Indian J Nephrol 2005;15, Supplement 1: S1-S6

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Guidelines for the Management of CKD

Guidelines 1 and 2
Chronic Kidney is a new name for what was in the past known as Chronic Renal Failure. By redefining this entity, the National Renal Societies of western countries have achieved the following objectives: 1 . Chronic Kidney disease has been defined and classified into 5 stages according to severity. This helps to make accurate epidemiological estimates of the incidence and prevalence of CKD and its stages, particularly in its early stages and also identifies the populations at risk of developing CKD. The complications associated with each stage of CKD have been identified. The clinical, laboratory and imaging parameters used to define these stages have been standardized so that the staging of disease is unambiguous. The interventions recommended for the risk factors associated with progression of renal disease and the associated cardiovascular morbidity and mortality are standardized so that they can be uniformly applied and critically evaluated for the claims they are credited with. This ensures uniform care of every CKD patient. 5 . In view of the shortage of qualified nephrologists, the general physicians and less qualified doctors are also practicing nephrology and they need to be informed about good practice guidelines. The insurance companies, TPAs and medical care providers, are emerging as a large body who have a say in the management of nephrology patients. They need to know and use standard practice guidelines. The acceptability of the living donor for kidney transplantation on the basis of renal function tests, particularly GFR estimation by creatinine clearance is often questioned because Indian patients appear to have much lower values of GFR in the face of normal renal function. These guidelines would help to define normalcy in the Indian population. With increase in medico legal litigation in India, the standard guidelines would help nephrologists to defend their appropriate actions taken in the interest of their patients. However these guidelines would not put the practicing nephrologists at risk if they are not adhered to, because they serve as guidance and are not mandatory or binding. Many recommendations made in western guidelines are not possible to implement in Indian circumstances due to lack of facilities, infrastructure and resources.

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The two best and well known CKD best practice guidelines are (1) the KDOQI of the NKF USA and the (2) 2002 recommendations of the ERA/EDTA. CKD in India differs from CKD in developed nations in the following ways. 1 . The incidence and prevalence of CKD is not accurately known due to lack of epidemiological studies. Lack of financial resources, laboratory facilities and qualified personnel makes it difficult to practice with same degree of depth of investigation in the Indian scenario. Laboratory parameters of normal renal function are not well defined in the Indian population and may differ from the western data. This is particularly true of markers which are derived from the protein content of the diet and the quantum of muscle mass such as urea and creatinine. The Indian spectrum of renal diseases is clearly different from that seen else where.

Any guidelines must necessarily

1 ) Emerge from the deliberation of the national society and be produced as a consensus.

2) Be along the lines of existing worldwide guidelines 3) Be suitably modified according to Indian research and publications 4 ) Unfortunately the evidence available at present is not always of the highest level and yet it is meaningful. These limitations therefore need to be acknowledged even as recommendations are made on the basis of this evidence.

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The goals of the CKD work group would be as follows:

i . i . Definition of CKD and staging. Defining normalcy of renal function in India.

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i. Enumerate guidelines for management at each i i stage of CKD and for each systemic
Copyright 2005 by The Indian Society of Nephrology

S 2 Indian Journal of Nephrology derangement due to CKD. i. GCP recommendations when RRT should be v initiated and when AV fistula or CAPD catheter should be put. v . Recommendation for immunization schedules for CKD patients.

Indian J Nephrol 2005;15, Supplement 1: S1-S6

A major drawback is the identification of CKD due to tubulointerstitial diseases and vascular renal diseases (such as ischemic nephropathy) is that the usual markers of CKD i.e low GFR, urinary, blood and imaging abnormalities are not sensitive and many patients with CKD due to these diseases cannot be identified at early stages.

v. Recommendations for measures to prevent i progression of established CKD from lesser to more severe stage. a )

The classification has 3 unique grey areas that deserve special attention.
Patients with low GFR between 60ml and 90ml without HBP, markers of kidney damage in urinary, blood or imaging tests. A large number of normal Indians are likely to fall in this category because of their small physical build and low protein intake due to predominant vegetarianism. Every physician who has evaluated normal renal donors for kidney living donor donation will bear out the statement that in India, the normal population has lower GFR than normal western counterparts. The normal values in K-DOQI guidelines for CKD have been formulated for the US populations. Protein intake in the developed nations has been found to be 50% more than in developing countries as India (105 g/day compared to 57.3 g/day)2. Furthermore, in those vegetarians who ingest no animal products such as milk and eggs, the average protein intake is 20-40% less than in lacto-ovovegetarians3.Studies have demonstrated that there is an acute and a delayed increase of GFR with a protein load4. The GFR, renal plasma flow and splanchnic blood flow increase within 1 hr after a meat meal and remains elevated for several hours. Habitually increased protein intake causes structural and hemodynamic alterations leading to renal hyperemia and hyperfiltration in conjunction with diuresis and natriuresis5. There are studies to confirm that vegetarianism results in a low GFR which can be stimulated by ingestion of a large protein meal. An infusion of aminoacids mimics a large protein

Defining CKD
Chronic Kidney Disease is identified when the following c i e i a ef l i l d . rtra r ufle1 Duration: 3 months or more Kidney damage is either functional or structural with or without reduction in GFR as identified by any one or all o t r ec i e i . f he rtra 1 . 2 . 3 . Abnormal gross or microscopic pathology. Laboratory markers of kidney damage in blood, Urine, Imaging tests GFR less than 60ml/min/1.73m in the absence of any other renal abnormality

This definition propounded by the KDOQI guidelines is now almost universally adopted and in the absence of any significantly data emerging from our country, it needs to be adopted unchanged for the present. With the adoption of this definition in the USA there has been a dramatic realization of the large number of persons suffering from CKD and the immense effect CKD will have on the health care budget of the nation, if CKD continues to progress relentlessly. It has made the public health authorities sit up and plan strategies to prevent the morbid outcomes. The adoption of this definition followed by epidemiological studies should help to identify the extent of the health care problem posed by CKD in India.

Copyright 2005 by The Indian Society of Nephrology

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Guidelines for the Management of CKD

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meal and the resultant increase in GFR has been called the Renal reserve which may be as high as 80-100% of the base line value6. Other causes of chronically decreased GFR without kidney damage in adults include vegetarian diets unilateral nephrectomy, extra cellular fluid volume depletion and systemic illness associated with decreased kidney perfusion such as heart failure and cirrhosis. Thus, in clinical practice, it is difficult to determine whether the individual with decreased GFR has chronic kidney disease. In this subset of patients, the presence of other markers for kidney diseases such as urinary abnormalities (hematuria, proteinuria, and pyuria) and hypertension help to differentiate the CKD patient from the non-CKD. b ) Patients with HBP and normal GFR without urinary, blood and imaging abnormalities of renal disease do not fall into the subgroup of CKD stage I; but should definitely be treated as a subgroup that needs close follow up for future development of CKD. These individuals would be considered at- risk for development of CKD. The other such patients requiring close follow up are : STAGE 0 CKD (patients at high risk of developing CKD) Patients above 65 Those with family history of renal disease Diabetics Autoimmune diseases Systemic infections 0Urinary tract infections Urinary stones Lower urinary tract obstruction Drugs including NSAID abuses c ) Individuals with HBP and GFR values between 90 and 60 ml / mt, although technically still not CKD in the absence of urinary, blood and imaging abnormalities, are commonly those with essential hypertension above 65 years of age and would often have other target organ damage such as retinal changes, LVH and remodeling on echocardiography and history of cerebrovascular accidents. These patients deserve the same management as stage I CKD. 7 . 6 . 2 . 3 .

Urinary , blood and imaging abnormalities Blood pressure GFR

The patient must be assigned a stage for adequate management (I-V). In order to give specific treatment every possible investigation should be done to determine the etiopathological cause of CKD. Inspite of investigations a significant number of patients of CKD will be left without a confirmed etiopathological diagnosis due to limitations of the investigating techniques and their applicabilities. Over and above the specific interventions, there are certain interventions applicable to all cases of CKD irrespective of their etiology and pathology. There are appropriate interventions suggested for each stage of CKD. These interventions are aimed at Reducing the rate of progression to stage V. Reducing the incidence of complications associated with each stage and in particular reducing the incidence of cardiovascular morbidity and mortality. CKD in India is different from CKD in the world in the west and there is a need for Indian epidemiological studies. Until such time that Indian epidemiological studies are developed, an attempt should be made to adopt western data in modified form.

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Estimation of GFR
The level of GFR is a strong predictor of the time to onset of ESRD as well as the risk of CKD. GFR cannot be measured directly the amount of a physiological, freely filterable and non-secreted or metabolized solute, such as inulin, in the urine is an indirect marker of the amount filtered at the glomerulus. The most widely used measures of GFR are based on the 24 hrs creatinine clearance or serum creatinine concentration.

Laboratory evaluation of GFR

1 . Insulin clearance (gold standard) This is the gold standard but very difficult to carry out in clinical practice. Blood urea / Blood urea nitrogen : Historically one of the earliest methods developed, it clearly does not have a linear relationship with GFR because a ) Urea is not exclusively excreted only by goeua flrto. lmrlr itain

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Guideline I
1 . The patient assigned a diagnosis of CKD should conform to the definition and fulfill the criteria of Duration > 3 months

Copyright 2005 by The Indian Society of Nephrology

S 4 Indian Journal of Nephrology b ) Urea levels are influenced by dietary protein intake, GI bleeds, volume depletion, steroid intake, liver disease and hypercatabolic states Few symptoms of CKD have correlation with urea levels.These recommendations, however, do not suggest that blood urea is not a useful test only that it has little value as a marker of CKD. The test has many applications in other renal situations such as ARF, Kidney transplantation, MHD and adequacy of dialysis but that is beyond the perview of this study.

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The usual method of estimating GFR in clinical practice is by collection of the 24 hour urinary sample with estimation of its creatinine content and using the formula ; creatinine clearance = uv/p, with correction for body surface area of 1.73sq.mts. The major drawbacks of this method are a ) Inaccurate collection 1 Samples are thrown away ) 2 Timing is wrong ) 3 Urine passed with faeces is lost ) 4 Most patients do not understand the collection ) process as also many of the laboratory or ward staff designated to do this b ) c ) It is laborious, obnoxious due to smell, messy and time consuming. It has been shown that the prediction equations described hereafter are equally accurate and much easier to use in clinical practice.

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Serum creatinine and creatinine clearance Creatinine is mainly derived from the metabolism of creatinine in muscle, and its generation is proportional to the total muscle mass. Creatinine generation is higher in men, younger individuals and in blacks than in whites. Meat intake, low protein diets difference in S. creatinine according to age, gender and race exist. Moreover, the traditional method of serum creatinine estimation (alkaline picrate method) also detects non-creatinine chromogens compared to modern autoanalysers (were such interference is not seen) leading to lab-variations in serum creatinine and overestimation of GFR when measured by the latter method. Substances like ketones and bilirubin may lead to spuriously elevated and decreased creatinine respectively. The amount of creatinine excreted in the urine is a composite of both the filtered and the secreted creatinine. Creatinine clearance overestimates GFR by 10-40% in normal individuals, and is greater and more unpredictable in patients with CKD. As much as 2/3 of total daily creatinine excretion can occur by extra-renal creatinine elimination in patients with severely reduced kidney functions. The normal level of GFR varies according to age, gender and body size. After age 20-30 yrs, the GFR declines at the rate of 1ml/mt/1.73m2/year. Thus by age 70, it is approximately 70ml/mt/1.73m2. The variability of creatinine excretion with protein intake, muscle mass and sex have been dealt with earlier.That the GFR varies with race has not been studied extensively in populations of the developing countries although certain ethnic groups like Hispanic and non-Hispanic blacks have higher creatinine excretions than other populations7. Similar studies for the Indian populations have not yet been conducted, but keeping in mind the lower creatinine production (due to a lower body mass index coupled with a lower dietary protein intake in Indians), a comparatively lower creatinine excretion can be expected. Whether ethnic origins and genetic makeup contributes to this difference remains to be evaluated.

Estimating the creatinine clearance from prediction equations

Equations used to predict GFR in Adults Based on Serum Creatinine\Equation Cockcroft-Gault Equation Cr.cl (ml/min) = (140-Age) x Weight x (0.85 if female) 72 x S. Cr _________________________________________________ ________________________________________________ MDRD, Serum Variables GFR (ml/min/1.73m2) = 170 x (S.Cr.)-.999 x (Age)0.176 x (SUN)-0.170 x (Alb) +0.318 x (0.762 if female) x (1.180 if black) Equations used to predict GFR in Children Based on Serum Creatinine Equation _________________________________________________ ________________________________________________ Schwartz Formula Cr.cl. (ml/min) = 0.55xLength S.Cr _________________________________________________ ________________________________________________ Counahan-Barratt Equation GFR (ml/min/1.73 m2 ) = 0.43xLength S.Cr

a. Cockcroft Gault equation

While the C-G equation provides an easy and readily available estimate of the creatinine clearance, its major drawback is that it does not take into account body size.

Copyright 2005 by The Indian Society of Nephrology

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The accuracy of the C-G equation has been validated in several studies, which indicated that the majority of estimated GFRs were within 30% of the measured GFR, accuracy considered sufficient for good clinical decision making8. Some studies have standardized the results for body surface area, while others have suggested using lean body mass (rather than total weight, especially for obese individuals) or ideal body wt calculated by the Hamwi method9, as follows; Females: 44 kg for the first 150 cms of height and 0.9 kg for every cm beyond 150cm. Males: 46.7 kg for the first 150 cms of height and 0.9 kg for every cm beyond 150cm. Other drawbacks of the CG include 1 . Use of s.creatinine to estimate GFR relies on the individual being in steady state and the ability to estimate the average rate of productions of creatinine. Using prediction equation to estimate the degree of kidney damage is not very accurate at the higher range of GFR as in CKD stage 1-2. Early glomerular injury may lead to compensatory hypertrophy and hyperfiltration in less affected nephrons, thereby maintaining or increasing GFR .Additionally, with a mild decrease in kidney function, only a slight increase in the serum creatinine may be seen because of an increase in tubular secretion. Measurement of progression of kidney disease is substantially more difficult than diagnosis of the presence of kidney disease since the progression of many forms of kidney disease is slow. The C-G allows for reliable detections of substantial progression (>2550%) but may not satisfactorily differentiate the fall in GFR in those with slowly progressive kidney disease

The timed collection technique should be reserved for usage in the following situations: 1 . Estimation of GFR in individuals with exceptional dietary intake (veg-diet, creatine supplements) or muscle mass (amputation, malnutrition, muscle wasting and extremes of ages). Rapidly changing kidney function. Assessment of diet and nutritional status. Prior to using drugs that one excreted by the kidney and with significant toxicity. To confirm the need to start dialysis when patients are unable to accept this eventuality. For research purposes.

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Nuclear methods to measure GFR

When precise measurements of GFR are necessary, or when muscle mass may deviate substantially from values predicted by age, race, sex in adults or height in children, clearance measures using exogenous filtration markers may be necessary. Nuclear methods to measure the GFR in such situations provides an easy and reliable atraie lentv. The radiolabelled compounds used for such measurement include I-125 iothalamate, Tc -99 diethylenetriamine pentaacetic acid etc. I-125 iothalamate, the most reliable among the available compounds, can be used as a subcutaneous injection which is followed by slow release to the circulation providing stable plasma and urine concentration for some hours. Its half life is 60 days and can safely be stored. Its efficacy in measuring GFR has been reported to be comparable to inulin clearance in adults and children. The advantages of using radiolabelled compounds for GFR assessment include Measurement of the compound at even very low concentrations using conventional counters is very precise. Very small, non toxic amounts are given. The disadvantages include its high cost and need for supportive infrastructure.

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b. MDRD equation
The MDRD study equation has the advantage of having been derived based on 10: a . b . c . d . GFR measured directly by urinary clearance of I125- Iothalamate. A large sample of greater than 500 individuals with a wide range of kidney diseases was done. Inclusion of different ethnic groups in the study It has been validated in a large separate group of individuals as part of its development.

This equation provides estimates of GFR standardized for the body surface area. The calculations, however, needs web based and downloadable medical calculators which makes it difficult to implement on a day to day basis for most physicians and nephrologists practicing i Ida n ni.

In Indian circumstances, the utilization of these tests on regular basis is difficult because of lack of nuclear medicine laboratories performing these tests on regular basis with reliable reproducibility, and most Indian practitioners therefore avoid their usage.

Guideline 2 GFR estimation

1 . 2 . Blood urea / BUN is a poor estimate of GFR. S. creatinine should not be used alone as an
Copyright 2005 by The Indian Society of Nephrology

S 6 Indian Journal of Nephrology estimation of renal function and extent of renal damage. Creatinine clearance by timed urine collections or prediction equations provide additional information in defining and staging CKD. 3 . Every laboratory should supply estimated GFR by prediction equations using one of the two available adult or child formulae derived from serum creatinine. This would adjust for age, sex and body mass index. Timed urinary collections of creatinine clearance may be reserved for the specific circumstances outlined in the text. 5 .

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Nuclear methods of GFR estimation are to be used as confirmatory tests in confusing circumstances if the lab used inspires confidence. Low GFRs in otherwise normal individuals, commonly seen in normal Indians are due to predominantly vegetarian diet and low protein intake. The GFR of such persons can be stimulated to increase to values in the normal ranges by infusion of amino acids followed by timed collections. This may help establish normalcy in the individual once the tests have been standardized.

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References
1. 2. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification Young. V R, Pellett PL: Protein intake and requirements with reference to diet and health. Am J Clin Nutr 1987: 45: 1323 1343. Taber LAL, Cook RA: Dietary and anthropometric assessment of adult omnivores, fish-eaters and lactoovo-vegetarians. J Am Diet Assoc 1980: 76:21-29. Bosch JP, Lauer A, Glabman S: Short term protein loading in assessment of patients with renal disease. Am J Med 1984: 77: 873 879. Jones MG, Lee K, Swaminathan R: The effect of dietary protein on glomerular filtration rate in normal subjects. Clin Nephrol 1987: 27: 71- 75 6. Bosch JP, Saccaggi A , Lauer A, Ronco C, Belledonne M, Glabman S: Renal functional reserve in humans. Effect of protein intake on glomerular filtration rate. Am J Med 1983: 75: 943-950. 7. James GD, Sealy JE, Alderman M, Ljungman S, Laragh JH: A Longitudinal study of urinary creatinine and creatinine clearance in normal subjects: Race, sex and age differences. Am J Hypertens 1988; 1: 124- 131 8. Levey AS: Use of measurements of GFR to assess the progression of renal disease. Semin Nephrol 1989; 9: 370- 379. 9. Gurney JM, Jelliffe DB. Anthropometry in nutritional assessment: Am j Clin Nutr 1998: 26: 913: 435-452. 10. Klahr S : The modification of diet in renal disease study. N Eng J Med. 1989: 320, 864-866.

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