CHRONIC KIDNEY DISEASE, Part 1

Rene VanDeVoorde, MDChildren’s Hospital at Vanderbilt2021 ASPN Board Review Course

• Epidemiology of CKDGeneticsRisk Factors

• Hematologic derangements in CKDAnemia in CKDPlatelet dysfunction

CKD Topics

• You are consulted on a 10 day old Caucasian newborn who was small for gestational age. This first time mother had very limited prenatal care but it is estimated that the child’s gestational age was 37 weeks. During the course of evaluation in the nursery, the newborn’s serum creatinine has not varied and was 0.92 mg/dl as of today. This prompted a renal ultrasound to be obtained and the child was found to have bilateral small kidneys with increased echogenicity consistent with renal hypoplasia but no evidence of lower urinary tract obstruction.

Vignette

• Which of the following statements is MOST ACCURATE about renal hypoplasia?

A. It is caused by a single gene mutationB. It is the result of disordered interaction between

the branching ureteric bud and the metanephricmesenchyme.

C. It is a rare cause of CKD in children.D. The kidneys are small but there is a normal

complement of nephrons

Question 1

• A mutation to which of the following genes is MOST LIKELY to have caused this finding?

A. APOL1B. EYA1C. NPHS1D. PKHD1

Question 2

• Which of the following are risk factors for the development of CKD in this child?

A. Caucasian raceB. First bornC. Gestation of 37 weeksD. Low birth weight

Question 3

Definition of CKD

• Two independent criteria for CKD:– Kidney damage for ≥ for 3 months as defined by structural or

functional abnormalities of the kidney, with or without decreased GFR, manifest by either: pathological abnormalities; or markers of kidney damage, including abnormalities in the composition of the blood or urine; or abnormalities in imaging studies.

– GFR < 60 ml/min/1.73m2 for ≥ 3 months, with or without kidney damage.

3 components: Anatomical/Structural, Functional, Temporal

Epidemiology of CKD• US has one of the highest incidence of pediatric ESRD of

Westernized nations• Incidence of ESRD in US children has been slowly decreasing

since 2008.• Prevalence of ESRD plateaued between 2008-2012.• Minorities are disproportionately affected by CKD in

adolescence and young adulthood in part due to higher incidence of glomerulonephritis in minority populations.

• Most common causes of CKD in adults (diabetes and hypertension) have their origins in childhood but do not lead to CKD until adulthood.

• With the rising incidence of obesity and type II DM in our youth, the incidence of CKD is expected to increase.

NC Med J. May/June 2008, 69:3

CAKUT Glomerular disorders Hereditary disorders NAPRTCS 2010 Annual Report (Tx)

Epidemiology of CKD

Risk Factors for CKD

• Clinical FactorsLow birth weightReduction in renal massObstructive uropathiesFamily history of CKDUrinary Tract InfectionsDiabetesHypertensionAutoimmune diseasesExposure to certain drugsRecovery of AKI

• Sociodemographic FactorsUS ethnic minority status:

AA, Native American, Hispanic, Asian, Pacific Islander

Exposure to certain chemical and environmental conditions

Low incomeLow education

• CAKUTEYA1 (BOR), PAX2 (renal coloboma)other syndromes (Trisomy 21, VACTERL,…)Copy Number Variants (CNV)

• Hereditary nephropathiesPKHD1, PKD1/2, BBS1/10, UMOD,… (ciliopathies)CTNS, OCRL,… (tubulopathies) COL4A3/4A4/4A5 (Alport)

• Glomerular disordersNPHS1/2, ACTN4, WT1, PLCE1,… (SRNS)

• Susceptibility genesAPOL1 (FSGS, HIVAN), MYH9 (FSGS, HTN)

Genetics and CKD

A 10 year-old Caucasian girl presents with new onset nocturnalenuresis x6 months. She has been going to the bathroom frequently aswell as having fatigue. Her past medical history is negative including nohistory of UTIs. On physical exam, the girl has marked pallor but noother gross abnormalities, including her genital and spine exams.Urinalysis reveals: specific gravity 1.005, pH 5, and no blood, protein,glucose, LE, or nitrite. Serum creatinine is 1.6. CBC is notable for aHemoglobin of 6.2 gm/dl with normal MCV.Her MOST likely diagnosis is:

A) Sickle cell nephropathyB) Renal dysplasiaC) X-linked Nephrogenic Diabetes InsipidusD) Juvenile nephronophthisisE) Lithium toxicity

Question 4

That same girl later progresses to ESRD and is initiated on hemodialysis. She is getting good daily clearance with estimated Kt/V of 1.7. Her blood pressure is well-controlled on no medications, while she continues to have urine output. However, after 3 months on dialysis, her hemoglobin remains around 8-8.5 gm/dl despite doubling her ESA dose during the course of the month. Her CBC is otherwise normal with an MCV of 90. She has been given monthly doses of iv iron and her iron studies are: Serum Iron 120, TIBC 240, Ferritin 200. Her phosphorus remains elevated at 6.5, likewise her PTH is elevated at 1200. Her albumin level is 4.1 gm/dl with CRP of 0.8. Which of the following medications is MOST LIKELY to improve her anemia?

A) ACE inhibitorB) Folic acidC) ParicalcitolD) Prednisone

Question 5

• Definition of Anemia-Old K/DOQI- Hgb <11 gm/dl Newer- <5th %ile for age, sexKDIGO:0-5 y.o. (<11.0 gm/dl), 5-12 (<11.5), 12-15 (<12.0)Males >15 (<13.0), Females >15 (<12.0)

• Prevalence in CKD-Increasing prevalence with worsening GFRNo absolute GFR threshold- 18.5% of children with Stage 2 CKD

Anemia in CKD

• EPO- produced by Type 1 interstitial cells (fibroblast) of the renal cortex

• As GFR ↓, ↓ renal reabsorption of Na,↓ O2 utility leading to↑renal tissue O2 pressure↓ Epo production↑ apoptosis of erythroid progenitor cells↓ red cell production

Erythropoiesis

• Erythropoietin deficiency-more notable in interstitial diseases

NephronophthisisInterstitial Nephritis

• Iron deficiency

• Hemolytic diseases (↑LDH, ↓haptoglobin, DAT+)Hemolytic Uremic Syndrome (incl typical)

SLESickle cell disease

Anemia in CKD

• CBC with red cell indicesMCV (size of cells), RDW (deviation in

volume of cells)• Reticulocyte count (typically decreased)

Corrected: % retic x (pt hct/45)• Ferritin• Iron• Total iron binding capacity (TIBC)

Evaluation of Anemia in CKD

• Serum Folate levelsrbc folate levels

• Serum Vitamin B12 levels

• Other markers of iron statusreticulocyte Hgb Content (CHr)% hypochromic red blood cells (%HYPO)

• hs-CRP

Evaluation of Anemia in CKD

Low MCV (microcytosis)

Normal MCV High MCV (macrocytosis)

High RDW

Iron deficiencyHb S-β thalassemiaHemoglobin HErythrocyte fragmentation

Early iron deficiencyHemoglobinopathy (SS, SC)MyelofibrosisSideroblastic anemia

Folate deficiencyVitamin B12 deficiencyHemolytic anemiaCold agglutinin

Normal RDW

Heterozygous thalassemiaChronic disease

NormalChronic disease (renal, liver disease)Hemoglobinopathy (AS, AC)TransfusionChemotherapyHemorrhageCMLHered. spherocytosis

Aplastic anemiaPre-leukemia

Evaluation of Anemia in CKD

from Management of Renal Anemia in Pediatric Dialysis by Warady B, et al., Springer, 2004.

• TSAT = iron availability to support erythropoiesis

• Ferritin = storage of ironbut also an acute phase reactant

• Absolute Fe defic. = TSAT <20%, ferritin <100• Functional Fe defic. = TSAT <20%, ferritin >100

Evaluation of Anemia in CKD

• Potentially correctable versus non correctable factors involved in the anemia of CKD, in addition to ESA deficiency

• Easily correctable Potentially correctable Impossible to correct Absolute Fe defic. Infection/ inflammation Hemoglobinopathies Vit B12/folate defic. Under dialysis Bone marrow disorders Hypothyroidism Hemolysis ACEi/ARB Bleeding Non-adherence Hyperparathyroidism

MalnutritionMalignancy Pure Red Cell Aplasia

KDIGO Guidelines, KI, 2012

Evaluation of Anemia in CKD

Evaluation of Anemia in CKD

• Mainstays of Therapy- ESAs + supplemental iron• Correction of anemia has shown to improve:

Appetite Exercise toleranceOxygen utilization Sleep behaviorsIntelligence testing Quality of life scoresLVMI

• Hgb goals- debatable, esp for childrenK/DOQI- Hgb 11-12 gm/dlFDA- Hgb 10-12 gm/dlKDIGO- Hgb 11-12 gm/dl age dep. (<15), gender

dep. (>15)

Anemia in CKD

• ESAs in US for childrenrHuEPO (Epoetin-alfa- Epogen, Procrit)Darbepoetin-alfa (Aranesp)- aa substit.,

add’l N-glycosylation sites- longer t 1/2

• Complications:Too rapid rise of hgb (HTN, clotting access)HTN- direct effect on endotheliumCancer risk (myelogenous cancers)

Pure Red Cell Aplasia (drop in Hgb &retic- send Epo abs)

Anemia in CKD

• Other agents being considered

CERA (Cont Epo Receptor Activator)longer t 1/2

Epo mimetic peptides- PEGylated

Activin traps- traps TGF-β proteins

HIF stabilizers- prolyl hydroxylase inhib.oral agentsendogenous Epo- ↓ overall levels

enhance iron availability

Anemia in CKD

• Although thrombophilia is concern, uremia assoc’d. state of plt dysfct.

• Multifactorial:↑ NO synthesis by plt- ↓ plt aggreg.↓ plt ADP, serotonin- ↓ plt activ↓ Tx A2- poor plt adhesion & aggreg.↓ vWF and fibrinogen binding to GP

IIb/IIIa- ↓ plt adhesion to endothel.↑ phenolic acid- ↓ plt aggreg. to ADP↓ plt # and volume

Platelet Function in CKD

Platelet Function in CKD

• Evaluation-CBC (plt count)PT/PTT- should be normalBleeding time- typically uselessBleeding history- incl. family hx**

• Treatment-ddAVP- ↑vWF, ristocetin cof., TPAestrogens- ↓ NO synthesiscryoppt- risk of blood productscorrection of anemia

Platelet Function in CKD

• Thromobocytopenia-HUSSLE, autoimmune disordersRVT- typically 1st mo. of life

• Macro-thrombocytopenia-Epstein and Fechtner syndromes (w/ hereditary

nephritis)• Thrombophilia-

NS (↓ AT III levels, ↑ plt)SLE (Antiphospholipid Ab)

Platelets in Kidney Diseases