The spectrum of renal scarring Parvex, Willi, Kossovsky, Girardin, pediatric nephrology, Geneva University, Switzerland

Background UTI is common condition in childhood with a prevalence of 3%, the prevalence of pyelonephritis (PNA) is not clearly reported Infant and children presenting unexplained fever of ≥ 38° and positive urine culture will be diagnosed with PNA

Background The goal of medical management of PNA Initiate early treatment to decrease renal inflammation and subsequently scars Identify risk factor to avoid new infections episodes and prevent scars development Exclude urologic anomalies (renal echography) Detect vesico-ureteral reflux (cystography)

Pathogenesis of scars It is important to differentiate acquired segmental scarring associated with VUR and PNA From congenital “scars” corresponding to an anomaly in the metanephric development in boys and associated with high grade VUR Histological analyses of these later lesions showed renal dysplasia which may mimic scarring without an acute episode of PNA

Renal scintigraphy Since 1980, renal scintigraphy with TechnetiumTc labeled with dimercapto-succinyl-acid DMSA replaced IVP and improved in the detection of renal scars has been validated to be the most sensitive method for imaging in the diagnosis of acute PNA and for renal scars

Normal kidney Acute PNA Renal scars

What is known form the literature Did early antibiotic treatment avoid scar formation? How important is the grade of VUR? Is the risk to do scars related to age? Are scars leading to hypertension (HTA) in adulthood?

Early treatment (T)? Recent data suggest that if early T decrease renal inflammation in the acute phase However in this patients (n=186) early T seems not to decrease the risk of later scars (T<24H or T>24H) Doganis, D. et al. Pediatrics 2007;120:e922-e928

Role of VUR? VUR is considered to be the principal risk factor to favor PNA and therefore renal scars The incidence of VUR in children presenting PNA varies among studies from 30 to 50% Even if scars can develop without VUR or low grade VUR however the risk increased with high grade VUR

VUR and severity of scars Gonzalez et al. The Journal of Urology , Volume 173 , Issue 2 , Pages 571 - 575

Age and risk factor Benador et al Vol 379, January 1997, Pages 17-19

Vol 379, January 1997, Pages 17-19

HTA One of the main concern are further development of hypertension in children presenting scars Hypertension affects among series 5-27% of children; however the literature have not showed strong evidence until known

Risk for the future: HTA A 15 years follow-up of BP studied 78 Pts with reflux nephropathy All were normal BP at time of inclusion 18/78 pts became HTA(>95th) during the following 15 years; 6 from them had a family history for HTA

Systolic and diastolic BP at 5,10,15 years follow-ups Chulananda et al. Vol 347, March 9,1996

Risks for the future: HTA The following recorded 24HBP in 61 pts classified in different groups according to the severity of DMSA lesions Type 1: normal reniforme shape but polar area with photon deficiency Type 2: focal defect in a nondeformed kidney Type 3: Smaller kidney compared to controlateral Type 4a:Loss of renal contour with normal size kidney Type 4b:similar from above with small kidney

Is this increase of BP at night a sign of further evolution of HTA in adulthood needs to be confirmed by long term studies J Pediatr. Patzer et al 2003 Feb;142(2):117-22.

What is the long term significance of scars?

Background The presence of lesions on DMSA 6 month after PNA are considered to be definitive kidney scars According to the literature the rate of acute lesions and later scars varies among studies

Questions? Did these lesions still have the potential to evolve after 6 month Did this lesions interfere with normal renal growth

Aim of the study To analyze long term progression of renal lesions in children with presence of scars on the first DMSA To assess long term renal growth To identify variables which could impact on renal growth in this children

Material This prospective study was conducted over two years and included Children from 0-18 years with a diagnosis of PNA and who presented renal scars 6 month after the first episode of PNA Exclusion criteria Children with complex uro-genital malformations, dysplastic kidneys, megaurether, hydronephrosis

Methods Each patient with scars was contacted to have a repeated DMSA 3 years later At the same time we repeated a renal echography to measure kidney size

To analyze progression of DMSA defects, RU was divided in 3 areas Scar progression was analyzed separately for each area by 3 observers in a blinded fashion and classified as follow No change Partial resolution Total disappearance Upper pole Mid zone Lower pole

b b a a 1B 1A 1A DMSA 6 month after PNA 1B DMSA 3 years later: we observe 2 types of lesions: a) the lesion situated in the mid-zone of left kidney did not change b) The lesion located in the right upper pole improved. 2A a a 2A b 2B b 2A DMSA 6 month 2B DMSA 3 years later: we observe a) disappearance of mid-zone lesion of left kidney b) no change in lower lesion of right kidney Parvex et al The Journal of Urology on Press

Kidney growth (cm) Kidney size was measured Time 0 corresponding to the PNA (T0) and 3 years later Time 3 (T3) at the same time of the repeated DMSA

*AJR Am J Roentgenol 1984;142(3):467-9. Renal size was measured at T0 and T 3 and values compared to standard deviation score (SDS ) renal sizes* relative to age The following equation were used*to calculate Z-score *<1 year length (cm)= 4.98+0.55 x age(mths)(t90 = 6.86, p<0.001;SD=0.69;r2=0.3437 *≥ 1 year length (cm)= 6.79+0.22 x age(years)(t326 = 28, <0.001;SD=0.79;r2=0.7077 Renal growth between T0 and T3 was calculated with the ∆z-score = or + ∆z-score correspond to adequate renal growth - ∆z-score correspond in loss of renal growth *AJR Am J Roentgenol 1984;142(3):467-9.

Results 50 (30G:20B) children; M age of 4.1 Boys were younger 15/20 ≤2years(75%) against 9/30 (30%) girls VUR was present in 36% of patients and 25% of renal units (RU)

Incidence and evolution of VUR

Number of scars & Grade of VUR P=0.01 Number of scars NO VUR VUR GI-II VUR GIII-IV Parvex et al The Journal of Urology in Press

Progression of renal scars % scar improvement 27% 63% 9% no change partial improvement total disappearance Altogether 72% of lesions improved over 3 years

Impact of scars on kidney growth Analyze Coefficient ∆z-score Significance (p) 95% conf. interval 1 defect* Reference - 2 defects -0.32 0.41 -1.09 to 0.45 3 defects -0.81 -2.75 to 1.14 4 defects -1.59 0.000 -2.10 to -1.09 5 defects -1.73 0.006 -2.94 to -0.51 Table1: Univariate linear regression analysis of the association between the numbers of defects and renal growth (coefficient=∆ z-score) Parvex et al The Journal of Urology in Press

Analyze coefficient Significance (p) 95% conf. interval Sex (M vs. F) 0.49 0.14 -0.16 to 1.14 Age (years) ≤ 1* (n=13) > 1 to ≤ 4 (n=20) > 5 (n=17) - 0.28 0.72 0.42 0.12 -0.41 to 0.96 -0.18 to 1.62 Total n° of defects (Per additional defect) -0.70 <0.001 -1.05 to -0.35 Lesions progression (Improvement vs. no change) 0.70 0.15 -0.26 to 1.66 Grade of VUR at time of PNA No reflux * Grade I or II Grade III or IV 0.75 0.33 0.34 -0.21 to 1.72 -0.36 to 1.02 Improvement of VUR >3 years (Yes vs. No) 0.25 0.23 -0.17 to 0.67 Persistence of VUR >3 years (Yes vs. No) -1.67 to 0.30 Surgery (Yes vs. No) 0.41 -0.36 to 0.86 Table 2: Multivariable analysis of factors associated with renal growth (coefficient = ∆z-score) Parvex et al The Journal of Urology in Press

In summary The topographic analyses of renal defects over 3 years showed 72% of improvement The number of scars were statistically significantly higher in RU with high grade VUR versus low grade or no VUR. Parvex et al The Journal of Urology in Press

Loss of kidney growth over 3 years was observed with an increased number of scars and this was highly significantly >3 scars persistence of VUR>3 years The kidney growth did not seem affected by Sexe, age Grade of VUR Improvement of DMSA defects Parvex et al The Journal of Urology in Press

Conclusion Renal defects seen at 6 month post PNA can still evolve with time and this raise the question of the definition of scars From this study preventing additional renal defects seems to be the best way to optimize kidney growth during childhood Parvex et al The Journal of Urology on Press

Open questions and further perspectives Improve knowledge of the congenital “scar” associating renal dysplasia and HGVUR To define if the best way to prevent renal lesions in high grade VUR is prophylaxis? surgery? Long term studies to assess the risk HTA in scarred kidneys, with decreased renal growth

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