decrements in GFR largely correlates to the deterioration and other - - PowerPoint PPT Presentation

• is a physiological property determine function of

all single nephrons taken together

• decrements in GFR largely correlates to the

deterioration and other kidney function including hormonal production and metabolic function

• Diet and time of the day of the measurement can

affect GFR, thus an average GFR over the period of time may be the most accurate assessment of GFR

• There is no easy to directly measure the number of

nephrons and single nephron GFR

• GFR is measured INDIRECTLY of exogenous

and endogenous markers

• In clinical practice, GFR is most often

estimated from serum level of endogenous filtration markers.

• Serum creatinine is the most widely available

marker for GFR estimation of clinical practice

• It is not a perfect filtration marker as it is

actively secreted by renal tubules, and also affected by factors such as age, sex, diet supplements, and extreme of muscle mass or medications.

• The second most common marker used to

estimate GFR

• Produced by all nucleated cells at near constant

rate

• Filtered by the glomerulus with total tubular

reabsorption and metabolism

• Used for eGFR and NOT to measure GFR
• Compared with creatinine, serum Cystatin C of

thought to be less affected by age, sex, muscle mass, and dietary changes

• Certified reference material for Cystatin C were

distributed in 2010. However significant variation still exist

• Developed in 1976 and incorporates age, sex, lean

body weight along with serum creatinine concentration for estimated creatinine clearance

• Historically been used for drug labeling and for dose

adjustment with impaired kidney disease

• Lean body weight can be difficult to estimate in an
• bese individual
• Several studies have reported over-estimation of

kidney function using the question in obese individuals

• This equation probably require normalization for body

surface area to improve accuracy

• Intended to improve Cockcroft-Gault and

MDRD study accretions especially in person with normal or near normal GFR

• Use 4 variables: Age, sex, race, serum

creatinine

• Remains dependent on serum creatinine

concentration thus accuracy may be limited in population with extreme of muscle mass and in those with unusual diet

• CKD EPI collaboration developed

recommendation incorporating both serum creatinine and Cystatin C and appears to be more accurate than either marker alone and as precise as in iothalamate measured GFR

• The combined equation is likely the most

accurate noninvasive assessment of kidney function available in the routine use

• Albumin excretion greater than 30 mg/day is generally thought to reflect pathologic

alteration of the glomerular filtration barrier

• Directly measuring urine albumin than protein is a more sensitive and precise

method for detecting changes in the glomerular permeability

• URINARY DIPSTICK
• Semi quantitative approach
• URINE ALBUMIN CREATININE RATIO
• Normalizing to urinary creatinine can negate the effect of concentrated urine
• The central assumption of normalization is that urinary creatinine excretion is

fairly stable over 24 hours roughly 1 g/day and therefore changes in the spot urine albumin creatinine ratio or affect changes in urinary albumin excretion

• URINE ALBUMIN EXCRETION
• 24 hours urine collection
• Considered the gold standard of albuminuria measurement due to the

circadian rhythm of urine albumin excretion

• Spot urine done for ease of testing

Distribution of GFR for using multiple equation

eGFRTrajectory

• Avoid predicting trajectory of kidney disease progression

based only on the most recent value of EGFR

• Emphasis on the need for constant readjustment of EGFR

trajectory is based on the totality of data from a given patient

• Extrapolation of EGFR trajectory might require more than 2

EGFR measurement beyond 1 year interval to allow better end-stage kidney disease risk prediction

• A graded association exists between EGFR decline and
• mortality. Moderate EGFR decline versus severe. With

significant association with increased risk of congestive heart failure, acute myocardial infarction and stroke.

• Causal mechanisms underlying the association

between EGFR decline and increased risk of mortality and cardiovascular disease.

• Worsening of kidney function could be a

marker of subclinical atherosclerosis, endothelial dysfunction, or oxidative stress.

• Activation for angiotensin system.
• Blood pressure dysregulation.
• Higher level of uremic toxin.
• Disorder of bone and mineral metabolism and

chronic inflammation.

• Growing evidence indicates a positive slope.

increasing or improving EGFR trajectory is associated significantly and independently with high risk of various adverse clinical outcomes such as mortality and end-stage kidney disease.

• It has been shown most clearly for individuals with urinary

albumin excretion greater than 300 mg/g creatinine.

• In individuals with high level of proteinuria, RAS blockade

slow decrease of GFR and progression to end-stage kidney disease by about 16% - 56%

• Benefits of RAS blockade in individuals with proteinuria has

been shown for diabetic kidney disease, hypertensive kidney disease, and a glomerular disease.

• -The data in favor of RAS blockade are less strong for

individuals with lower level of albuminuria 30-300 mg/g creatinine especially for individual without diabetes

• Aldosterone has been linked to the progression of renal kidney disease

through stimulation of cell proliferation and hypertrophy resulting in fibrosis and inflammation

• Several studies with CKD have shown that aldosterone blockade

added to the standard therapy further reduce albuminuria

• Treatment with MRA is often limited by the occurrence of hyperkalemia
• Phase 3 study of Finerenone is ongoing and will evaluate the effect of

this medication and the progression of kidney disease and cardiovascular event.

• At least one trial will complete September 29, 2019.
• Despite the improvement of proteinuria, they have not become a

routine part of clinical practice because there is not enough data on

• utcomes such as mortality, end-stage kidney disease, and safety in

point.

• Joint National committee 8 recommends blood pressure goal less than

140/90 patient with CKD

• KDIGO recommends blood pressure less than 140/90 without albuminuria,

blood pressure less than 130/80 with albuminuria greater than 30 mg/g creatinine

• MDRD: No overall relationship between blood pressure and rate decrease

in GFR. However individuals with more than 1 g/day proteinuria had slower rate of GFR decreased with lower blood pressure.

• AASK no significant difference in the decrease GFR with lower blood

pressure overall however there was a benefit of low blood pressure in individual of proteinuria

• Ramipril efficacy and nephropathy 2 trial showed no difference between

conventional and lower blood pressure group.

• -Intensive therapy to reduce the risk of proteinuria and progression of early

vascular and neurology complication among patient with type 1 diabetes for 15 years, these result are persistent 7-8 years after the end of the DCCT trial

• Follow-up analysis of the DCCT trial showed a long-term benefit of intensive

glucose control on eGFR loss but the benefit was not seen until after 10 years of follow-up.

• Newly diagnosed type 2 diabetes, tight control showed 25% reduction in risk
• f microvascular endpoint.
• The positive effect of the intensive therapy and urine albuminuria and

doubling serum creatinine were evident only after 9-12 years and 12 years

• f follow-up respectively

• Decrease in risk of albuminuria with intensive glucose
• control. However, intensive glycemic control was associated with a

higher incidence of hypoglycemia event and increase cardiovascular mortality in the ACCORD trial

• No benefit was shown on loss of eGFR in advanced type 2 diabetes
• Therefore, will need to consider life expectancy, associated

comorbidities, and time course of kidney disease as a beneficial effect

• f tight glycemic control and progression of renal disease are not seen

for many years and risk of hypoglycemia and CKD is higher.

• Acidosis had been implicated in the progression of renal failure,
• Retrospective analysis showed about 54% increased risk of renal disease

progression and patient with bicarbonate level of 22 or less compared with normal

• Small experimental studies have shown that correction of acidosis and CKD

slow the progression of chronic kidney disease

• Daily sodium bicarbonate supplementation significantly reduced rate of EGFR

decrease.

• To answer the question regarding the optimal dose of bicarbonate, The

bicarbonate administration to stabilize estimated GFR rate study is evaluating the safety and tolerability of high and low dose of bicarbonate supplementation in individuals with CKD and sodium bicarb level of 20-28.

• Endothelin is a peptide synthesized by endothelial cell that act as a potent
• vasoconstrictor. It has pro-fibrotic effect
• Avosentin studies show decrease in proteinuria by 40-50% however the study

was stopped early due to high rate of cardiovascular events, mainly congestive heart failure and volume overload associated with treatment

• Atrasentan is a more selective endothelin receptor has been shown in phase 2

studies to decrease urine albumin excretion in diabetic nephropathy treated with RAS blockade.

• Ongoing study SONAR is evaluating the effect of this agent compared with

placebo on time to doubling of serum creatinine level and the onset of end- stage kidney disease in subjects with type 2 diabetes and nephropathy and maximum RAS blockade.

• In the empagliflozin trial The composite microvascular

endpoint occurred in fewer patients in the empagliflozin group (14 versus 20.5 percent).

• In the canagliflozin trial progression of albuminuria (a secondary

endpoint) occurred less frequently in the canagliflozin group (89.4 versus 128.7 participants per 1000 patient-years in the placebo group, HR 0.73, 95% CI 0.67-0.79)

• GLP-1 receptor agonist liraglutide reduced the incidence of a

composite renal endpoint (consisting of new onset of albuminuria >300 mg/day, doubling of serum creatinine, end-stage renal disease, or renal death) in a large trial of patients with type 2 diabetes . The effect was predominantly due to a reduction in new-

• nset albuminuria

• Diabetes is characterized by increased oxidative chemical

modification of tissue proteins

• PYRIDOXAMINE inhibits a formation of the AGE products limiting

the increased chemical modification of tissue proteins and associated pathology and aging and chronic diseases including diabetes and atherosclerosis.

• Phase 2 studies have looked into the safety and tolerability

PYRIDOXAMINE for 6 months and diabetic patient with overt

• nephropathy. Positive outcome was found
• Unfortunately, multicenter double blinded placebo controlled trial was

recently stopped due to financial reasons

• One pathway that can be selectively

targeted by drugs is the system of small GTPase proteins of the Rho family. Activation of RhoA in podocytes induces FSGS with disruption of the actin cytoskeleton

• Other promising targets with protective

effects on the podocyte actin cytoskeleton, and for which therapeutic agents are already available, include blockade of the tumor necrosis factor alpha pathway and stimulation of the calcium-sensing receptor

Nintedanib, a triple tyrosine kinase inhibitor, attenuates renal fibrosis in chronic kidney disease

• Bardoxolone

• Increases blood flow to the microcirculation
• Has antifibrotic, antiproliferative, and anti-inflammatory effect
• It does decrease albuminuria in diabetic patient irrespective of RAS

blockade

• Open label trial as an add-on therapy to RAS blockade suggested benefit
• The renal protective blood pentoxifylline and angiotensin receptor blockade

in the chronic kidney disease study will be multicenter randomized double blinded placebo controlled clinical trial will investigate the renal protective effect of combined PFT and valsartan compared with placebo and valsartan and diabetic and nondiabetic patient with stage III and IV kidney disease.