Approach and Management

of CKD
dr.bouni
Outlines of the presentation

• Definition
• Epidemiology
• Approach to CKD
Definition and classification of CKD

• DEFINITION OF CKD
• CKD is defined as abnormalities of kidney structure or function, present for >3 months, with
implications for health.
 STAGING OF CKD
• CKD is classified based on cause, GFR category, and albuminuria category (CGA).
(1B)
Evaluation of chronicity
• Proof of chronicity (duration of >3 months) can be established by:
• review of past measurements/estimations of GFR;
• review of past measurements of albuminuria or proteinuria and urine
microscopic examinations;
• imaging findings such as reduced kidney size and reduction in cortical
thickness;
• kidney pathological findings such as fibrosis and atrophy;
• medical history, especially conditions known to cause or contribute to CKD;
• repeat measurements within and beyond the 3 month point.
 CKD as a Public Health Issue
• 30 million American affected
• Prevalence is 11-13% of adult population in the US
• 28% of Medicare budget in 2013, up from 6.9% in 1993$42 billion in 2013
• Increases risk for all-cause mortality, CV mortality, kidney failure (ESRD), and other adverse
outcomes.
• 6 fold increase in mortality rate with DM + CKD
• Disproportionately affects African Americans and Hispanics

ESRD, end stage renal disease 1. NKF Fact Sheets.

http://www.kidney.org/news/newsroom/factsheets/FastFacts.
Accessed Nov 5, 2014.
2. USRDS. www.usrds.org. Accessed Nov 5, 2014.
3. Coresh et al. JAMA. 2007. 298:2038-2047.
Diabetes and hypertension are
leading causes of kidney failure

Incident ESRD rates, by primary diagnosis, adjusted for age, gender, & race.

ESRD, end stage renal disease

USRDS ADR, 2007
Risk factors for CKD
• Age
• Sex and race/ethnicity
• Black higher risk for KRT
• Sickle cell trait and APOL1 gene
• Social determinants
• Comorbid conditions
• Diabetes
• Hypertension
• Obesity
 Approach to CKD

• Should involve the following :

1.screening,etiologic diagnosis and staging

2.Prevention of disease progression

3.Management of complications related to CKD

4.Timely referral to nephrologist

5.preparing the patient for renal replacement therapy(RRT)

1.screening
Screening…cont
 Screening cont…
• The most important tools for screening are proteinuria and RFT
• Should focus on CKD risk factors:
• Diabetes
• Hypertension
• Cardiovascular disease
• Smoking
• Obesity
• Age>60 years
• Family history of CKD
 Screening Tools: eGFR
• considered the best overall index of kidney function.
• normal GFR varies according to age, sex, and body size, and declines with age.
• equation that uses both cystatin C and serum creatinine recognized as being
the most accurate
• the best available GFR estimating equation is that developed by the Chronic
Kidney Disease Epidemiology Collaboration (CKD-EPI)
 Sources of error in GFR estimation from SCr
concentration:
 nonsteady state conditions,
 nonGFR determinants of SCr,
 measurement error at higher GFR, and
 interferences with the creatinine assays

Recommendation 1.2.2.1: We recommend using eGFRcr-cys in

clinical situations when eGFRcr is less accurate and GFR
affects clinical decision-making (1C).
KDIGO Recommendation: Evaluation of albuminuria

• it suggest using the following measurements for initial testing of proteinuria (in
descending order of preference, in all cases an early morning urine sample is
preferred) (2B):
1) urine albumin-to-creatinine ratio (ACR);
2) urine protein-to-creatinine ratio (PCR);
3) reagent strip urinalysis for total protein with automated reading;
4) reagent strip urinalysis for total protein with manual reading.
1.2 :Establishing underlying cause of CKD

• Is important
• There may be a treatable condition, like hypertension
• Those with genetic causes,like PCKD may require appropriate counselling
• Some kidney disease may recur after transplantation.
1.2: Establishing underlying cause of CKD
2.Prevention of CKD progression

• 2.1 :DEFINITION AND IDENTIFICATION OF CKD PROGRESSION

1: Assess GFR and albuminuria at least annually in people with CKD.
more frequently for individuals at higher risk of progression, and/or where
measurement will impact therapeutic decisions .
2: small fluctuations in GFR are common and are not necessarily indicative of progression.
3: CKD progression is defined based on one or more of the following (Not Graded):
.Decline in GFR category (>90 [G1], 60–89 [G2], 45–59 [G3a], 30–44 [G3b], 15–29
[G4], <15 [G5] ml/min/ 1.73 m2 ).
.A certain drop in eGFR is defined as a drop in GFR category accompanied by a 25% or
greater drop in eGFR from baseline.
• Rapid progression is defined as a sustained decline in eGFR of more than 5 ml/min/1.73 m2
/yr.
• The rate of decline in GFR of patients with diabetic nephropathy has
been among the fastest, averaging around −10 mL/min/yr.
• Control of hypertension slows the rate of GFR decline to −5 mL/min/yr, with
further improvement (−1 to −2 mL/min/yr) expected in patients with
optimally controlled glycemia and hypertension.
• In nondiabetic nephropathy, patients with chronic glomerulonephritis
exhibit a rate of CKD progression that is more than twice as fast as
patients with chronic interstitial nephritis and 1.5 times faster than
patients with hypertensive nephrosclerosis
SLOWING PROGRESSION OF CKD

• progression of CKD is strongly

influenced by repeated AKI
episodes, often hemodynamically
driven
• Optimal hydration,
• relief of obstruction (where
indicated),
• discontinuation of nephrotoxic
agents,
• control of hypertension
SLOWING PROGRESSION OF CKD
• recognize reversible causes of acute-on-chronic kidney disease
(mimicking progression), such as acute illnesses with volume
depletion
• Patients with comorbid burden – older age, Chronic heart disease and
use of specific medics (diuretics, NSAIDs, SGLT2i, RAASi) are at high
risk for acute on chronic kidney disease.
• Advice for patients ‘Sick day rules’ – temporary discontinue this drugs during
acute illness
• For decades, BP control and RAAS inhibition have been the
cornerstones for preventing progression of CKD
• More recently, exciting new evidence has emerged concerning the
benefits of SGLT2 inhibitors.
• landmark studies have demonstrated the efficacy of these agents on adverse
health outcomes (kidney failure, CV events, and mortality) among patients
with CKD, irrespective of the presence or absence of diabetes.
• Thus, slowing progression of CKD in the current era will depend on
BP control, RAAS inhibition, and use of SGLT2 inhibitors
supplemented by nontherapeutic (lifestyle) and other therapeutic
strategies, such as lipid-lowering therapy
Generic approach to the management of chronic kidney disease
Physical activity and optimum weight
Diet
Blood pressure control
Discussed in prev lectures
Reduction in Albuminuria
• proteinuria is associated with a faster rate of progression and high risk
of kidney failure and CVD, irrespective of the underlying cause of CKD
• reduction of albuminuria via lifestyle and therapeutic measures is associated
with better outcomes
• The superiority of RAAS inhibition compared with other
antihypertensive treatments is due at least in part to its efficacy in
reducing albuminuria
• Recent studies showed that SGLT2i results in reduction of albuminuria

• Clinical trials in T2DM – this agents reduced albuminuria by 30% to 50% and
the incidence of composite hard kidney outcomes by 40% to 50%.
• SGLT2i interfere with the major mechanism of proteinuric CKD
progression (i.e., glomerular hypertension and hyperfiltration)
• The benefits of these agents appear to be similar in patients with or
without diabetes-related CKD, including patients with chronic
glomerulonephritides.
• It is important to consider the baseline level of kidney function before
these agents are initiated
Sodium--glucose contransporter-2 inhibitors
(SGLT2i)
• Several large RCTs have provided clear demonstrations of the efficacy
of SGLT2i
• which substantially reduce risk of kidney failure, AKI, hospitalization
for heart failure as well as moderately reduce the risk of
cardiovascular death and myocardial infarction in people with and
without CKD
• These benefits appear to be irrespective of diabetes status, cause of
kidney disease, or level of GFR
Effect of SGLT2i with kidney disease outcomes by diabetes

In a collaborative metanalysis including those 2 and 11 other trials (13 trials with just over
90,000 randomized participants) in comparison to placebo, those allocated to an SGLT2i
experienced a 37% reduction in the risk of kidney disease progression and a 23% reduction
in the risk of AKI irrespective of diabetes status
status.
• The same meta-analysis showed that, compared with placebo, allocation
to an SGLT2i reduced the risk of the composite of cardiovascular death
or hospitalization for heart failure by 23% irrespective of diabetes status,
although there were limited numbers of CV events in people with CKD
without diabetes
• SGLT2i also afford an approximate 10% relative risk reduction in major
adverse cardiovascular events (MACE), primarily from reduced risk of
cardiovascular death and myocardial infarction with no clear effect on
stroke
Effects of sodium-glucose cotransporter-2 inhibitors (SGLT2) inhibition versus placebo
on kidney failure (CKD trials)
• Furthermore, SGLT2i also importantly reduce:
• risk of hospitalization from any cause,
• reduce BP,
• uric acid levels,
• weight/fluid overload,
• reduce the risk of serious hyperkalemia
• It is safe to continue or even initiate an SGLT2i when the eGFR falls
below 20 ml/min per 1.73 m2 and continue their use until the time
KRT is initiated
• Some uncertainty remains about the effects on kidney disease progression in people
without diabetes with urine ACR <200mg/g
• EMPA-KIDNEY was the key trial to assess effects in people with CKD at risk of
progression with urine ACR <200mg/g, there was significant interaction ACR status
• Relative effects appeared to be larger in people with higher levels of albuminuria
Effects of empagliflozin versus placebo on annual rate of change in eGFR by key subgroups in The Study of Heart and
Kidney Protection With Empagliflozin (EMPA-KIDNEY).
Effects of empagliflozin versus placebo on annual rate of change in eGFR by key subgroups in The Study of Heart
and Kidney Protection With Empagliflozin (EMPA-KIDNEY).
Side effects SGLT2i

• Reversible AKI
• Ketosis
• Risk of infection (uti)
• Mycotic genital infections
• Limb amputation risk

• any risk of ketoacidosis or lower limb amputation resulting from SGLT2i use was substantially lower than the
potential absolute benefits and generally restricted to people with diabetes.
Prevention of CKD progression :Glycemic control:KDIGO 2020 recommendation
Prevention of CKD progression :Glycemic control:KDIGO 2020 recommendation
Prevention of CKD progression :Glycemic control:KDIGO 2020 recommendation
Prevention of CKD progression :Glycemic control:KDIGO 2020 recommendation
Dyslipidemia
• Experimental data show that statins may have synergistic effects with
RAAS inhibitors in slowing CKD progression
• Beyond their effects on cholesterol, statins have additional
(“pleiotropic”) effects, including antiinflammatory and antifibrotic
• However, these potential benefits were not supported in the most
rigorous RCT to date, the SHARP trial, simvastatin and ezetimibe did
not reduce the risk of progressive kidney function loss or incident
albuminuria
• But statins have been consistently shown to reduce mortality and
major CV events by 20% in people with CKD not requiring dialysis
• Lipid lowering therapy kDIGO recommendation
• In adults >50 yrs, statin with or without Ezetimibe eGFR < 60 ml/min/1.73m2
• But not in kidney failure
• In adults < 50 yrs, statin if history of known CAD, MI, DM, stroke, >10% ASCVD risk
• Treatment is indicated irrespective of baseline cholesterol level (a “fire-and-forget” approach).
• Overall, the indication for statin treatment is prevention of CVD events rather than preventing progressive
CKD.
3.Management of common complications of CKD
Anemia in CKD
• Anemia is a condition in which the number of RBCs or oxygen carrying
capacity is insufficient to meet physiologic needs

• For diagnosis and further evaluation Hgb values according to KDIGO

guidelines:
• <13.0 g/dl in men
• <12.0 g/dl in women
 Anemia in Chronic Kidney Disease
• Anemia is universal complication of
CKD
• It is associated with poor quality of
life
• Increased risk of CV related
morbidity and mortality
• Medicare data shows that CKD=100%
and CKD+Anemia=270% in 2yr mortality
 Anemia in CKD/ Pathogenesis
• Renal anemia is typically an isolated NN anemia
• Rate of production and RBC life span are reduced
• The normal bone marrow has considerable
capacity to increase the rate of erythropoiesis
• However, this EPO-induced compensatory
increase in erythrocyte production is impaired in
CKD
• Serum EPO levels remain within the normal range
• Fail to show the inverse exponential relationship
with blood oxygen content characteristic of
other types of anemia
Anemia in CKD/ Pathogenesis
• Mechanisms impairing renal EPO production in diseased kidneys
remain poorly understood
• The production capacity for EPO remains significant, even in ESKD

• The main problem is failure of EPO production to increase in response

to chronically reduced Hgb concentrations
Erythropoietin
• EPO (a 30.4-kDa glycoprotein) regulatory hormone of erythrocyte
production
• Produced by interstitial fibroblast in renal cortex
• EPO secretion is stimulated by hypoxia
• specific hypoxia-sensing mechanism called “hypoxia-inducible factors(HIF)”

• HIF regulates expression of genes that modulate the responses to

hypoxia
Erythropoiesis
• Hypoxia-inducible transcription factors (HIFs) are
composed of:
• Oxygen-regulated α subunit (HIF-1α or HIF-2α) and a
constitutive β subunit

• They regulates wide range of process:

• Erythropoiesis, iron metabolism, oxidation, cellular
metabolism, glycolysis, vasculogenesis, cell cycle
progression, and apoptosis
Erythropoiesis

• HIF-2α is critical for the induction of the EPO gene and erythropoiesis
• Increased transcription of the EPO gene  increased circulating levels
of EPO  enhance the differentiation and proliferation of RBC
precursors.

• HIF also induces expression of the EPO receptor in BM and proteins

that promote iron absorption and recycling
 Erythropoiesis

• Their production is largely

independent of oxygen, but their
degradation is related to cellular
oxygen concentrations
• Destruction and inhibition of HIF
transcriptional activity is:
• By hydroxylation of specific
prolyl and asparagyl residues of
HIF-α,
• molecular oxygen is required
as a substrate
 Erythropoiesis

EPO stimulates RBC production by binding to homodimeric

EPO receptors, located on early erythroid progenitor cells

Salvages these progenitor cells and the subsequent earliest

erythroblast generation from apoptosis, thereby permitting
cell division and maturation into RBCs.
Erythropoiesis
General Treatment

Target Hgb between 10-11.5g/dl

• Replenish Iron,
• ESA treatment
• Hgb <10g/dl, TSAT >20% and ferritin
>200ng/ml
• Maintenance Iron
ESA Therapy

Benefit Risk
• Effective in treating anemia • Increased risk of tumor growth or recurrence
• In patients with stroke increase risk of
• Reduce the need for transfusion
recurrence
• Improve quality-of-life symptoms • Hypertension and seizure
• Exercise tolerance • Access thrombosis
• Increased risk of mortality from blood clots,
• Left ventricular hypertrophy
heart failure
ESA
Therapy
• Epoetin Therapy (IV/SC)
• EPO alfa, EPO beta, Darbepoetin Alfa
• Replace endogenous erythropoietin

• Investigational novel oral ESA

• HIF-PHIs
• Stimulates EPO gene
 Anemia of CKD

Exclude causes other than EPO deficiency (e.g., iron, B12,

folate deficiency)

if ferritin <100 µg/L, consider trial

of IV iron alone, 200–500 mg

if ferritin .100 µg/L or no response

to IV iron, start EPO, 4000–6000 IU/wk
or darbepoetin alfa 20–30 mg/wk

Adjust ESA dose by 25%–50% monthly

until Hb in target range of 10–12 g/dL

Maintain iron status by IV iron

4.Timely Referral to Nephrologist
Indications for Referral to Specialist Kidney Care Services for
People with CKD
• Acute kidney injury or abrupt sustained fall in GFR
• GFR <60 ml/min/1.73m2 (GFR categories G4-G5)
• Persistent albuminuria (ACR > 300 mg/g)*
• Atypical Progression of CKD**
• Urinary red cell casts, RBC more than 20 per HPF sustained and not readily
explained
• Hypertension refractory to treatment with 4 or more antihypertensive
agents
• Persistent abnormalities of serum potassium
• Recurrent or extensive nephrolithiasis
• Hereditary kidney disease
*Significant albuminuria is defined as ACR ≥300 mg/g (≥30 mg/mmol) or AER ≥300 mg/24 hours, approximately
equivalent to PCR ≥500 mg/g (≥50 mg/mmol) or PER ≥500 mg/24 hours
**Progression of CKD is defined as one or more of the following: 1) A decline in GFR category accompanied by a 25%
or greater drop in eGFR from baseline; and/or 2) rapid progression of CKD defined as a sustained decline in eGFR of more than
5ml/min/1.73m2/year. KDOQI US Commentary on the 2012 KDIGO Evaluation and Management of CKD
Observational Studies of Early vs. Late
Nephrology Consultation

Chan M, et al. Am J Med. 2007;120:1063-1070.

http://download.journals.elsevierhealth.com/pdfs/journals/00
02-9343/PIIS000293430700664X.pdf
KDIGO CKD Work Group. Kidney Int Suppls. 2013;3:1-150.
 5.Preparing a patient for RRT

• Preemptive transplantation Vs Dialysis

• placement of vascular or peritoneal access

• choosing the most appropriate mode and location of dialysis (i.e., peritoneal dialysis,
outpatient hemodialysis center, home hemodialysis)

• vaccinations—infleunza,pneumococcal ,HBV

• continued nutritional management, particularly in terms of phosphorus control; and

prevention of fluid overload and hypertension.
TIMING THE INITIATION OF RRT

• We suggest that dialysis be initiated when one or more of the following are present:
• symptoms or signs attributable to kidney failure (serositis, acid-base or electrolyte abnormalities, pruritus);
• inability to control volume status or blood pressure;
• a progressive deterioration in nutritional status refractory to dietary intervention; or
• cognitive impairment.
• This often but not invariably occurs in the GFR range between 5 and 10 ml/min/1.73 m2 . (2B)

• Living donor preemptive renal transplantation in adults should be considered when the GFR is <20 ml/min/ 1.73
m2 , and there is evidence of progressive and irreversible CKD over the preceding 6–12 months. (Not Graded)
References
• Comprehensive clinical nephrology,7th edition
• KDIGO guidelines
• Hand book of dialysis,5th edition
• THANK YOU!!!!