Year : 2022 | Volume
: 27 | Issue : 6 | Page : 663--665
Congenital anomalies of the kidney and urinary tract, biomarkers, and chronic kidney disease in children: A trajectory for the surgeon-scientists of the next generation
Minu Bajpai, Sachit Anand
Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
Professor and Head, Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi; Professor-In-Charge, International Co-Operation, Domestic and International MoU, All India Institute of Medical Sciences, New Delhi; Vice-President & Honorary Executive Director, National Board of Examination in Medical Sciences (NBEMS); Member of the Governing Council, National Board of Examination in Medical Sciences (NBEMS); Member of the Governing Council, Translational Health Science and Technology Institute (THSTI); Past President, Indian Association for Paediatric Surgeons; Editor, Journal of Indian Association for Paediatric Surgeons; Editor-in-Chief, Journal of Progress in Paediatric Urology; Convener, Indian & Asian Societies for Paediatric Urology, Delhi
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Bajpai M, Anand S. Congenital anomalies of the kidney and urinary tract, biomarkers, and chronic kidney disease in children: A trajectory for the surgeon-scientists of the next generation.J Indian Assoc Pediatr Surg 2022;27:663-665
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Bajpai M, Anand S. Congenital anomalies of the kidney and urinary tract, biomarkers, and chronic kidney disease in children: A trajectory for the surgeon-scientists of the next generation. J Indian Assoc Pediatr Surg [serial online] 2022 [cited 2022 Dec 7 ];27:663-665
Available from: https://www.jiaps.com/text.asp?2022/27/6/663/360975
As surgeon scientists, due to intense involvement in clinical activities, we have our triumphs but fewer Eureka moments during our lifetime. We must celebrate the minor victories in research that serve as morale boosters for the team and keep us moving forward. Our journey with biomarkers began in 2002 when we demonstrated the role of captopril renography in managing children with unilateral hydronephrosis. At that time, children with ureteropelvic junction obstruction (UPJO) were managed conservatively unless the differential function of the obstructed renal unit was <35%. The study unmasked an activated renin-angiotensin system (RAS) in a group of patients who later turned out to be surgical candidates. This study paved the way for another exciting research on the role of plasma renin activity (PRA) in the management of children with vesicoureteral reflux (VUR). It not only suggested that PRA levels could be helpful for therapy monitoring in a subset of cases with VUR but also concluded that raised PRA levels significantly correlate with the need for surgery in these cases.
Our interest in the homeostatic mechanisms and renal physiology kept on growing. In 2004, we conducted the first study that demonstrated the influence of genetic polymorphism in the angiotensin-converting enzyme (ACE) gene in Asian Indian children with congenital uropathies. In the study cohort, the presence of the D allele significantly correlated with progressive renal scarring and deterioration of kidney function. Our initial research had provided enough evidence on the activation of the RAS pathway in children with congenital anomalies of the kidney and urinary tract (CAKUT) and the underlying mechanism for ongoing renal injury. Therefore, as a next step, it was justified to explore the role of blockade of the RAS pathway in retarding the pace of renal injury in an experimental model of VUR. It was observed that the severity of renal scarring can be reduced on the treatment with agents causing blockade of the RAS pathway. The experimental model of unilateral UPJO also highlighted the beneficial effect of RAS-blockade on renal recovery and suggested that simply reversing the obstruction is not sufficient.
In our cohort of patients with posterior urethral valve (PUV), raised levels of PRA significantly correlated with the fall in glomerular function rate. In fact, a latent period between the rise in PRA levels and the fall in GFR suggested that PRA is an early marker for prognostication in these patients. With similar observations noticed in patients with unilateral UPJO, we concluded that both conditions engineer obstructive stress in the tubulointerstitial compartment which is reflected by raised PRA levels. In addition, the chronicity of rise in PRA levels had a bearing on the extent of recovery in these cases. Therefore, it is imperative to operate the patients with UPJO-type hydronephrosis and raised PRA levels at the earliest.
Similar to the International Reflux Study, we had followed the cases of primary VUR which were on nonoperative follow-up. On analyzing the mid-term results, it was noted that more than 60% of these cases required surgery. While a reduction in the PRA levels after surgery indicated the benefit of this intervention in one subgroup, the stabilization of PRA at levels higher than normal in patients continuing on nonoperative management suggested acquisition of autonomy by the juxtaglomerular apparatus. The latter now serves as an independent seat of activated RAS, thus, leading to ongoing injury and related consequences. Not only this, a subset of patients showed a resurgence of RAS activation after initial postsurgical fall, reflected by way of rising PRA and falling GFR. With therapy by RAS inhibitors, we demonstrated the benefits of RAS inhibitors in retrieving lost renal function.,
Consequent to these observations, it was logical to shift our focus to identify injury at its inception. This would enable us to do early intervention by anti-reflux surgery in VUR and institution of RAS inhibitors in late presenters in CAKUT for optimal recovery of function. With this premise, in 2013, we explored the role of urinary biomarkers such as Transforming growth factor-beta (TGF-β1), tumor necrosis factor-alpha (TNF-α), interleukin-16 (IL-6), and microalbumin for monitoring therapy in cases with PUV. In one subgroup, urinary TGF-β1, TNF-α, and microalbumin fell significantly after valve ablation. In another subset, the levels of these biomarkers showed a continued rise after a period of initial decline. This subgroup benefitted from the introduction of ACE-Inhibitor (ACE-I). The study proved that the introduction of ACE-I plays a significant role in retarding the pace of renal damage in these patients.
PRA levels were also studied in subsequent studies with distinct patient populations.,, In the first study, PRA levels correlated well with the extent of injury in patients with bilateral UPJO. In another study including children with VUR managed with endoscopic injection therapy with bulking agents, the levels of PRA significantly correlated with reflux resolution. The third study demonstrated the utility of cord blood PRA as a diagnostic marker in assisting the prenatal diagnosis of children with PUV. In the post hoc analysis, we had observed that a subset of children with deterioration of renal function in the form of fall in GFR during early follow-up had significantly elevated PRA levels in the cord blood. The phenomenon of dysregulation of RAS in hydronephrosis was also depicted by Stipsanelli et al. The authors had compared the levels of renin (both active and inactive) between fetuses with and without hydronephrosis. In fetuses with hydronephrosis, the levels of active and inactive renin were significantly elevated as compared to those without hydronephrosis, thus, highlighting that dilatation of the renal pelvis upregulates the RAS system.
Recently, we have explored the utility of new biomarkers, i.e., trefoil family factors (TFF), for predicting progressive deterioration of renal function in children with CAKUT. TFF3, a peptide responsible for restitution and repair, is believed to be the best predictor of progressive renal damage in these cases. Furthermore, the levels of TFF3 were sky high in subjects with genetic polymorphisms of RAS-candidate genes, thereby supporting the role of an activated RAS pathway in these cases. Ongoing search demanded identification and differentiation between disease-causing genetic influences and gene modulations in CAKUT. For this, we have now employed transcriptomics to unravel events at the early stages of mRNA mobilization and a study on exosomes. The “proof of mechanism of injury” has been established by observing the footprints of RAS activation in the form of nuclear factor-kappa B, osteopontin, clusterin, etc., in experimental rat models. In addition, our early observations highlight the correlation of nephrogenic genes on influencing the phenotypes of CAKUT, and the risk conferred by them on the simultaneously existing genetic polymorphisms in RAS pathway. The results have signaled the “double hit” hypothesis and promise close monitoring of “at risk” CAKUT children even before any signs of evident injury with a potential for genetic counseling.
In the past two decades (2002–2022), we have conducted a number of clinical and experimental studies comprising more than a 1000 children and several projects on Wistar rats, respectively. We have explored a host of different biomarkers with diagnostic and/or prognostic significance during this period. These studies have flagged off, hitherto, and unexplored territory for the gaps in knowledge that need to be bridged if the burden of renal morbidity due to CAKUT is to be decisively addressed. We believe that our journey with biomarkers for CAKUT is a Eureka moment for us. It certainly supports the motto that “Science is not the truth, but the search for the truth.”
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|2||Bajpai M, Pal K, Bal CS, Gupta AK, Pandey RM. Role of plasma renin activity in the management of primary vesicoureteric reflux: A preliminary report. Kidney Int 2003;64:1643-7.|
|3||Bajpai M, Pratap A, Somitesh C, Tyagi J. Angiotensin converting enzyme gene polymorphism in Asian Indian children with congenital uropathies. J Urol 2004;171:838-40.|
|4||Singhal AK, Bajpai M, Dinda AK. Blockade of Rennin-Angiotensin system blunts the fibrotic response in experimental acute pyelonephritis. J Indian Assoc Pediatr Surg 2005;10:20-4.|
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|12||Mandelia A, Bajpai M, Agarwala S, Gupta AK, Kumar R, Ali A. The role of urinary TGF-β1, TNF-α, IL-6 and microalbuminuria for monitoring therapy in posterior urethral valves. Pediatr Nephrol 2013;28:1991-2001.|
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|17||Anand S, Bajpai M, Khanna T, Kumar A. Urinary biomarkers as point-of-care tests for predicting progressive deterioration of kidney function in congenital anomalies of kidney and urinary tract: Trefoil family factors (TFFs) as the emerging biomarkers. Pediatr Nephrol 2021;36:1465-72.|
|18||Anand S, Bajpai M, Khanna T, Kumar A. Influence of genetic polymorphism in renin-angiotensin system-candidate genes on urinary trefoil family factor 3 levels in children with congenital anomalies of kidney and urinary tract. Pediatr Nephrol 2022;37:139-45.|