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Home , Leukocyte esterase, Proteinuria, UPCR

Storm in a Pee Cup: and

Sudha Garimella MD Pediatric , Children's Hospital-Upstate Greenville SC Conflict of Interest

• I have no financial conflict of interest to disclose concerning this presentation. Objectives

• Interpret the current guidelines for screening urinalysis, and when to obtain a urinalysis in the pediatric office. • Interpret the evaluation of asymptomatic/isolated proteinuria and definitions of abnormal ranges. • Explain the evaluation and differential diagnosis of microscopic hematuria. • Explain the evaluation and differential diagnosis of gross hematuria. • Explain and discuss appropriate referral patterns for hematuria. • Racial disparities in nephrology care 1. APOL-1 gene preponderance in African Americans and risk of proteinuria /progression(FSGS) 2. Race based GFR calculations which have caused harm 3. ACEI/ARB usage in AA populations: myths and reality Nephrology Problems in the Office

• • Proteinuria • Microscopic Hematuria • Abnormal Renal function The Screening Urinalysis

• Choosing Wisely: • Don’t order routine screening analyses (UA) in healthy, asymptomatic pediatric patients as part of routine well child care. • One study showed that the calculated false positive/transient abnormality rate approaches 84%. • Population that deserves screening UA: • patients who are at high risk for chronic disease (CKD), including but not necessarily limited to patients with a personal history of CKD, acute kidney injury (AKI), congenital anomalies of the urinary tract, acute , hypertension (HTN), active systemic disease, prematurity, intrauterine growth retardation, or a family history of genetic renal disease.

• https://www.choosingwisely.org/societies/american-academy-of-pediatrics-section-on- nephrology-and-the-american-society-of-pediatric-nephrology/ Screening Urinalysis: Components

A positive test for may be seen in genitourinary inflammation, irritation from instrumentation or catheterization, , UTIs and sexually transmitted . Leukocyte esterase has a good negative predictive value but poor positive predictive value to diagnose . A positive test for nitrite can indicate presence of gram-negative , but it does not diagnose UTI in the absence of symptoms. Similarly, a negative test for nitrite does not rule out UTI, as some urinary pathogens like enterococcus do not produce nitrite. In addition, false-positive results for nitrite occurs on exposure to air or , or from preanalytic contamination. As such, nitrite has poor sensitivity and specificity for diagnosing a UTI. Advani, S., Polage, C., & Fakih, M. (2021). Deconstructing the urinalysis: A novel approach to diagnostic and antimicrobial stewardship. Antimicrobial Stewardship & Healthcare Epidemiology, 1(1), E6. doi:10.1017/ash.2021.167 When should we obtain a screening Urinalysis?

• Until 2007, the American Academy of (AAP) recommended that all children undergo a dipstick urinalysis at 5 years of age and during adolescence if sexually active. The AAP no longer recommends that children undergo screening dipstick urinalysis. • Pre-Participation physicals may require UA results but the form developed by the AAP Council of sports and fitness does not. • Asymptomatic youth should get a screening urinalysis only if they have risk of . • ,sickle cell,AKI,PIGN,HSP or strong family history of kidney disease. Proteinuria

• Most common findings in healthy asymptomatic children undergoing routine UA: Proteinuria/microscopic hematuria. • Most common reason for proteinuria remains orthostatic proteinuria. • A false positive dipstick reading for can be present when Ph>7 (alkaline urine). • Ascorbic acid interferes with , , nitrite, and at different concentrations causing false-negative results. Definition

• Normal urine protein varies by age in children, 150 mg in adults. • 50%, Tamm Horsfall protein • Measurement • Dipstick- Albumin detected Semi-quantitative ( 1+=30 mg/dl ) Dependent on Urine pH and Concentration Ascorbic Acid Measurement

• Spot Urine Protein Ratio on a first morning sample. • 24 Hr urine protein is estimated by multiplying the ratio by 0.63 • • Beta-2 Microglobulin • Alpha -1- microglobulin • Retinol Binding protein UPCR

• Upper limit of normal for the spot urine protein-to-creatinine ratio varies by age as follows: • Age 6 months to 24 months (infants and toddlers) <0.5 mg protein/mg creatinine. • Age 24 months to 18 years (children and young adults) <0.2 mg protein/mg creatinine. • The spot urine protein-to-creatinine ratio that is indicative of nephrotic range proteinuria is >3 mg protein/mg creatinine.

APOL-1 FSGS

• Rates of many types of severe kidney disease are much higher in Black individuals than most other ethnic groups. Much of this disparity can now be attributed to genetic variants in the apoL1 (APOL1) gene found only in individuals with recent African ancestry. These variants greatly increase rates of hypertension-associated ESKD, FSGS, HIV-associated nephropathy, and other forms of nondiabetic kidney disease. ACE Inhibitors: A nephrologist’s best friend!

• One recent study suggests that hypertension in Black individuals may respond differently to angiotensin-converting enzyme inhibitors on the basis of APOL1 genotype, with APOL1 high-risk genotype carriers experiencing greater response in BP than noncarriers . • Studies in adults that showed better BP control with diuretics for Black patients (AASK, ALLHAT) but gains were marginal and ACEi/ARBs should be considered especially if kidney disease present. • Some Afro-Caribbean families do have angioedema type reactions with ACEi. Always ASK. Approach

• History • Recent illnesses; ; exercise • Weight gain, swelling, urine output • Growth history • Medications causing interstitial nephritis-, NSAIDs, Chemotherapy • Recurrent UTIs • Familial Kidney diseases Approach

Leung AK, Wong AH, Barg SS. Proteinuria in Children: Evaluation and Differential Diagnosis. Am Fam . 2017 Feb 15;95(4):248-254. PMID: 28290633. Microscopic Hematuria

• Common finding on routine urinalysis • Common early finding in children with kidney stone risk • Common early finding in progressive kidney diseases like chronic glomerulonephritis Approach

Microscopic hematuria

Isolated transient Isolated persistent Associated with proteinuria

Benign familial IgAN TBMD HSPN UTI,STONES,TRAUMA Hypercalciuria Complement GN Alport IgAN Approach • False Positive for Red Blood Cells • • • with high pseudoperoxidase activity-staph, strep, enterococci Approach

• History • family hx of benign hematuria • family hx of stones • deafness/ckd/dialysis/transplant • PE :Usually healthy appearing child but look for local erythema/trauma/sexual abuse red flags • Consider obtaining a urine culture in young child • Urine calcium creatinine ratio/Litholink Urine Calcium Creatinine ratios by age

AGE MG/DL

0 - 6 months

7 - 11 months

>/= 1 year

James D. Sargent, Therese A. Stukel, James Kresel, Robert Z. Klein Normal values for random urinary calcium to creatinine ratios in infancy, The Journal of Pediatrics, Volume 123, Issue 3,1993,Pages 393-397. Pediatric GFR Calculations:

• https://www.kidney.org/professionals/kdoqi/gfr_calculatorped • CKiD Formula 0.413*Height(cm)/ creatinine (mg/dl) • Adult formulae-MDRD, Cockcroft-Gault add a race correction which was based on a false premise that AA had a higher muscle mass. • Patients are placed on a kidney transplant list when their GFR drops below 15, preemptive transplants need GFRbelow 20. This led to systematic delays in transplantation for AA adults. • Ped formula never included any correction( Schwartz). Cystatin C

• 13 kD non-glycosylated basic protein produced by all nucleated cells • Freely filtered at the , reabsorbed and catabolized by PCT, very little escapes in urine normally • Less affected by age, sex, muscle mass • Normative data exists in pediatrics , even for premature infants and IUGR • Clearly shown to be better at estimating GFR But..

• Cannot calculate urine clearance, so hard to study factors affecting clearance and generation • Some studies have reported increased cystatin levels with increased CRP, hyperthyroidism or steroid use • More intra-individual variability in transplant population • BMI seems to affect cystatin C