CREATININE CLEARNCE RATE ( CCR ) IN DIGNOSING DIFFERENT STAGES OF CHRONIC KIDNEY DISEASE ( CKD )-AN UPDATE AND REVIEW

Chronic Kidney Disease refers to an irreversible deterioration in renal function, which classically develops over a period of months to years. Serum creatinine concentration is a reliable guide to renal function, as it is produced from muscle at a constant rate and almost completely filtered in the glomerulus.1 But, serum creatinine does not rise above the normal range until there is a reduction of 50% 60% in glomerular filtration rate (GFR). So, a normal serum creatinine is not synonymous with a normal glomerular filtration rate. Measurement of the GFR is necessary to define the exact level of renal function.2


Introduction
Chronic Kidney Disease refers to an irreversible deterioration in renal function, which classically develops over a period of months to years.Serum creatinine concentration is a reliable guide to renal function, as it is produced from muscle at a constant rate and almost completely filtered in the glomerulus. 1 But, serum creatinine does not rise above the normal range until there is a reduction of 50% -60% in glomerular filtration rate (GFR).So, a normal serum creatinine is not synonymous with a normal glomerular filtration rate.Measurement of the GFR is necessary to define the exact level of renal function. 2 clinical practice, the clearance rate of endogenous creatinine, the creatinine clearance rate (CCR), is the usual means of estimating GFR 3 .Creatinine Clearance Rate is relatively simple to measure can be estimated by assessing urine and serum creatinine concentration.Typically 24 hours urine is used for the study.Since, urine collection may be difficult, creatinine clearance rate can be estimated from the formula of Cockcroft and Gault, which incorporate age, sex and weight to estimate creatinine clearance rate from plasma creatinine level without any urinary measurement. 5 can be used to estimate the glomerular filtration rate in a patient with chronic kidney disease (CKD).It can be measured once a year in person with stable renal function to detect any deterioration over time. 6Some times, in early stages, chronic kidney disease cannot be detected confidently by the measurement of serum creatinine concentration alone.In these situations, measurement of creatinine clearance rate would be helpful.on either side of the aorta and inferior vena cava.Each kidney contains 1 million functional units, or 'nephrons'.These consists of glomerulus's (where filtration of plasma occurs), proximal convoluted tubule, loop of Henle and distal convoluted tubule (where selective reabsorption of fluid and solutes from the filtrate occurs), and the collecting duct.The collecting ducts of multiple nephrons drain into the renal pelvis and ureter.There is a rich blood supply (20% -25% of cardiac output).Intralobular branches of the renal artery give rise to the glomerular afferent arterioles which supply the capillaries within the glomerulus.The efferent arteriole, leading from the glomerulus, supplies the distal nephron and medulla in a 'portal' circulation.

Glomeruli 7
The glomerulus contains three main cell types: endothelial cells lining the glomerular capillaries, epithelial cells and mesangial cells.Mesangial cells lie in the central region of the glomerulus.They have similarities to vascular smooth muscle cells.(eg.contractility), but also some macrophage-like properties.Filtration occurs across the glomerular basement membrane (GBM), produced by fusion of the basement membranes of epithelial & endothelial cells.The glomerular capillary endothelial cells contain pores (fenestrae) which allow access of circulating molecules to the underlying GBM.On the outside of the GBM, glomerular epithelial cells (Podocytes) put out multiple long foot processes which interdigitate with those of adjacent epithelial cells.As well as maintaining the filtration barrier, podocytes are involved in the regulation of filtration and of GBM turnover.
The filtration barrier at the glomerulus is normally almost absolute to proteins the size of albumin (67KDa) or larger, while proteins of 20KDa or smaller are able to filter freely.Between these sizes the ability of individual molecules to cross the GBM is influenced by their shape and charge.Anionic proteins are relatively less freely filtered than cationic proteins.Little lipid is filtered.
Filtration pressure at the GBM is controlled by afferent and efferent arteriolar tone.Auto regulation maintains a constant glomerular filtration rate (GFR) by altering this arteriolar tone over a wide range of systemic blood pressure and renal perfusion pressure.In response to a reduction in perfusion pressure, angiotensin-II mediates constriction of the efferent arteriole, which restores filtration pressure.
Functions of the kidneys: 7 In health, the volume and composition of the body fluids are tightly regulated and the kidneys are largely responsible.This achieved by making large volume of an ultra-filtrate of plasma (120 ml/min, 170 liters/ day) at the glomerulus, and selectively reabsorbing components of this ultra-filtrate at points along the nephron.The rates of filtration are under the control of many hormonal and haemodynamic signals.
Some metabolites either are not reabsorbed from the filtrate, or are actively secreted into it.The kidney is primarily responsible for excretion of many metabolic breakdown products (including ammonia, urea and creatinine from protein, and uric acid from nucleinc acids), drugs and toxins.In addition, the kidney has a number of hormonal functions.Three of these are particularly important: release of erythropoietin in response to hypoxia, vitamin D metabolism, secretion of renin.
Before going to the main discussion we would like to highlight some points about Chronic Kidney Disease.

Chronic kidney disease Definition and stages:
National kidney foundation defines chronic kidney disease (CKD) as either kidney damage or a decreased glomerular filtration rate of< 60 ml/min / 1.73m 2 for 3 or more months.Whatever the underlying aetiology, it is that the destruction of renal tissue or a progressive decline in GFR within determines the progression of CKD.Stage 02 : Kidney damage with (GFR= 60-89 ml/ min.)slightly low GFR.
The K /DOQI definition and the classification of CKD allow better communication and intervention at the different stages.

Frequency of CKD :-
Internationally -the incidence rates of end stage renal disease (ESRD) have increased steadily since 1989.The United States has the highest incidence rate of ESRD followed by Japan.Which has the highest prevalence per million population, with the United States taking second place. 8 the United States: The US Renal Data System has shown a dramatic increase in patients with CKD who require chronic dialysis or transplantation.In 1999 there were 340,000 such patients, but, 2010, this number is projected to reach 651,000. 9CKD, particularly at the stage requiring renal replacement therapy, is already a major burden to health care resources, and this will only worsen in time. Because

Pathophysiology of CKD :-
Each nephron contributes to the total GFR.Regardless of the aetiology of renal injury, with progressive destruction of nephrons the kidney has an innate ability to maintain GFR by hyperfiltration and compensatory hypertrophy of the remaining healthy nephrons.This nephron adaptabiliy allows for continued normal clearance of plasma solutes such that, substances such as urea & creatinine start to show significant increaser in plasma level only after total GFR has decreased to 50% , when the renal reserve has been exhausted.The plasma creatinine value will be double with a 50% reduction of GFR.A rise in plasma creatinine from a base line value of 0.6 mg /dl to 1.2 mg /dl in a patient, although still within the reference range, actually represents a loss of 50% of functional nephron mass.
Since, uraemic syndrome resembles asystemic intoxication, the search for a putative uraemic toxin has been the subject of intensive investigation.As yet, however, no single compound has been found to produce the clinical picture of uraemia.Therefore, it is more likely that multiple factors confribute to the pathogenesis of this syndrome.e.g.

A.
Retained metabolic Product:-Many chemical compounds have been suspected to be responsible for the uremia syndrome, e.g.Acetone, amino acid, amines, creatinine, â2 microglobulin.

B. Over production of counter regulatory hormones:-
Overproduction of parathyroid hormone (PTH) in response to hypocalcaemia and natriuretic hormone in responde to volume overload could contribute to many aspects of the uraemic state.

C. Under Production of renal hormones:-
Decreased erythropoietin production causes anemia.Decreased 1α-hydroxylation of vit D3 contributes to bone disease.Clearly, these and other such deficiencies could play a role in the uraemic state.
Diagnosis: 14 The first step is to determine whether the renal failure is acute, chronic or acute superimposed on chromic.Progression to CKD is common when the serum creatinine concentration is >1.5 to 2 mg / dl.This may occur even if the underlying disorder is not active.Obtaining a precise diagnosis becomes increasingly difficult as the patient approaches end stage renal disease.The definitive diagnostic tool is renal biopsy, but it is not recommended when ultrasonography indicates that the kidneys are small and fibrotic.

Investigations done in chronic Kidney disease:
The Therefore, a creatinine clearance must be calculated simply by Cockcoroft & Gault formula in elderly people so that, patient in different stages of chronic kidney disease can be detected more confidently than that would be suggested by the serum creatinine alone. 12 Prior to February 2002, no uniform Classification of the stages of CKD existed.At that time, K/DOQI published a classification of the stages of CKD as follows:-Stage 01 : Kidney damage with normal (GFR > 90 ml /min.) or high GFR.
Moreover, after 30 years of age, progressive physiological glomerulosclerosis occurs, with GFR and creatinine clearance falling linearly at a rate of appropriately 8 ml/min/1.73m 2 /year from a maximal GFR 140ml/min/1.73m 2 .Aging also results in concomitant progressive physiological decrease in muscle mass such that daily urinary creatinine concentration also decreases.This combination of factors result in constant serum creatinine values over time in a given individual; despite a decrease in creatinine clearance (and GFR).Therefore, a serum creatinine value of 0.8 mg/dl in a 70kg, 25 years old man versus one who is in 80 years old represents a creatinine clearance of 140ml/min and 73ml/min respectively.What can appear as only mild renal impairment in an 80 yr old 70 kg man with a pathologically elevated serum creatinine of 2.0 mg/ dl; actually represents severe renal impairment when the creatinine clearance is calculated to be 29 ml/ min.