DIALYSIS MACHINE - DIALYSATE DELIVERY SYSTEM.

INVESTIGATION IN CKD & DIALYSIS

What are the important functions of kidneys?

1] Excretory functions:- Excretory of nitrogenous waste products of metabolism, drugs, and toxins.

2] Regulatory functions:- Maintenance of body composition, the kidney regulates volume, osmolarity, electrolyte content, and concentration. The acidity of fluids in the body.

3] Synthetic or endocrinal function:-

A] Production of erythropoietin, a 165-aminoacid protein produced by renal cortical interstitial cells stimulates the maturation of Erythrocytes in the bone marrow.

B] 1, 25, dihydroxy vitamin D3 the active form of Vit D3, is formed by proximal tubule cells. This steroid hormone plays an important role in the regulation of body calcium and phosphate balance.

C] Renin is the enzyme produced by the granular cells of the juxtaglomerular apparatus responsible for the production of angiotensin II which potent vasoconstrictor and growth factor contribute importantly to salt balance and blood pressure regulation.

What is the Aim of Investigation in Kidney diseases?

1] Is kidney disease present?

2] What is kidney disease?

3] What is the cause of kidney disease?

4] What is the degree of functional impairment?

5] Is functional impairment reversible or irreversible?

6] What is the rate of progression?

7] What are co-morbidities present?

What are Laboratory tests included in Dialysis patients?

1] Anemia profile:- Haemoglobin, Haematocrit RBC indices, T.WBC, D.C., Platelet & Iron studies,

2] Renal Biochemistry:- BUN, S.Creatinine, Measurement of GFR, Measurement of Residual renal function, Serum electrolytes- Na, K, Chloride, and bicarbonate, S.uric acid.

3]Test for CKD-Mineral Bone Disease:- Bone, Mineral disease, Serum calcium, phosphates, Parathyroid hormone (PTH) Vit. D level, Bone alkaline phosphatase.

4]Serological Test:- Hepatitis B, Surface antigen, Antibodies to Hepatitis C, Hepatitis Virus C RNS level, HIV antibodies by ELISA.

5] Nutrition & Lipids:- Serum albumin, Serum cholesterol, Serum triglycerides, HDL &, LDL, Cholesterol.

6] Other Biochemical Tests:- Blood glucose level, Total protein, Liver function tests- Serum Bilirubin, ALT, AST.

7] Tests to determine Adequacy of Dialysis:-

URR:- Urea Reduction Ratio, Kt/V & Solute removal index, Protein catabolic rate.

8] Urine- Routine

1] Anemia and Haematological profile:-

Anemia is a constant feature in a patient on hemodialysis. Almost 100% of the patient on dialysis have some degree of anaemia.

Definition of Anaemia:- Hb < 13.5 gm/dl in Male and <12gm/dl in female.

Evaluation:- A complete blood count including in addition to hemoglobin concentration, Red blood cell indices, Mean corpuscular volume (MCV), Mean corpuscular Haemoglobin (MCH), Mean corpuscular hemoglobin concentration (MCHC), White blood cell count, differential count, absolute retic count and serum ferritin to asses iron stores, Serum transferrin saturation (TSAT), or content of Hb in reticulocytes to assess the adequacy of iron for erythropoiesis.

TEST	NORMAL VALUE	TARGET VALUES IN DIALYSIS  PT	INTERPRETATION
Hb	12-17g/dl	11-12g/dl	Low Hb- anemia
Haematocrit	40-52 %	33-36 %	Assess the severity of anemia
MCV	30-100 fl	N	It helps to decide type of anaemia. Microcytic, macrocytic, normocytic
MCHC	32-36 %	N
MCH	27-31 pg	N
RETICULOCYTE COUNT	0-2%	N	Assess bone marrow response
S.IRON	65-170 ug/dl		Adequate iron store required for an adequate response to EPO therapy.
S.FERRITIN	27-377 /ng/ml	>200 ug/ml (non HD)	Required for adequate EPO response
TIBC	220-428	>100 ug/ml In HD pt.	Do
TRANSFERRIN SATURATION	20-50 %	>20 %	Do

2] Renal Profile:-

     Blood Urea Nitrogen:-

     . The end product of exogenous protein metabolism, synthesized in the Liver from ammonia.

     . Rate of production depends on protein intake.

     . As GFR decreases urea increases, Normal Bun 10-15 mg/dl.

     . Influenced by a number of factors, independent of GFR.

Ý BUN	ß BUN
. High protein diet. . G.I. Bleeding . Catabolic State -          Hemorrhage -          Trauma -          Corticosteroid -          Tetracycline	. Low protein diet . Liver disease . Pregnancy

          Blood urea is a surrogate marker for low Molecular weight toxins. Pre. And Post-dialysis Bun is estimated for the adequacy of dialysis.

Serum creatinine:-

-          Normal 0.6-1.2 mg/dl.

-          This is a convenient and inexpensive and most commonly used test to assess kidney function.

-          Generated from non-enzymatic metabolism of creatine in skeletal muscle. Production is proportional to muscle mass. 25% is derived from dietary meat.

-          Serum Creatinine varies inversely with GFR: decrease GFR – increase Sr. Creat.

-          Decrease Muscle mass – decrease creatinine production.

-          Serum creatinine level increases when more than 60% decrease in GFR.

-          Serum creatinine is a better marker of renal function than BUN.

-          Early functional impairment is mainly assessed by measurement of glomerular filtration rate (GFR).

GFR Measurement:-

  Ø  Serum creatinine is probably the most widely used indirect measure of GFR. For most patient serial plasma creatinine measurement a\can be used to monitor change in renal function (deterioration or improvement).

  Ø  Unfortunately serum creatinine is insensitive to even a substantial decline in GFR. The GFR measured by more accurate technique may be reduced by 50% before Scr. Becomes elevated. Failure to consider variation in creatinine production due to differences in muscle mass frequently leads to misinterpretation of serum creatinine levels. This confusion may be compounded by the use of standard “normal” ranges for serum creatinine level that appears on routine laboratory reports. For example, a serum creatinine that falls in the “Normal” range may indicate normal GFR in a young healthy individual. However same serum creatinine in an elderly individual could indicate a two-fold reduction in GFR owing to a comparable reduction in muscle mass. Therefore K/DOQI guidelines recommend that clinical laboratories report serum creatinine with an estimated GFR using a serum creatinine-based formula

The GFR is equal to the sum of the filtration rates in all of the functioning nephrons. GFR gives a rough measure of the number of functioning nephrons. GFR is surrogate for the amount of functioning renal tissue. The GFR is useful for detecting early renal functional impairment, monitoring, the progression of CKD, staging CKD, forecasting the need for RRT, and determining appropriate drug doing in renal impairment. It provides no information on the cause of renal insufficiency. GFR cannot be measured directly but could be estimated from urinary clearances of a marker. The GFR is most accurately determined by the measurement of a marker. Which is completely filtered by the glomerulus and neither reabsorbed,  secreted nor metabolized by the renal tubule. The sugar inulin is an ideal marker for such a study. Inulin was once considered the gold standard of exogenously administered markers of GFR, because inulin is not an endogenous marker, high cost, and scarcity is not practical in routine clinical settings.

     Determination of the clearances of endogenous creatinine is a more convenient, simple, cheap method to estimate GFR. Because roughly 10% of creatinine is excreted by the process of tubular secretion, the creatinine clearance will overestimate GFR. The creatinine clearance is calculated as C=UcrxV/Pcr

     Pcr is plasma creatinine in mg/dl, Ucr. Is urine creatinine in mg/dl and V is the volume of the urine excreted over a specific time interval in ml/min. Normal values ranges from 95-105ml/min/1.73sq.m. When normalized to body surface area. Females will have low GFR (85-100ml/min/1.73sq.m.) values than males because of less muscle mass. Indian studies have shown normal GFR values ranging from 60-90 ml/min/1.73sq.m. with mean value of 80 ml/min/1.73sq.m.

     The creatinine clearance is normally increased 30 to 50 percent over baseline values in pregnancy because if the increase in the renal plasma flow during gestation. Protein loading is also associated with an incremental rise in creatinine clearance in the basis of similar intrarenal hemodynamic changes and can be used as a measure of the functional reserve capacity of the kidney GFR tends to fall by around 0.5ml/year over the age of 30 years.

The limitation with creatinine clearance:-

     There are two major errors that can limit the accuracy of the creatinine clearance 1) An incomplete urine collection and 2) increasing creatinine secretion as GFR declines. The completeness of the collection can be estimated from knowledge of the normal rate of creatinine excretion. Adults under the age of 50, daily excretion should be 20-25mg/kg of lean body weight in men and 10-15mg/kg of lean body weight in women. As the GFR falls there is enhance creatinine excretion by tubules. This leads to a potentially large overestimation of GFR in CKD. As creatinine clearance overestimates GFR and urea clearance under-estimate GFR in CKD, the mean if urea and creatinine clearance approximate better with GFR. More accurate determination requires measurement of the other exogenous compounds such as iothalamate, iohexol, or DTPA. The method used is a single IV injection followed by venous sampling at regular intervals (increased interval as expected decreased GFR). GFR is calculated by plasma disappearances (clearance) of iohexol or iothalamate. Measurement of insulin or iothalamate, iohexol, and DTPA is not routinely available. Another alternative also not widely used clinically is to competitively inhibit creatinine secretion by the administration of Cimetidine which is secreted by the same pathway. However, there are inter and intrapatient variability in the effect of cimetidine blockade which can make results difficult to interpret.

Cystatin C –

     Cysteine protease inhibitor is produced by all nucleated cells It is easy to measure has a stable production rate, is freely filtered at the glomerulus, and is not influenced by age, gender, muscle mass, diet, or inflammation. This measure correlates well with GFR increase concentration in advance of Cr. As GFR fall. This test is not yet available in routine clinical practice. Beta2 microglobulin: Early increased in plasma levels occurs as GFR decrease susceptible to non-renal election (eGFR:- formulas based on creatinine:-

     The need to collect a urine sample remains a major limitation of the creatinine clearance technique. Therefore many attempts have been made to mathematically transform or correct serum creatinine so that it may more accurately reflect GFR. Recent guidelines emphasize the need to diagnose and monitor kidney function with an equation based on serum creatinine. Which attempt to correct for the confounding effect of body weight, age, gender, race, and muscle mass. Such equations are still based on Serum creatinine. And do not take into account tubular secretion, extra-renal elimination, or differences in production between individuals of the same age and gender or the same individual over time.

1] Cockcroft – Gault equation:-

     This allows the creatinine clearance to be estimated from serum creatinine in a patient with a stable creatinine. This is the most widely used formula.

(140-age) x lean body weight in kg

C Cr ml/min = --------------------------------------------

                        72x Cr.[ mg/dl ]

     This formula takes into account the creatinine production with increasing weight and the decline in creatinine production with age. For women, the formula requires multiplication by 0.85 to account for small muscle mass compared to men. The equation is not adjusted for body surface area, Normalization of body surface area increases the accuracy of this equation.

2] MDRD Study Equations:-

     Developed from data in the modification of diet in renal disease ( MDRD study ). Several equations were derived from data on adult patients enrolled in the MDRd study who had GFR measured of baseline using urinary clearance of iothalamate.

     The six variable equation was described in the original publication eGFR in ml/min per 1.73 m2= 170 x ( S.cr.mg/dl ) exp [ -0.999]x(age) exp [-176] (xBUn [mg/dl ]) exp [o.170]x(Alb[g/dl])exp[+0318]x(0.762) is female &x*(1.18 if black simplified version

rGFR = 186.3xScr.(exp[-1.154]) x (Age. Exp[-0.203]) x 0.742 female & 1.21 if black

     This formulas remain invalidated in children under the age of 18 years, the elderly, age>70 years, during pregnancy and ethnic group other than Caucasians and Africans, Americans, and without CKD. Several small studies have indicated some degree of inaccuracy in the use of the MDRD equation for the subject with normal renal function. Cockcroft Gault tends to overestimate & MDRD underestimates GFR. Therefore up to 25% of patients will be misclassified if either is used to categorized patients according to KDOQI CKD classification. Serum creatinine formulas to estimate GFR may not be reliable in vegetarians, patients with unusual muscle mass & individual consuming creatine. These formulas are not well validated in Indian patients yet. The formulas are available as web-based downloadable calculators form web sites.

3] tests to detect CKD-MBD (Chronic kidney disease- Mineral bone disease) Mineral & bone disease is constant features of chronic kidney disease stage 3-5 and dialysis. In CKD serum calcium is decreased & phosphates are increased.

CKD		Ca	PO4	PTH
Stage 3	Target	8.5-9.5mg/dl	2.7-4.6mg/dl	35-70pg/ml
	Frequency of evaluation	6monthly	6monthly	Every 6-12 month
Stage 4	Target	8.5-9.5mg/dl	2.7-4.7 mg/dl	70-110pg/ml
	Frequency of evaluation	Monthly	Monthly	6monthly
Stage5 & Dialysis pt	Target	8.5-9.5 mg/dl	3.5-5.5mg/dl	150-300pg/ml
	Frequency of evaluation	Monthly	Monthly	3monthly

     All patients should have alkaline phosphatase and Vit.D 25(OH) D. evaluation at diagnosis Raised alkaline phosphates, Suggest active bone disease,

Vitamin-D deficiency is common in all stages.

4] Serological Tests:-

     Haemodialysis patient and staff is a high risk for acquiring Hepatitis B, C viral, and HIV infection. All patients at the initiation of hemodialysis should be tested for hepatitis B surface antigen, HCV antibodies, and HIV antibodies. In a hemodialysis unit with a low prevalence of HCV initial testing with enzyme immune assays (EIA) should be done. If positive followed by nucleic acid testing should considered. Patients should be tested when they first start haemodialysis or they are transferred from another hemodialysis facility. All patients should be screened for HBV for every 3-6 monthly. HCV for every 6 months and HIV on starting dialysis with consent.

     All patients vaccinated for HBsAg should be tested for HBs Antibodies to detect the protective level of antibodies.

     
5) Malnutrition:is very common in CKD & dialysis patients. Mortality and morbidity are directly proportional to state of nutrition. Nutrition can be assessed by subjective global assessment score. Serum albumin level, protein catabolic rate, and serial weight measurement. Target S.albumin > 3.5-4.0 g/dl, S.bicarbonate> 22 and ideal body weight.

Dyslipidemia & cardiac risk factors evaluation:-

     CKD is a major risk factor for coronary artery heart disease. All adult abd adolescents with CKD should be evaluated for dyslipidemia. The assessment of dyslipidaemias should include a complete fasting lipid profile with total cholesterol, LDL, HDL, and triglycerides. patients with CKD stage 5 & dialysis should be evaluated upon presentation at 2-3 months after a change in treatment or other conditions know to cause dyslipidaemias and at least annually thereafter, H.D. patients should have lipid measure either before dialysis or on days not receiving dialysis. Targets for adults with CKD stage 5 and dialysis will be LDL < 100 mg/dl, fasting triglycerides <200 mg/dl and non- HDL cholesterol less than 130 mg/dl, patients on dialysis also should be evaluated for LP(a) and homocysteine level which are emerging risk factors for coronary artery heart disease.

Tests to determine the adequacy of Haemodialysis:-

     
6) Adequacy of dialysis: Once the patient is on regular dialysis, He should be evaluated & monitored for adequacy and complications. Every monthly patient should have complete renal profile haemogram, serum albumin, serum Ca, PO4 electrolytes. Pre-Post BUN & nutrition & quality of life evaluations.

Urea Reduction Ratio:-

     This is most simplified and widely utilized measure of dialysis described by lowrie. URR is the percent reduction in urea nitrogen over the course of single hemodialysis treatment.

URR (%) = 100 x 1-[BUN (post)/BUN(pre.)]

     Where the BUN pre and Bun post are blood samples obtained immediately before and after dialysis.

URR > 65% approximately corresponds to Kt/V of 1.2 considered as adequate:

Kt/V: Kt/V gives idea about fraction of urea removed from body. K-clearance of dialyzer t:time on dialysis and v=volume distribution of urea.

     Various equations have been described to calculate Kt/v: most commonly used & validated is Daugirdas formula

1)   Kt/v = In(R-008 x t) + (4-3.5xR)x0.55UF/V

Where R=is the ratio of the post dialysis to pre-dialysis Bun,

T= is the length of the dialysis session in hours,

UF= is the ultrafiltration volume in liters and

V= is the volume distribution of urea (55% of post-dialysis weight in kilogram). K/DOQI recommended Kt/v >1.2 (single pool) measured monthly as adequate dialysis.

          Never machines have an online measurement Bun & calculating directly Kt/v.

          Adequately dialyzed patients should have Kt/v >/= 1.2-1.3, URR=65%, Hb: 11-12gm/dl, Pre dialysis B.P. </= 140/90, S.Na=135-145mEq/L, K </=5.00 meq/L.

          S.Ca= 8.5-9.5 mg/d, Po4= 4-5.00 mg/dl

Euvolemia, working almost full time, good quality of life. Adequate dialysis. Prolongs life.

Assessment of adequacy of dialysis, nutritional status, bone mineral disorders, anemia and monitoring for infections all require frequent laboratory investigations. As a result of the differences in the test methodologies and the standardization and calibration of equipments, widespread inter laboratory variation is often observed. It is therefore necessary for a unit performing HD to have access to a laboratory with reliable and reproducible results and to establish a protocol of investigations. We recommend access to laboratories where the following test required for monitoring the management of patients on HD can be carried out.

Investigation recommended for patients on maintenance hemodialysis:

Monthly

Blood urea, Serum creatinine, sodium, potassium, Hemoglobin, Platelet count, TLC Every 3 months of Serum calcium, phosphate, alkaline phosphatase, albumin, uric acid, alkaline phosphatase, SGOT, SGPT Every 6-12 months iPTH, 25(OH) vitamin D, iron studies.

    1)   Once in 2 weeks if heparin-induced thrombocytopenia is suspected

    2)   Once a month If the patient is on calcitriol/doxercalciferol/paricalcitol. Weekly after starting cinacalcet until stable values reached

    3)   More frequently in malnourished patients who are being treated

    4)   More frequently when being treated for SHPT

    5)   Once a month if Hb target not achieved on EPO