disturbances in glucose metabolism as occurs in diabetes mellitus, Cushings syndrome, liver and pancreatic disease or conditions that cause reduced tubular reabsorption e.g. Fanconis syndrome lead to glycosuria(20). Several other substances including blood, ketones, nitrites, leukocyte esterase, bilirubin and urobilinogen may be chemically tested for in urine to aid diagnosis and/or monitoring of various metabolic conditions and Urinary Tract Infection. The microscopic examination of urine for casts, cells, crystals, and bacteria is performed to further aid diagnosis of urological, metabolic and/or UTI conditions. 4.2 Biochemical Markers of Renal Function. Measuring endogenous substances in blood such as creatinine (Cr) formed from the metabolism of creatine in skeletal muscle and urea a waste product of protein metabolism that are primarily excreted by the kidneys has been traditionally used to evaluate renal function (70). 4.2.1 Serum creatinine concentration. The concentration of creatinine in plasma of a health individual is fairly constant. Since excretion is mainly renal, increased serum creatinine levels therefore may indicate decreased excretion by the kidney i.e. renal failure. Although serum creatinine concentrations are generally considered a better maker of renal function, creatinine levels are also influenced by body mass, age, gender, race, intake and metabolism (71;72). Creatinine is freely filtered by the glomerulus and under normal urinary flow shows minimal or no reabsorption. It is however secreted by the tubules and an increase in serum creatinine leads to increased tubular secretion and hence over estimation of GFR. Because of this serum creatinine levels may not raise until the glomerular filtration rate (GFR) has moderately reduced making it an insensitive marker of small decreases in GFR characteristic of initial stages of CKD due to the so-called creatinine blind GFR area (40-70ml/min/1.73m2)(71;73;74).

The reaction between picric acid and creatinine in an alkaline medium i.e. the Jaff reaction is the most widely used method for the quantitative determination of creatinine in body fluids(75). The reaction is not specific as many other substances present in serum/plasma including glucose, ketones, pyruvate as well as creatinine homologs and derivatives interfere with this reaction (76;77). Attempts to improve the specificity of the Jaff reaction have been made through several approaches including specific adsorption, extraction of interfering substances, dialysis, measurement at different PH levels and using kinetic measurements(75;78-81). Enzymatic methods for the determination of creatinine improve specificity and have been shown to give more accurate results provided optimum conditions are met. Enzyme combinations and combinations of enzymes with the Jaff reaction have been used with some protocols adapted on automated analyzers making current methods more specific, and less laborious and practical for routine use (82;83).

4.2.2 Serum urea concentration. Urea is formed in the liver by the reactions of the Krebs urea cycle and is excreted by the kidneys. Other factors remaining constant, increased serum urea levels can therefore indicate decreased excretion i.e. renal failure. Compared to creatinine, serum urea is a less reliable marker of kidney function as serum levels are influenced by many none kidney factors. High protein diet, increased tissue breakdown, major gastrointestinal hemorrhage, stress and corticsteroid therapy can lead to increased serum urea. Up to 70% of the Urea is passively reabsorbed with water depending on the persons state of hydration with more urea being reabsorbed in states of dehydration and therefore high levels may be observed in dehydrated patients with normal renal function. Low serum urea levels may not necessarily denote normal renal function as they may be due low protein diet, liver disease, poor tubular reabsorption or pregnancy. 4.2.3 Serum electrolytes. Electrolytes help in the assessment of the tubular function of the kidney. The most commonly used electrolytes are Sodium (Na+), Potassium (K+), Chloride (Cl-) and Bicarbonate (HCO3-). 4.3 Estimation of Glomerular Filtration rates (GFR)

4.3. Cystatin C as a maker of renal Function.

4.3 Estimation of Glomerular Filtration rates (GFR) using Prediction Formulas.

Because of the difficulties associated with the use of exogenous substances in the estimation of GFR and the pitfalls of using serum creatinine, the search for a better endogenous marker continues. Cystatin C a 13kDa protease inhibitor belonging to the cystatin superfamily is a promising molecule. Cystatin C is encoded by housekeeping gene and is produced by all nucleated cells[44] . It is freely filtered at the glomerulus and not secreted by the tubules. Unlike creatinine it is not affected by gender, age and muscle mass[45, 46]. Several studies have demonstrated that cystatin c is superior to creatinine and urea [47-49]. a recent report has however indicated that Cystatin C is inferior to creatinine based methods and supports the use of the MDRD formula in HIV infected individuals but suggests validation in larger studies before generalisation[50] . There is limited data regarding the use of Cystatin C concentration, GFR estimates based on cystatin C and those based on creatinine in HIV infected individuals.

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