When Is One Kidney Not Enough? Shoe Kidney

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multicystic dysplastic kidney, and horse- When is one kidney not enough? shoe kidney. By 30 years of age, 19% of all patients were receiving dialysis treatment, 1 Robert L. Chevalier the majority of whom had posterior urethral valves, bilateral hypodysplasia, or Most renal failure in children results from congenital anomalies of the solitary kidney. Consistent with previous kidney and urinary tract (CAKUTs). Sanna-Cherchi et al. predict that by studies, patients with posterior urethral 30 years of age, nearly 50% of patients with a solitary kidney would be valves had the most rapid progression to receiving dialysis. This outcome differs markedly from that of renal- dialysis. Surprisingly, however, the analysis transplant donors, who have no increased risk for renal failure. Because revealed that patients with solitary kidney have a probability of nearly 50% of requir- morbidity from CAKUTs may not develop until adulthood, these patients ing dialysis by 30 years of age.5 Because of should be closely followed throughout life. a lack of universal renal imaging, there are Kidney International (2009) 76, 475 – 477. doi: 10.1038/ki.2009.244 few published reports on the epidemiology of solitary kidney, and no previous long- term studies. It should be noted that the A global epidemic of chronic kidney dis- whom may have impaired nephrogene- majority of patients with solitary kidney in ease has highlighted the need for under- sis, contributing also to reduced neph- this study were diagnosed beyond the neo- standing of the factors determining ron number. 3 Th ese reports underscore natal period, at a mean age of 15 years, but progression to end-stage renal disease, the the importance of birth weight and peri- had normal mean creatinine concentra- development of biomarkers to improve natal history in determining long-term tion. 5 Th e patients diagnosed at birth had early detection, and new strategies for risk of progression of renal disease. slightly elevated mean creatinine concen- intervention and preservation of renal Unlike in the adult, most renal failure in tration for age (0.68 mg / dl), which was function. Although attention is largely the child is due to congenital anomalies of lower than that of neonatal patients with focused on the rapid increase in obesity, the kidney and urinary tract (CAKUTs). 4 bilateral hypodysplasia or posterior ure- hypertension, and diabetes in adults, the Although some of these disorders are thral valves. epidemiology of renal failure in children detected as part of a syndrome aff ecting In a retrospective review of 157 adult is also relevant to nephrologists caring for multiple organ systems, or a positive fam- patients with unilateral renal agenesis diag- adults because increasing numbers of ily history, most are sporadic and isolated nosed at the Mayo Clinic between 1960 patients with congenital renal disease are to the urinary tract. In many developed and 1975, 47% developed hypertension, surviving to adulthood. countries, maldevelopment of the urinary 19% proteinuria, and 13% decreased Evidence is accumulating to suggest tract is detected most oft en by fetal ultra- glomerular fi ltration rate, and 4 % died of that progression of renal disease in sonography, with fewer patients present- renal failure.6 All of these patients demon- adulthood is accelerated in subjects with ing in later childhood with urinary tract strated compensatory renal growth and low birth weight (and decreased number infection, hypertension, or proteinuria. had no proteinuria at the time of diagnosis, of nephrons).1 It is also now clear that Unfortunately, most reports of progres- but 54% of patients tested had an increased there is an eightfold range in normal sion of pediatric kidney disease are lim- fi ltration fraction. Th e investigators con- variation in the number of glomeruli in ited by small patient numbers and short cluded that unilateral renal agenesis poses humans, ranging from 200,000 to 1.8 follow-up periods. significant risks even in the absence of million. 2 It is therefore likely that sub- Sanna-Cherchi et al. 5 (this issue) have structural anomalies of the kidney.6 Look- jects at the lower end of this spectrum analyzed the long-term renal outcome of ing at the natural history of solitary kidney are at greater risk of progression of renal over 300 children with CAKUTs recruited from a diff erent perspective, pathologists insuffi ciency regardless of etiology or over a 20-year period in a single pediatric reviewed over 500 surgical renal specimens age of onset. Advances in technology for nephrology center in Italy. With simple and identifi ed 29 cases of focal and seg- the care of preterm infants have led to selection criteria (presence of anomalies mental glomerulosclerosis; fi ve of these the survival of increasing numbers of in kidney number or size), dialysis-free (18 % ) were cases of unilateral renal agen- very-low-birth-weight infants, many of survival from birth was modeled to esis. 7 Moreover, in 9200 autopsies, solitary account for concomitant vesicoureteral kidneys were found in seven cases, of refl ux, age at diagnosis, hypertension, pro- which two had died of focal glomeruloscle- 1 Department of Pediatrics, University of Virginia , teinuria, and serum creatinine concentra- rosis.7 In adults who had undergone uni- Charlottesville , Virginia , USA tion. Th e investigators designed a practical lateral nephrectomy in childhood for Correspondence: Robert L. Chevalier, Department of Pediatrics, Box 800386, University classifi cation of six categories, comprising medical indications (obstructive uropathy, of Virginia Health System, Charlottesville, solitary kidney, unilateral and bilateral vesicoureteral refl ux, or Wilms’ tumor), Virginia 22908, USA. E-mail: [email protected] hypodysplasia, posterior urethral valves, 30 % developed renal insuffi ciency, 27 %

Kidney International (2009) 76 475 commentary

autoregulation of renal blood flow is impaired in rats subjected to unilateral nephrectomy in the neonatal period, but autoregulation is preserved in uninephrectomized adult animals. 13 Th is would

Obstetrics Pediatrics Adult care augment glomerular pressure in the nor- 100% motensive uninephrectomized young but not the adult animal, contributing to increased glomerular injury in the former. Additional risk factors for progression at any age include urinary tract infection, ischemic/ hypoxic renal injury, and expo-

Renal function sure to nephrotoxic drugs. An important fi nding in the study of Sanna-Cherchi et al. is the increase in the 10% rate of progression of the various catego- Birth 18 years 80 years ries of CAKUT in late adolescence.5 To Age optimize nephrogenesis in the fetus, prenatal care is important in controlling Figure 1 | Progression of congenital renal disorders. Optimal management of the fetus with congenital anomalies of the kidney and urinary tract (CAKUTs) requires prenatal care to maternal diabetes, optimizing maternal optimize maternal nutrition, and to avoid exposure to nephrotoxic drugs that can interfere with nutrition, and minimizing maternal use of nephrogenesis. The pediatric nephrologist and urologist establish a diagnosis, assess risk factors, drugs known to impair renal growth or and initiate a plan for monitoring renal status and slowing progression of renal insufficiency. development (angiotensin or prostaglan- Handover of care from pediatric to adult health providers is a critical transition in the life of the child with CAKUTs (curved arrow): many patients experience accelerated deterioration in renal din inhibitors, glucocorticoids). Detection function in late adolescence (dashed line). With adherence to quality initiatives,14 renal function of CAKUT in the fetus or child should be may be maintained (solid line). followed by lifetime monitoring of the patient, using age-appropriate guidelines.14 Transition from pediatric to adult proteinuria, and 10% hypertension. 8 In whatever factors led to absence of the con- health care forms a critical bridge in the contrast, the long-term prognosis of renal- tralateral kidney, and can result from muta- maintenance of renal function throughout transplant donors appears to be excellent. tions, epigenetic factors mediated by the life (Figure 1). If this transition is not eff ec- Among 3698 donors undergoing unilateral intrauterine environment, or teratogens. 10 tive, there is greater risk of acceleration of nephrectomy between 1963 and 2007, and Asymmetry of the CAKUT phenotype is progression of renal insuffi ciency (dashed studied between 2003 and 2007, the rate of well described even in mice with targeted line); whereas attention to risk factors and development of end-stage renal disease gene deletions and this underscores the renoprotection may maintain adequate was actually lower than in the general pop- importance of nongenomic factors.10 renal function throughout life (solid line). ulation. 9 Th is is presumably attributable to In response to loss of one kidney, the It should be noted that although angi- the stringent health screening provided to contralateral kidney undergoes compen- otensin-converting enzyme inhibitors or prospective renal-transplant donors, which satory growth, a phenomenon that occurs receptor blockers are eff ective in control- selects candidates lacking known risk fac- even in the fetus with a single functioning ling hypertension, reducing proteinuria, tors for progression to renal insuffi ciency. kidney.11 Whether in response to con- and attenuating renal interstitial fi brosis Th e available literature therefore suggests genital renal agenesis or to surgical in older children or adults, angiotensin that there are fundamental differences nephrectomy for Wilms’ tumor, compen- inhibition in the infant can impair renal between the long-term outcomes of satory growth of the remaining kidney in maturation, exacerbate sodium wasting, patients with congenital solitary kidney (or children is similar, achieving parenchymal and markedly reduce glomerular fi ltration unilateral nephrectomy in childhood) and mass 180% of the volume of a healthy rate. Moreover, angiotensin-converting those of healthy adults undergoing unilat- paired kidney. 12 Since over 50% of adult enzyme inhibitors have been shown to eral nephrectomy. One possibility is that patients with unilateral renal agenesis lack effi cacy in the progression of hypo- nephron endowment in children with have hyperfi ltration, 6 the consequences of dysplastic nephropathy in children. 15 solitary kidney is well below the median, compensatory growth presumably depend At the present time, monitoring children whereas nephron number in the renal- at least in part on the number of function- with CAKUT involves monitoring diet, transplant donor is above the median ing nephrons: those with fewer nephrons nutritional status, growth, blood pressure, (reflecting a robust pre-nephrectomy would be more likely to develop lesions of plasma creatinine concentration, proteinu- glomerular filtration rate). 2 Reduced focal glomerulosclerosis. While hyperten- ria (or microalbuminuria), and possibly nephron number in the patient with con- sion of any etiology would accelerate renal imaging. Because most cases of end- genital solitary kidney may be mediated by progression of renal insufficiency, stage renal disease in children result from

476 Kidney International (2009) 76 commentary

tubulointerstitial rather than glomerular disorders, serum creatinine and urine pro- see original articles on pages 534 and 546 tein determinations are relatively insensi- tive. New biomarkers are needed with greater sensitivity and specifi city to follow A novel classification changes in renal status before they become irreversible. This will require a better for IgA nephropathy understanding of the natural history of 1 1 these challenging disorders that have an Ryohei Yamamoto and Enyu Imai impact on the entire life cycle. IgA nephropathy is a common glomerulonephritis. About 30 % of

DISCLOSURE patients develop end-stage kidney disease within 20 years. A strategy The author declared no competing interests. for predicting prognosis from biopsy-based pathological evaluation has not been well established because of lack of reproducibility and REFERENCES 1 . Luyckx VA , Brenner BM . Low birth weight, nephron inappropriate categorization. The new Oxford classification of IgA number, and kidney disease. Kidney Int 2005 ; 68 : nephropathy provides a histopathological grading system with S68 – S77 . 2 . Hughson MD , Farris AB , Douglas-Denton R et al. reproducibility for prediction of renal prognosis of IgA nephropathy Glomerular number and size in autopsy kidneys: the relationship to birth weight. Kidney Int 2003 ; independent of the clinical features. The classification must be validated 63 : 2113 – 2122 . in the different cohorts. 3 . Rodriguez MM , Gomez AH , Abitbol CL et al. 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Dinkel E , Britscho J , Dittrich M et al. Renal growth oil, and so on, the inclusion and exclusion same section — and, second, a strong pre- in patients nephrectomized for Wilms tumor as criteria of the subjects were based mainly dictive power for clinical outcomes. Only compared to renal agenesis. Eur J Pediatr 1988 ; 147: 54 – 58 . on renal function, urinary protein, and / or a few studies of renal histopathological 13 . Chevalier RL , Kaiser DL . Autoregulation of renal blood pressure, but rarely on histopatho- classifications, however, evaluated the blood flow in the rat: effects of growth and logical lesions. One of the main reasons reproducibility, which has been relatively uninephrectomy . Am J Physiol 1983 ; 244 : F483 – F487 . why histopathological lesions were not well investigated for classifi cations of renal 14 . Hogg RJ , Furth S , Lemley KV et al. National Kidney included in the inclusion and exclusion transplants and lupus nephritis. 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