Can We Slow CKD Progression?

Hesham Safouh, MD

Cairo University

Childhood chronic kidney disease usually progresses towards end-stage renal failure once a critical impairment of renal function has occurred.

Factors Affecting CKD Progression

Quicker Progression: • Severe proteinuria

• Hypertension

• Short term gestation

• Glomerular disease > CAKUT anomalies

• Older age (puberty)

• Non-Caucasian ethnicity

• Patients who present at stage 4 CKD

Warady BA, et al: Predictors of rapid progression of glomerular and nonglomerular kidney disease in children and adolescents: the chronic kidney disease in children (CKiD) cohort. Am J Kidney Dis 2015;65:878-888.

Ethnicity and CKD Progression

Chance of ESRD in comparison with whites:

• African Americans 3.6

• Native Americans 1.8

• Hispanics 1.5

Why?

• Genes?

• Hypertension?

• Access to care?

Lee et al: Circulating TGF-beta1 as a reliable biomarker for chronic kidney disease progression in the African-American population. Kidney Int. 2009 Jul;76(1):10-2.

• Puberty is associated with deterioration in kidney function.

• Probability of RRT (ItalKid Project): – 9.4% during the 1st decade

– 51.8% during the 2nd decade

• In both males and females.

• Effect of sex hormones on mesangial cell proliferation, collagen synthesis, and apoptosis.

Ardissino G, et al: Puberty is associated with increased deterioration of renal function in patients with CKD: data from the ItalKid project. Arch Dis Child 2012;97:885-888.

Puberty and CKD Progression

Proteinuria and CKD Progression

• Proteinuria is the main predictor of CKD progression.

• The first therapeutic target in the management of CKD.

Ruggenenti P, Perna A, Mosconi L, et al. Proteinuria predicts ESRF in nondiabetic chronic nephropathies. The ‘Gruppo Italiano di Studi Epidemiologici in Nefrologia’ (GISEN). Kidney Int Suppl 1997; 63:S54–S57.

Studies in Children

• The European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood: proteinuria and hypertension are major independent determinants of GFR decline.

Wingen et al. Randomised multicentre study of a low-protein diet on the progression of chronic renal failure in children. European Study Group of Nutritional Treatment of Chronic Renal Failure in Childhood. Lancet 1997 Apr 19;349(9059):1117-23.

Studies in Children

• The ItalKid Project: proteinuria predicts progression in children with renal hypodysplasia.

Ardissino et al. Proteinuria as a predictor of disease progression in children with hypodysplastic nephropathy. Data from the Ital Kid Project. Pediatr Nephrol. 2004 Feb;19(2):172-7. Epub 2003 Dec 13.

Studies in Children

• ESCAPE trial: residual urinary protein excretion during ACE inhibition is quantitatively associated with renal failure progression.

Wuhl et al. (2009) Strict blood-pressure control and progression of renal failure in children. N Engl J Med 361:1639–1650.

Mechanisms underlying the activation of inflammatory

and fibrogenic pathways in proximal tubular epithelial

cells by ultrafiltered protein load.

Mauro Abbate et al. JASN 2006;17:2974-2984

TGF-β1

• TGF-β1 is a profibrogenic cytokine.

• Plays an important role in CKD progression.

• Blockade of this cytokine in experimental models prevents progression of CKD.

Figure 1

Kidney International 2009 76, 10-12DOI: (10.1038/ki.2009.130)

Bidirectional Activities of TGF-β and the RAAS

Kidney International 2009 76, 10-12.

Renin or angiotensin II induces TGF-β activation, and TGF-β1 also stimulates angiotensin I.

Hypertensive Renal Disease in African-Americans Janice P. Lea, MD, MSc Associate Professor of Medicine Clinical Specialist in Hypertension Renal Division, Emory University, USA

Renin Angiotensin Aldosterone System (RAAS)

Activation causes glomerular hypertension and tubulointerstitial fibrosis leading to progressive nephron loss.

Inhibition with ACEIs and/or ARBs has a beneficial effect on hypertension, proteinuria and CKD progression.

RAAS Antagonists

• 1st step in renoprotective antiproteinuric treatment (level 1 evidence).

• Reduce urinary protein excretion.

• Residual proteinuria continues.

• Reduce BP and intraglomerular pressure.

• Diminish local release of cytokines, chemokines.

• Attenuate renal inflammation and fibrosis.

• Excellent safety profile.

The Antiproteinuric Effect of Vitamin D

• Intrinsic antiproteinuric properties of vit D.

• An additive effect to RAS antagonist treated individuals.

• More than one mechanism for reduction of CKD progression.

Shroff et al. Normal 25-Hydroxyvitamin D Levels Are Associated with Less Proteinuria and Attenuate Renal Failure Progression in Children with CKD. J Am Soc Nphrol. 2016 Jan;27(1):314-22.

Vanessa Pérez-Gómez et al. Vitamin D and proteinuria: a critical review of molecular bases and clinical experience. Nefrologia 2013;33(5):716-26

Hypertension and CKD Progression

Pathophysiology:

• Ischemia pathway (essential hypertension).

• Barotrauma-mediated pathway (CKD, impaired renal autoregulation).

Bidani AK, Griffin KA, Epstein M. Hypertension and Chronic Kidney Disease Progression: Why the Suboptimal Outcomes? The American journal of medicine. 2012;125(11):1057-1062. doi:10.1016/j.amjmed.2012.04.008.

Hypertension and CKD Progression

ESCAPE Trial: • First RCT demonstrating renoprotection of tight BP

control in children.

• 24-h BP monitoring.

• 5 yr observation period

• 29.9% (intensified BP control) vs. 41.7% (conventional treatment group) attained doubling sCr or GFR deterioration to < 10 ml/min/1.73m2, or need for RRT.

• This corresponds to a risk reduction by 35%.

Wuhl E, Trivelli A, Picca S, et al. Strict blood pressure control and renal failure progression in children. The ESCAPE Trial Group. N Engl J Med 2009;361:1639–1650.

Hypertension and CKD Progression

Recommendations:

The European Society of Hypertension recommends BP target below the 50th percentile in proteinuric, and below the 75th percentile in nonproteinuric children with CKD-associated hypertension.

Lurbe E, Cifkova R, Cruickshank JK, et al. Management of high blood pressure in children and adolescents: recommendations of the European Society of Hypertension. J Hypertens 2009; 27:1719–1742.

Pediatrics, June 2013, VOLUME 131 / ISSUE 6

Late gestation is critical for nephrogenesis in both humans (A) and mice (B)

Brenner’s Hypothesis

Pediatrics June 2013, VOLUME 131 / ISSUE 6

Pediatrics June 2013, VOLUME 131 / ISSUE 6

Brophy P.D. et al. (2018) Chronic Kidney Disease: A Life Course Health Development Perspective. In: Halfon N., Forrest C., Lerner R., Faustman E. (eds) Handbook of Life Course Health Development. Springer, Cham

Follow Up Strategies For NICU Graduates

Pediatrics, June 2013, VOLUME 131 / ISSUE 6

CAKUT and CKD Progression

Complex Molecular Mechanisms

Mordi Muorah Hopital Necker Enfants- Malades, Paris, FRANCE

Stretch induces TGFβ secretion leading to

inflammation.

Apoptosis / Proliferation Interstitial Infiltration

Balance

(reduced excretory function of the kidney)

(induction of cytokines and growth factors)

(complete scarring of the renal parenchyma)

Pope et al. How They Begin and How They End: Classic and New Theories for the Development and Deterioration of CAKUT. Am Soc Nephrol 10: 2018–2028, 1999

Metabolic Acidosis and the Progression of CKD

• Acidosis is not only a consequence of, but is a contributor to CKD progression.

• Several (adult) trials now suggest that the treatment of acidosis with oral alkali can slow the progression of kidney disease.

Chen and Abramowitz BMC Nephrology 2014, 15:55 http://www.biomedcentral.com/1471-2369/15/55

In CKD, ammonia generation per nephron increases. Ammonia reacts with C3 to trigger the alternative complement pathway. Acidosis has been shown to increase endothelin (ET). ET-1 promotes the synthesis of fibronectin and collagen. Chronic metabolic acidosis induces a sustained stimulation of aldosterone secretion.

Chen and Abramowitz BMC Nephrology 2014, 15:55 http://www.biomedcentral.com/1471-2369/15/55

In CKD, ammonia generation per nephron increases. Ammonia reacts with C3 to trigger the alternative complement pathway. Acidosis increases endothelin (ET). ET-1 promotes the synthesis of fibronectin and collagen. Acidosis induces a sustained stimulation of aldosterone secretion.

Chen and Abramowitz BMC Nephrology 2014, 15:55 http://www.biomedcentral.com/1471-2369/15/55

704 children in the Cardiovascular Comorbidity in Children with CKD Study, a prospective cohort of pediatric patients with CKD stages 3-5, were studied. Children with serum bicarbonate under 18 mmol/l had a significantly higher risk of CKD progression compared to those with a serum bicarbonate of 22 or more mmol/l (adjusted hazard ratio 2.44; 95% confidence interval 1.43-4.15).

Uric Acid: A Marker and Contributor to CKD Progression

Associations Between Hyperuricemia and Chronic Kidney Disease: A Review. Prasad Sah OS, Qing YX - Nephrourol Mon (2015)

URIC Acid

Anemia and CKD Progression

Besarb et al. Iron Metabolism, Iron Deficiency, Thrombocytosis, and the Cardiorenal Anemia Syndrome. The Oncologist September 2009vol. 14 Supplement 1 22-33

Ruan, X. Z. et al. Nat. Rev. Nephrol. 5, 713–721 (2009)

Dyslipidemia and CKD Progression

Diet and CKD Progression

Two studies (250 children) were identified, 124 received a protein restricted diet and 126 a control diet. No significant differences was found in the number of renal deaths (RR 1.12, 95% CI 0.54 to 2.33), progression of kidney disease (creatinine clearance at two years: MD 1.47, 95% CI ‐1.19 to 4.14) or growth (weight ‐ MD ‐0.13, 95% CI ‐1.10 to 0.84; height ‐ MD ‐1.99, 95% CI ‐4.84 to 0.86).

Reducing protein intake does not appear to have significant impact in delaying the progression to ESKD in children.

In Conclusion……..

• Gradual progression of CKD towards ESRD is common.

• This occurs irrespectively of the underlying kidney disorder.

• A successful strategy to slow down the progression of CKD would be truly cost-effective preventive measure to improve life expectancy and quality in this patient group.

• Hypertension and proteinuria are the most important independent risk factors for CKD progression.

In Conclusion……..

• Pharmacological renoprotection currently focuses on antihypertensive and antiproteinuric treatment by blockade of the renin–angiotensin system.

• Intensified blood pressure control can improve 5-year renal survival by 35% in children with CKD.

• Promising preliminary findings suggest an additional renoprotective potential by correction of metabolic acidosis and hyperuricemia and by administration of antiproliferative and antioxidative drugs.

Safouh, MD

Safouh, MD

Safouh, MD

Safouh, MD

Safouh, MD

MCQ Question 1

Two factors affecting CKD progression that may have activation of the alternative complement pathway as a contributing mechanism are:

A. Hypertension and proteinuria

B. Dyslipidemia and anemia

C. Proteinuria and metabolic acidosis

D. High dietary intake of protein and hypertension

MCQ Question 2

The antiproteinuric effect of vitamin D:

A. Is of no added value if given with RAAS antagonists.

B. May involve diminished RAAS activation.

C. Is due to its effect on the podocytes only.

D. Is due to its effect on renal cells apart from the podocytes.

MCQ Question 3

Recommendations for BP control in proteinuric children with CKD now include keeping the target BP:

A. Below the 95th % for age and gender

B. Below the 75th %

C. Below the 50th %

D. Below the 25th %