How to retard the progression of How to retard the progression of CKD?CKD?

Tarek Mohamed El TantawyTarek Mohamed El Tantawy MD, MSc Nephrology – Ain Shams MD, MSc Nephrology – Ain Shams

UniversityUniversity Egyptian Nephrology Fellowship Trainer Egyptian Nephrology Fellowship Trainer

– MNGH– MNGHSecretary-General of the Dakhlia Secretary-General of the Dakhlia

Nephrology GroupNephrology GroupHQM – CambridgeHQM – Cambridge

Introduction.

CKD definition and classification.

CKD Biomarkers.

Risk factors for CKD progression.

Interventions to slow CKD progression.

Conclusion.

Agenda

The management of progression of CKD is aimed at addressing a multiplicity of factors known to be associated with progression.

There are general measures which have been shown to address cardiovascular health and CKD. Addressing CVD risk factors may indirectly and directly impact CKD progression.

Strategies include general lifestyle measures which improve cardiovascular health, BP control, and interruption of the RAAS.

In addition, control of other metabolic parameters such as blood sugar, uric blood sugar, uric acid, acidosis, and dyslipidemia together with cessation of smokingacid, acidosis, and dyslipidemia together with cessation of smoking may also be important.

Introduction

-CKD is defined as either:-kidney damage (proteinuria, hematuria, or structural abnormalities of the

kidney) with or without impaired GFRor impaired GFR < 60 ml/min per 1.73m² with or without kidney damage that persists for > 3 monthsthat persists for > 3 months. KDIGO guidelines

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Albuminuria and eGFR provide independent information regarding risk of CKD progression, AKI , cardiovascular disease, and mortality.

CKD Classification

KDIGO recommends classification based on Cause, GFR category, and Albumin category (referred to as CGA). Cause is added because it provides important prognostic information, as well as influences treatment decisions.

The KDIGO guideline recommends that the cause of CKD be based on the presence or absence of systemic disease (e.g., diabetes, lupus) and the anatomic location of the pathologic abnormalities within the kidney (e.g., glomerular, tubulointerstitial diseases, vascular diseases, cystic and congenital diseases).

CKD classificationCGA

Ideal urinary and plasma urinary and plasma biomarkers for CKD would identify patients who develop progressive CKD, monitor effects of treatment, and be useful and convenient in clinical practice.

UrinaryUrinary albuminalbumin is a good example, although some patients will progress despite normoalbuminurianormoalbuminuria.

Other CKD biomarkers include markers of tubular damage markers of tubular damage ,those that reflect early inflammation/fibrosis, markers of mineral bone diseasemarkers of mineral bone disease, and natriuretic hormonesnatriuretic hormones.

O’Seaghdha et al., 2011 found that lower urinary connective tissue growth factor lower urinary connective tissue growth factor levels were associated with incident CKD.

Dieplinger et al., 2009 found that A-type natriuretic peptide A-type natriuretic peptide and adrenomedullinadrenomedullin plasma concentrations predict progression of nondiabetic kidney disease.

Large prospective studies are required to validate biomarkers, and establish threshold values for prediction of CKD progression; none of these biomarkers are presently ready none of these biomarkers are presently ready for clinical use.for clinical use.

CKD Biomarkers

proteinuria is an independent risk for renal outcomes regardless of eGFR. The Chronic Kidney Disease Prognosis Consortium examined a collaborative

meta-analysis, from 45 studies > 1,555,332 patients were examined and included those in the general population, at high risk, and with CKD.

A higher relative risk for progressive CKD and ESRD was associated with both lower eGFR levels and higher levels of albuminuria.

Increased risk for mortality and adverse renal outcomes was statistically significant for urine ACR > 30 mg/g, even when eGFR was > 60 ml/min per 1.73m² , consistent with the current threshold value for albuminuria (> 30 mg/g) as a marker of kidney damage.

The relative risk for ESRD in a patient with an eGFR of 60 to 75 ml/min per 1.73m² and an ACR ≥ 300 mg/g is greater than a patient with an eGFR of 30 to 45 ml/min per 1.73m² with an ACR <  10 mg/g (relative risk of 67 versus 56).

Risk factors for CKD progressionProteinuria

Obesity may contribute to both incident CKD and increased CKD progression by increasedincreased insulin resistance and sympathetic activity, activation of the insulin resistance and sympathetic activity, activation of the RAAS with local renin angiotensin and aldosterone synthesis in adipose tissue, RAAS with local renin angiotensin and aldosterone synthesis in adipose tissue, and increased inflammatory adipose-based cytokines such as leptin and and increased inflammatory adipose-based cytokines such as leptin and adiponectinadiponectin.

Significant proteinuria and obesity was associated with CKD progression and ACE inhibition was more renoprotective in obese patients, possibly due to inhibition of the enhanced baseline renin, angiotensin, and aldosterone levels in these individuals.

Obesity is associated with secondary focal and segmental glomerulosclerosis. secondary focal and segmental glomerulosclerosis.

Risk factors for CKD progressionObesity

11 studies of >30,000 participants showed that metabolic syndrome was associated with a 55% increased risk for the development of eGFR <60 ml/min per 1.73 m².

For individual components of the metabolic syndrome, the OR of developing an eGFR < 60 ml/min per 1.73 m² were 1.61 for elevated BP, 1.27 for elevated triglycerides, 1.23 for low HDL cholesterol, 1.19 for abdominal obesity, and 1.14 for impaired fasting glucose.

Risk factors for CKD progressionMetabolic Syndrome

In patients with normal albumin excretion, the traditional BP goal of < 130/80 < 130/80 mmHg in CKD patients did not slow the progression compared with < 140/90 < 140/90 mmHg . Those with albumin excretion > 300 > 300 mg/d may benefit from the lower target < 130/ 80< 130/ 80 mmHg.

In patients with proteinuric CKD ( >300 mg/d ), ( >300 mg/d ), inhibition of the RAAS is superior to other antihypertensive medications in slowing CKD progression. However, in those with less proteinuria, it is not clear which class of antihypertensive agents is most beneficial.

ACEIs combined with ARBs showed no benefit in preventing progression of microalbuminuria or ESRD over either medication alone in a systematic review systematic review of randomized controlled trials.of randomized controlled trials.

Risk factors for CKD progressionHypertension

The relationship between systolic, diastolic, and pulse pressure with ESRD risk was assessed in > 16,000 Kidney Early Evaluation Program study participants (2012) with an eGFR of < 60 ml/min per 1.73m².

After adjustment for demographics, comorbidities, BMI, eGFR, and albuminuria.

High Systolic BP accounted for most of the risk of progression to ESRD. There was a significant 36%36% increased risk for ESRD in participants with a Systolic BP Systolic BP ≥ ≥ 150 mmHg.150 mmHg.

Persons with Diastolic BP > 90 Diastolic BP > 90 mmHg were at 81%81% higher risk for ESRD compared with those with Diastolic BP of < 80 mmHg.

Higher pulse pressure (> 80 mmHg versus < 50 mmHg) was not associated with ESRD after adjustment for SBP.

Risk factors for CKD progressionHypertension

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CKD progression may increase with cardiac dysfunction by decreased renal decreased renal perfusion, increased renal venous pressure, increased endothelial dysfunction, perfusion, increased renal venous pressure, increased endothelial dysfunction, and altered neurohormonal factors.and altered neurohormonal factors.

Risk factors for CKD progression Cardiovascular Abnormalities

The cardiac concentricity” the ratio of left ventricular mass to left ventricular the ratio of left ventricular mass to left ventricular end-diastolic volume, end-diastolic volume, an early sensitive measure of early sensitive measure of cardiac remodelingcardiac remodeling” was associated with renal function decline.

Atrial fibrillation Atrial fibrillation is common in CKD and has been reported in up to 20% of CKD patients.

Takahashi et al., 2011 compared eGFR values before and 1 year after catheter ablation for atrial fibrillation in 386 Japanese patients.

• Baseline eGFR was 68 ml/min per 1.73 m² and 26% of patients had stage 3 CKD.

• The 72% of patients who remained free from arrhythmias over the 1-year follow-up had a significant 3 ml/min per 1.73 m² increase in eGFR, whereas those with recurrent arrhythmias had a 2 ml/min per 1.73 m² decrease compared with baseline.

Risk factors for CKD progression Cardiovascular Abnormalities

The role of uric acid as either a causal factor or as a marker of CKD is controversial. Proposed mechanisms for uric acid induced kidney damage include hypertension, hypertension,

with activation of the RAAS, renal afferent arteriolopathy, increased glomerular with activation of the RAAS, renal afferent arteriolopathy, increased glomerular hydrostatic pressure, and fibrosis.hydrostatic pressure, and fibrosis.

Bellomo et al.,2010 examined 900 healthy blood donors who had a serum uric acid measurement, and followed up with a serum creatinine 5 years later; those with an ACR > 300 mg/g Cr were excluded. The adjusted HR for loss of eGFR >10 ml/min per 1.73m² was 1.28 for every 1 mg/dl increase in serum uric acid. The eGFR decline was seen in men with serum uric acid ≥ 5.5 and for women ≥ 5 mg/dl.

Madero et al., 2010 who examined the association of baseline serum uric acid level with death and renal failure in 840 participants of the MDRD study over a median follow-up of 10 years. The mean measured GFR was33 ml/min per 1.73m² with median serum uric acid of 7.6 mg/dl in participants of the study. The highest tertile of serum uric acid ( 8.4 to 15.6 ) was associated with death (HR 1.57), but not with kidney failure.

Risk Factors for CKD Progression Hyperuricemia

There is insufficient evidence to support or refute the use of agents to lower serum uric acid concentrations in people with CKD and either symptomatic or asymptomatic hyperuricemia in order to delay progression of CKD. (Not Graded)

Treatment of asymptomatic hyperuricemia has also been reported to improve kidney function even in subjects with normal levels of GFR. Both GFR and endothelial function significantly improved in asymptomatic hyperuricemic subjects randomly assigned to 300 mg/day of allopurinol in comparison to placebo.

Other uric acid lowering agents have also been reported to improve outcomes in people with CKD. In an 8-week, placebo-controlled group comparison of rasburicase and placebo, a single 4.5 mg dose of rasburicase significantly lowered serum uric acid and resulted in a significant improvement in kidney function assessed by CrCl.

Risk Factors For CKD Progression Hyperuricemia – KDIGO 2013

Elevated serum phosphate appears to play a role in CKD progression rather than simply being consequences of CKD.

Zoccali et al., 2011 examined the relationship between serum phosphate and CKD progression in 331 participants in the REIN trial.

• In both the ramipril and placebo groups, those who had serum phosphate levels in the upper two quartiles progressed faster to ESRD or to the combined endpoint of ESRD and doubling of serum creatinine.

• Higher serum phosphate levels decreased the renoprotective effects of ramipril.

• One limitation of this study is that it did not have FGF-23 measurements.

Risk factors for CKD progression Phosphates

FGF-23 levels rise in CKD to increase urinary phosphate excretion to maintain normal serum phosphate levels.

FGF-23 is a biomarker for CKD, its levels increase before increases in serum phosphate or parathyroid hormone levels.

FGF-23 may cause kidney injury indirectly by reducing 1,25(OH)2 vitamin D levels, or directly via an unknown mechanism similar to the cardiac toxicity (LVH).

Isakova et al., 2011 examined the association of FGF-23 levels with both mortality and ESRD in patients with CKD in the Chronic Renal Insufficiency Cohort study.

• This study included nearly 3800 patients with stage 2–4 CKD, with 89% having normal phosphate levels. The mean FGF-23 level was 145.5 RU/ml (versus a reference median of 43 RU/ml in a non-CKD population).

• During 3.5 years of follow-up, 266 patients died and 410 reached ESRD.• Elevated FGF-23 was independently associated with death, but there was a more

complex relationship with progression to ESRD.

Risk factors for CKD progressionFGF-23

AKI is a risk factor for CKD progression and severity of AKI predicts worse outcomes. Those who required dialysis for AKI had a 500-fold increased likelihood for developing stage 4 CKD

Even complete recovery from AKI within 10% of baseline values leads to increased CKD incidence/progression and should be followed by a nephrologist.

Coca et al., 2012 conducted a systematic review of the incidence and relative risks of these long term consequences of patients with and without AKI.

Pooled data from 13 studies of >1.4 million people showed that the incidence of CKD and ESRD were 25.8 per 100 person-years and 8.6 per 100 person-years, respectively, in individuals with AKI.

The pooled hazard ratios for patients who had AKI for subsequent CKD, ESRD, and death were 8.8 (95% CI, 3.1–25.5), 3.1 (95% CI, 1.9–5.0), and 2.0 (95% CI, 1.3–3.1), respectively, compared with patients without AKI.

Risk factors for CKD progressionAcute Kidney Injury

Identifying genetic variants associated with CKD would be important for identifying those at risk, predicting progression, possibly initiating early therapy, and understanding the pathophysiology of CKD.

There is an increased risk for ESRD in African AmericansAfrican Americans. Genovese et al., 2010 described the finding of two risk alleles in the coding

region of apolipoprotein A1 apolipoprotein A1 (found on chromosome 22chromosome 22) that are associated with FSGS and hypertensive ESRD in African AmericansFSGS and hypertensive ESRD in African Americans.

• The association of “ApoL1ApoL1” with hypertensive ESRD was tested in approximately 1,000 African American cases and 1,000 controls and these alleles were strongly associated with hypertensivehypertensive ESRDESRD.

• The odds ratio for 2 “ApoL1” risk alleles was 7.3 versus 0 alleles and 5.8 versus 1 allele for hypertensive ESRD.

Risk factors for CKD progressionGenetics

Race and genetics represent two important nonmodifiable risk factors for progression.

Blacks and Hispanics with more African ancestry have an increased risk of CKD, which starts before an eGFR <60 ml/min per 1.73 m².

ApoL1ApoL1 risk alleles, low birth weightlow birth weight, and socioeconomicsocioeconomic factorsfactors and poorerpoorer accessaccess to health care to health care may all play roles in faster progression in blacks.

Risk factors for CKD progressionRace and Socioeconomic Status

Nephrolithiasis may increase CKD progression by interstitial calcificationsinterstitial calcifications, crystallization in tubulescrystallization in tubules, repeated urinary obstructionrepeated urinary obstruction, and lithotripsylithotripsy, which may cause parenchymal damage.

Alexander et al., 2012 examined the association of new kidney stones with CKD progression in a large registry cohort. Patients with pyelonephritis were excluded.

• >23,700 patients with at least one kidney stone, 5333 patients developed ESRD. • Having one or more stones was associated with two-fold increased two-fold increased risk of ESRD,

new stage 3b–5 CKD, and doubling of serum creatinine compared with those without kidney stones during 11 years of follow-up.

• The excess risk of stones seemed greater in women and in individuals aged <50 years.

Risk Factors for CKD progressionNephrolithiasis

Solitary cysts are not normally thought to affect kidney function. • It was postulated that tubular epithelial injury may lead to cyst formation, and

that cysts could be markers of prior tubular damage.• Cysts were associated with albuminuria in a single study “Rule et al; 2012 ”. Isolated microscopic hematuria without proteinuria revealed ” renal biopsies”

that many of these patients had IgA nephropathy, thin basement membrane IgA nephropathy, thin basement membrane disease, MPGN, or Alport syndromedisease, MPGN, or Alport syndrome, none of which have specific therapy.

• Vivante et al; 2011 designed a large cohort study revealed that isolated microscopic hematuria with < 200mg/d of proteinuria is associated with increased ESRD risk.

Risk Factors for CKD progressionRenal cysts – Isolated microscopic hematuria

Cigarette smoking is associated with abnormalabnormal urine albumin urine albumin and progression of CKD.

Smoking is an important renal risk factor, and nephrologists have to invest more efforts to motivate patients to stop smoking. Smoking cessation improves oxygen Smoking cessation improves oxygen delivery to the glomeruli. delivery to the glomeruli.

Multiple studies document a clear association between smoking and renal damage in the general population, patients with diabetes, and hypertensive patients.

Studies investigating the beneficial effects of smoking cessation on kidney function have all been positive.

Miscellaneous RF for CKD progressionSmoking- KDIGO 2013

Interventions to Slow CKD Progression

We recommend that people with CKD be encouraged to undertake physical activity compatible with cardiovascular health and tolerance (aiming for at least 30 minutes 5 times per week), achieve a healthy weight (BMI 20 to 25), and stop smoking. (1D)

Frailty, impaired physical performanceFrailty, impaired physical performance, disabilitydisability, and geriatric syndromes geriatric syndromes are common among older adults even with mild kidney disease.

CKD patients have a reduced exercise capacity and impaired physical functioning. Moreover, reduced physical activity is associated with increased mortality and poor increased mortality and poor QOL in people with CKD.QOL in people with CKD.

Regular exercise leads to increased exercise capacity, decreased morbidity, and to increased exercise capacity, decreased morbidity, and improved health-related QOLimproved health-related QOL. Exercise may reduce cardiovascular risk reduce cardiovascular risk through its beneficial effects on BP, triglycerides, high-density lipoprotein cholesterol , insulin BP, triglycerides, high-density lipoprotein cholesterol , insulin resistance, and glycemic controlresistance, and glycemic control.

In ESRD, exercise has been shown to improveimprove arterialarterial stiffnessstiffness, BPBP, cardiorespiratorycardiorespiratory function, and QOL.function, and QOL.

Interventions to Slow CKD Progression Lifestyle - KDIGO 2013

Dietary sodium restriction has traditionally been advocated for the beneficial effects on hypertension and assumed benefits of improved outcomes regarding CKD progression.

However, there has been recent controversy regarding the expected benefits versus possible harms from dietary sodium restriction. Dietary sodium restriction could Dietary sodium restriction could result in an increased activity of the renin-angiotensin-aldosterone system, result in an increased activity of the renin-angiotensin-aldosterone system, increased sympathetic activity, and insulin resistance, all of which might worsen increased sympathetic activity, and insulin resistance, all of which might worsen CKD progression.CKD progression.

The optimal dietary sodium intake for slowing CKD progression remains unclear. For those patients with moderate CKD and heavy proteinuria, high dietary sodium intake may worsen CKD progression.

The present recommendation of 2500 mg of sodium intake per day for hypertensive patients is reasonable, but extremely low dietary sodium intakes (<1250mg/d) should possibly be avoided.

Interventions to Slow CKD Progression Low Sodium Diet

We recommend a target HbA1c of ~7.0% to prevent or delay progression of the prevent or delay progression of the microvascular complications of diabetes, including diabetic kidney disease.microvascular complications of diabetes, including diabetic kidney disease. (1A)

We recommend not treating to an HbA1c target of < 7.0% in patients at risk of hypoglycemia, this risk will be higher in people with lower levels of kidney function. (1B)

We suggest that target HbA1c be extended above 7.0% in individuals with comorbidities or limited life expectancy and risk of hypoglycemia. (2C)

In people with CKD and diabetes, glycemic control should be part of a multifactorial intervention strategy addressing blood pressure control and cardiovascular risk, promoting the use of ACEI or ARB, statins, and antiplatelet therapy where clinically indicated. (Not Graded)

Interventions to Slow CKD Progression Glycemic control (NKF) KDOQI 2012

Fluid intake may influence CKD incidence because a high intake may help increase solute clearance and prevent kidney stonesincrease solute clearance and prevent kidney stones. Conversely, lower fluid intake with resulting urinary concentration may increase the metabolic demand of the kidneys.

Clark et al., 2011 assessed the effect of increased fluid intake on incident CKD and kidney function decline in a 6-year, prospective cohort study of >2100 participants.

• These participants had to have a baseline eGFR >60 ml/min per 1.73 m². Valid 24-hour urine samples were collected and participants were grouped in categories of < 1 L/d, 1–1.9 L/d, 2–2.9 L/d, and >3 L/d.

• Annual eGFR decline was progressively slower, from 1.3%, to 1.0%, to 0.8%, and to 0.5%, respectively (P = 0.02).

it seems reasonable to recommend a higher fluid intake of 2–3 2–3 L/d in patients with risk factors for CKD if there are no contraindicationsno contraindications.

Interventions to Slow CKD Progression Fluid Intake

A low protein diet has been advocated to slow the progression of CKD. Unfortunately, the MDRD study was unable to show conclusive benefit of a low protein diet (0.58 g/kg/d) versus a very low protein diet (0.28 g/kg/d) supplemented with essential ketoacids and amino acids in slowing non-diabetic CKD.

Menon et al., 2009 examined the long-term effects between these two diets used in the MDRD initial trial in 255 individuals with measured GFR values between 13 to 24 ml/min per 1.73m² who continued in a long term follow-up study with no dietary recommendations.

• Outcomes measured were ESRD, death, and the composite of both. In the low protein diet group, 90.7% reached kidney failure compared to 87.3% in the very low protein diet group. The composite end point was reached in 96.1% in the low protein group versus 95.2% in the very low protein group. However, 23.3% died in the low protein group compared to 38.9% in the very low protein group.

• The very low protein diet did not delay progression to kidney failure compared to the The very low protein diet did not delay progression to kidney failure compared to the low protein diet, but appeared to increase the risk of death.low protein diet, but appeared to increase the risk of death.

Interventions to Slow CKD Progression Low Protein Diet

Nath et al., 2012 showed that, with CKD, increased single nephron ammonia single nephron ammonia genesis can activate the alternative complement system and lead to genesis can activate the alternative complement system and lead to tubulointerstitial inflammation and injury.tubulointerstitial inflammation and injury.

Shah et al., 2012 performed a retrospective cohort study of over 5,422 outpatients with a mean age of 52 years; 69% were women, 45% were African American, 21% had diabetes, 41% had hypertension, and 9% had an eGFR< 60 ml/min per 1.73m². Kidney disease progressed in 6.2% as defined by a decrease in eGFR by 50% or reaching an eGFR< 15 ml/min per 1.73m² during follow-up.

• After adjustments for baseline eGFR, clinical, and demographic factors, individuals with a baseline serum bicarbonate < 22 mEq/L < 22 mEq/L had a hazard ratio of 1.541.54 for developing progressive kidney disease compared to those with baseline serum bicarbonate levels of 25 to 26 25 to 26 mEq/L.

• Alkali may have beneficial effects by decreasing tubulointerstitial damage. Alkali may have beneficial effects by decreasing tubulointerstitial damage.

Interventions to Slow CKD Progression Oral Alkali for Metabolic Acidosis

The potential beneficial effects of vitamin D on CKD progression include inhibiting the renin angiotensin inhibiting the renin angiotensin system system at multiple steps, having anti-inflammatory anti-inflammatory propertiesproperties, and reducing podocyte injuryreducing podocyte injury.

Fishbane et al., 2013 studied the effects of paricalcitol1g/d on proteinuria in 61 proteinuric CKD patients in a randomized, placebo-controlled double blind, 6-month study.

• The paricalcitol group had a significant decrease in proteinuria of decrease in proteinuria of 17.6% 17.6% from baseline compared to controls where there was a 2.9% increase.

Interventions to Slow CKD Progression Paricalcitol

Proper hydration 2-3 L /day if there are no contraindicationsno contraindications. Avoiding Drugs such as Aminoglycosides, NSAIDs.Avoiding exposure to radio - contrast agents.In presence of dehydration, even in absence of renovascular disease, ACEIs or ARBs can aggravate renal dysfunction.Dehydration is frequent in tubulo - interstitial disorders where urinary concentration is impaired. Proper Dosing of Drugs eg. Allopurinol, digoxin

Interventions to Slow CKD Progression Avoidance of Dehydration/Nephrotoxic Agents

Although CKD is generally progressive and irreversible, there are steps providers and patients can take to slow progression, enabling patients to live longer without complications or the need for renal replacement therapy.

BP control, reduction of proteinuria, RAAS inhibition and in patients with diabetes, glycemic control have been traditional strategies employed to slow progression of CKD.

Other factors that may influence or predict CKD progression, such as biomarkers, genetics, race, acidosis, uric acid, diet, kidney stones, and acute kidney injury.

Trials to slow CKD progression using certain antihypertensive agents, oral alkali, allopurinol, low salt &protein diets, paricalcitol and prompt glycemic control with avoidance of dehydration and nephrotoxic drugs.

CONCLUSIONS

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