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      Kidneys - kindergarten to graduation

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      Indian Journal of Nephrology
      Medknow Publications & Media Pvt Ltd

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          Abstract

          From diapers to the graduation hat, kidneys have to mature from their infancy, childhood, and adolescence before reaching adulthood. This crucial journey of kiddy kidneys needs a favorable environment for growth, development and nourishment so as to graduate into young adult kidneys at 18 years of age. Caring for such a dynamic phase of kidney maturation becomes the prime responsibility of the pediatric nephrologist. On account of the World Kidney Day 2016, that focuses on Kidney disease and children, it is befitting to look at the unique challenges posed by these pediatric kidneys from an Indian perspective. The Very Beginning The critical number Nephrogenesis begins at 9th week of gestation and continues through 34th–36th weeks of gestation after which time no new nephrons are formed. With an average of 1 million nephrons per kidney,[1] it is predicted that there is an increase of 257,426 glomeruli per kilogram increase in birth weight.[2] Clinical surrogates for low nephron number and susceptibility to hypertension and renal disease in adulthood are low birth weight, preterm birth, short stature, low kidney volume, glomerulomegaly, gene polymorphisms, and maternal gestational hyperglycemia.[3] Exploring the concept of adult diseases having their roots in childhood, South Asian adults are at high risk for premature severe chronic kidney disease (CKD)[4 5] and harbor a greater propensity to third-trimester growth restriction which impacts on the developing kidney, leading to reduced kidney volume.[6] Besides the fact that India is the cradle for 40% of all low birth weight babies in the developing world,[7] maternal nutrition including Vitamin A status could influence nephrogenesis and renal volumes in the newborn.[8] Developmental pangs Congenital anomalies of the kidney and urinary tract (CAKUT) are part of a syndrome or sequence that leads to end-stage renal disease in children. The genetic diagnosis of CAKUT has proven to be challenging due to genetic and phenotypic heterogeneity and influence of epigenetic and environmental factors on kidney development.[9 10] Specific renal diseases such as polycystic kidney disease and primary hyperoxaluria, known to be prevalent in India, progressing to CKD, share an autosomal recessive inheritance. Consanguineous marriage is a cultural phenomenon that is associated with kidney disease and is prevalent in many Asian countries[11] including rural India. Consanguinity and genetic predisposition add to the risk of CAKUT, reflux nephropathy, and urinary tract obstruction that are major contributors to CKD. Just born kidneys Newborn kidneys are immature and susceptible to hypoperfusion, low glomerular filtration rate, high renal vascular resistance, high plasma renin activity, decreased intercortical perfusion, and decreased reabsorption of sodium in the proximal tubules.[12] The paucity of Indian data on neonatal acute kidney injury (AKI) is alarming. Besides sepsis and hypovolemia, Gupta et al.[13] highlighted perinatal asphyxia as an important risk factor for neonatal AKI. With limitations in obtaining baseline serum creatinine values and urine output assessment in neonates, many categorical definitions of neonatal AKI such as the Neonatal Risk, Injury, Failure, Loss of kidney function and End stage kidney Disease (nRIFLE), AKI network (AKIN), and modified kidney disease improving global outcomes criteria (KDIGO) pose challenges in the stratification of levels of severity and early recognition of AKI in clinical practice.[14] The Formative Years An interesting feature of pediatric renal diseases is that there is a difference in the occurrence of disease with age and variation in the manifestation of the same disease at different phases of childhood: While tubular disorders predominate during infancy and early childhood, majority of glomerular diseases are generally seen beyond the first few years of life. Hypertension, urinary tract infection, and CKD are notorious to have contrasting clinical manifestations that vary with age. Challenging signs As in adults, hematuria, oliguria, and edema are the most striking signs of renal disease, commonly a signature of glomerular disease. However, in children, many signs of kidney disease are either hidden or they mimic other systemic diseases. For example, failure to thrive or growth retardation, recurrent vomiting, and respiratory distress could be the only signs of CKD or a tubular disorder. Bone deformities and neurological manifestations could be indicators of underlying tubular disorders. The Pandora's box on genetics Molecular genetics and genomic science have opened new challenges in patient care. In India, Pediatric nephrology has made considerable progress in establishing genetic analysis for diseases such as nephrotic syndrome and hemolytic uremic syndrome. The acute kidney injury-chronic kidney disease continuum The incidence of pediatric AKI (Acute Kidney Injury) in hospitalized children[15] is as high as 36%. The etiological spectrum ranges from tropical systemic infections, sepsis with multi-organ dysfunction, and snake envenomation to primary renal diseases. Use of alternative forms medicine poses an additional challenge. Neonates, who survive sepsis or asphyxia with neonatal AKI,[16] including urinary tract obstruction, are at high risk for developing CKD. Systematic monitoring of the AKI-CKD clinical syndrome is the need of the hour. Sensitization and active assessment of possible sequelae of AKI that has been proposed by the ASSESS-AKI study[17] need implementation in neonates and children in our country. Renal recovery To ascertain renal recovery in children is a challenge.[18] Glomerular filtration rate (GFR) increases over the 1st year of life from 15 to 90 ml/min/1.73 m2 resulting in difficulty in deriving an AKI threshold.[19] The current CKD studies and definitions exclude children under 1 year of age making the diagnosis of CKD difficult in small children.[20] Finally, children are born with substantial relative renal reserve, with more than sufficient clearance capacity in relation to their metabolic output. As estimated renal function is associated with height in children, linear growth plays a role in preserving renal function. The chronic blues Chronic glomerulonephritis, hypodysplasia, and obstructive uropathies have dominated the list of causes of pediatric CKD in many developing countries.[21] Advances in the management strategies and availability of certain immunosuppressive therapies have helped control common glomerular diseases.[22 23] Though dialysis therapy is considered a bridge to transplantation in children, we are faced with many challenges related to cardiovascular morbidity, nutrition, anemia, and bone mineral disease in addition to the issues of financial burden and quality of life. The gift of life Live related and deceased organ renal transplantation in children is gathering momentum in a few centers across the nation.[24 25 26 27 28] However, the real challenge lies not only in escalating the number of transplants but more importantly in optimizing the long-term care of the allograft posttransplant. The overall 5 years and 10 years graft survival are reported to be between 80–86% and 70–75%, respectively.[24 25 26 27 28] Urological issues and interventions play a vital role in pediatric transplantation. Focal segmental glomerulosclerosis is a major cause for End Stage Renal Disease, and we have shown the variation in the genetic polymorphisms among Indian children[29] with recurrence post renal transplant[30] being an additional economic burden. Graduation The graduation day for kidneys is when the adult nephrologist takes over care of young adult kidneys. The weaning period from the pediatric nephrologist has to be a gradual process undertaken in Transition Clinics. Care of kidneys in children often demands a multidisciplinary approach with formal psychosocial counseling services, which may need focus into adulthood. Parenting kidneys is just not treating children with kidney disease. The broader perspective lies in implementing Preventive strategies; Outreach initiatives for prompt and early diagnosis; Training and collaborations for faculty development and capacity building; and relevant research programs for holistic renal care - A message that should reverberate not only on World Kidney Day but on every other day!

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          Most cited references26

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          Glomerular number and size in autopsy kidneys: the relationship to birth weight.

          In the Southeast United States, African Americans have an estimated incidence of hypertension and end-stage renal disease (ESRD) that is five times greater than Caucasians. Higher rates of low birth weight (LBW) among African Americans is suggested to predispose African Americans to the higher risk, possibly by reducing the number of glomeruli that develop in the kidney. This study investigates the relationships between age, race, gender, total glomerular number (Nglom), mean glomerular volume (Vglom), body surface area (BSA), and birth weight. Stereologic estimates of Nglom and Vglom were obtained using the physical disector/fractionator combination for autopsy kidneys from 37 African Americans and 19 Caucasians. Nglom was normally distributed and ranged from 227,327 to 1,825,380, an 8.0-fold difference. A direct linear relationship was observed between Nglom and birth weight (r = 0.423, P = 0.0012) with a regression coefficient that predicted an increase of 257,426 glomeruli per kilogram increase in birth weight (alpha = 0.050:0.908). Among adults there was a 4.9-fold range in Vglom, and in adults, Vglom was strongly and inversely correlated with Nglom (r =-0.640, P = 0.000002). Adult Vglom showed no significant correlation with BSA for males (r = -0.0150, P = 0.936), although it did for females (r = 0.606, P = 0.022). No racial differences in average Nglom or Vglom were observed. Birth weight is a strong determinant of Nglom and thereby of glomerular size in the postnatal kidney. The findings support the hypothesis that LBW by impairing nephron development is a risk factor for hypertension and ESRD in adulthood.
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            Glomerular number and size in relation to age, kidney weight, and body surface in normal man.

            The number and size of glomeruli in normal, mature human kidneys were estimated by a direct and unbiased stereological method, the fractionator. The number was 617,000 on average, and the mean size 6.0 M microns3. Both glomerular number and size showed significant negative correlation to age and significant positive correlation to kidney weight. Apparently, humans loose glomeruli with age. Body surface area correlated positively to kidney weight and total glomerular volume but not to number of glomeruli. Body surface area correlates significantly with metabolic rate (Robertson and Reid, Lancet, 1: 940-943, 1952). Thus, intraspecies adaptation of kidney filtration capacity to the metabolic demand is performed by changing the size of glomeruli, i.e., the number of glomeruli in individuals of a given species is independent of the metabolic rate.
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              The clinical importance of nephron mass.

              Abundant evidence supports the association between low birth weight (LBW) and renal dysfunction in humans. Anatomic measurements of infants, children, and adults show significant inverse correlation between LBW and nephron number. Nephron numbers are also lower in individuals with hypertension compared with normotension among white and Australian Aboriginal populations. The relationship between nephron number and hypertension among black individuals is still unclear, although the high incidence of LBW predicts low nephron number in this population as well. LBW, a surrogate for low nephron number, also associates with increasing BP from childhood to adulthood and increasing risk for chronic kidney disease in later life. Because nephron numbers can be counted only postmortem, surrogate markers such as birth weight, prematurity, adult height, reduced renal size, and glomerulomegaly are potentially useful for risk stratification, for example, during living-donor assessment. Because early postnatal growth also affects subsequent risk for higher BP or reduced renal function, postnatal nutrition, a potentially modifiable factor, in addition to intrauterine effects, has significant influence on long-term cardiovascular and renal health.
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                Author and article information

                Journal
                Indian J Nephrol
                Indian J Nephrol
                IJN
                Indian Journal of Nephrology
                Medknow Publications & Media Pvt Ltd (India )
                0971-4065
                1998-3662
                Mar-Apr 2016
                : 26
                : 2
                : 77-79
                Affiliations
                [1]Department of Pediatric Nephrology, St John's Medical College Hospital, Bengaluru, Karnataka, India
                Author notes
                Address for correspondence: Dr. A. A. Iyengar, Department of Pediatric Nephrology, St John's Medical College Hospital, Bengaluru - 560 034, Karnataka, India. E-mail: arpanaiyengar@ 123456gmail.com
                Article
                IJN-26-77
                10.4103/0971-4065.177731
                4795440
                27051129
                9e0ffd1f-49c6-4050-ac96-ec31b5210631
                Copyright: © 2016 Indian Journal of Nephrology

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

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                Special Feature - World Kidney Day

                Nephrology
                Nephrology

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