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History of Childhood Kidney Disease and Risk of Adult End-Stage Renal Disease

To the Editor

In their article, Calderon-Margalit et al. (Feb. 1 issue)1 do not indicate whether the study participants had a history of prematurity or low birth weight. Were the persons who had a history of prematurity and presumed low nephron endowment at higher risk for the development of later end-stage renal disease (ESRD) than those who did not have such a history?

Also, was the prevalence of congenital anomalies of the kidney and urinary tract higher among persons classified as having “pyelonephritis” than among those who did not have that diagnosis? The overdiagnosis of “pyelonephritis” is suggested by the high prevalence (65.7%) during the 1967–1979 enrollment period (Table 1 of the article, available at NEJM.org), when there was less precision concerning the diagnosis of pyelonephritis than during later periods of enrollment. It is curious that more male participants than female participants were classified as having had “pyelonephritis” (55% vs. 45%) (Table 1 of the article). One would not have expected this finding in a country where circumcision is practically universal.

Ronald Kallen, M.D.
Northwestern University–Feinberg School of Medicine, Chicago, IL

No potential conflict of interest relevant to this letter was reported.

  1. 1. Calderon-Margalit R, Golan E, Twig G, et al. History of childhood kidney disease and risk of adult end-stage renal disease. N Engl J Med 2018;378:428438.

To the Editor

In the large retrospective cohort study by Calderon-Margalit et al., the risk of ESRD during adulthood was approximately four times as high among persons with a history of childhood kidney disease as the risk among persons who had no such history, even if renal function was apparently normal during adolescence. The authors interpret this finding as the result of loss of nephrons leading to hyperfiltration of residual nephrons and progressive decline in renal function.1

We contend that another, non–mutually exclusive interpretation is possible. Various kinds of acute and chronic injuries are associated with a maladaptive tissue repair regulated by epigenetic changes with accelerated cellular aging and loss of function.2 For example, patients with type 1 diabetes who have hyperglycemia during the early phase of the disease have an increased incidence of a diabetic nephropathy, even after a long period of normal metabolic control.3 Similarly, kidney injury during childhood might initiate epigenetic changes that, together with hyperfiltration of the residual nephrons, promote renal fibrosis and progression to ESRD.4 Since epigenetic modifications are reversible, these changes are an attractive therapeutic target to counteract the long-term deleterious effects of seemingly self-limited renal injuries.

Giuseppe Castellano, M.D., Ph.D.
University of Bari Aldo Moro, Bari, Italy

Paolo Cravedi, M.D., Ph.D.
Icahn School of Medicine at Mount Sinai, New York, NY

No potential conflict of interest relevant to this letter was reported.

  1. 1. Brenner BM, Humes HD. Mechanics of glomerular ultrafiltration. N Engl J Med 1977;297:148154.

  2. 2. Ghosh AK, Rai R, Flevaris P, Vaughan DE. Epigenetics in reactive and reparative cardiac fibrogenesis: the promise of epigenetic therapy. J Cell Physiol 2017;232:19411956.

  3. 3. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA 2003;290:21592167.

  4. 4. Tang C, Dong Z. Epigenetic regulation in acute kidney injury: new light in a dark area. Kidney Int 2015;88:665668.

To the Editor

Calderon-Margalit et al. present important data from the Israeli ESRD registry that suggest that childhood kidney disease requires lifetime follow-up because, although kidney function returns to normal by adolescence, the childhood history still confers a lifetime risk of ESRD. Kidney diseases in childhood include congenital anomalies of the kidney and urinary tract, pyelonephritis, and glomerular disease.

These data may have an implication for the future suitability of a person to be a living kidney donor if he or she has had childhood kidney disease that has apparently resolved. The authors conclude that “kidney injury or structural abnormality in childhood has long-term consequences.” The data used to determine the risk of ESRD among living kidney donors (which now indicate age at the time of nephrectomy, sex, and race1) are still evolving, and acute kidney injury may be consequential.2 Can the authors comment on whether childhood diseases, including those that involve urinary tract infection, constitute important historical information in considering whether a person can be a living kidney donor?

Francis L. Delmonico, M.D.
Massachusetts General Hospital, Boston, MA

No potential conflict of interest relevant to this letter was reported.

  1. 1. Gaston RS, Kumar V, Matas AJ. Reassessing medical risk in living kidney donors. J Am Soc Nephrol 2015;26:10171019.

  2. 2. Lam NN, Lentine KL, Levey AS, Kasiske BL, Garg AX. Long-term medical risks to the living kidney donor. Nat Rev Nephrol 2015;11:411419.


The authors reply: As Kallen states, according to the theory of the developmental origins of health and disease, the likelihood of the development of chronic kidney disease because of low nephron endowment (a reduced number of nephrons from birth) is increased in infants who had intrauterine growth retardation. This concept was supported by studies in rodents showing that intrauterine growth retardation is associated with a reduced number of nephrons1 and by epidemiologic studies in humans showing associations between low birth weight and poor renal function later in life and between low birth weight and an increased risk of early-onset ESRD, even in the absence of congenital anomalies of the kidney and urinary tract.2-4 Unfortunately, we did not have information on the birth characteristics of our study population. Nevertheless, there is only limited evidence to suggest that intrauterine growth retardation is associated with the full spectrum of kidney diseases seen in childhood. Thus, we would suggest that birth weight and gestational age at birth are not the mechanisms whereby childhood diseases are associated with ESRD. It would be of interest to study the possible interaction between birth weight and history of childhood kidney disease and the subsequent incidence of ESRD.

We concur with Kallen in assuming that at least some of the cases of congenital anomalies of the kidney and urinary tract were misclassified as pyelonephritis, and we discussed this in our article. Female participants accounted for 38% of the entire cohort and 45% of participants with pyelonephritis, yielding an odds ratio of 1.32 (95% confidence interval, 1.27 to 1.39) for pyelonephritis among female participants. This finding provides support for a higher incidence of pyelonephritis among girls and women than among boys and men.

Castellano and Cravedi suggest that epigenetic changes in kidney tissue following childhood kidney diseases may contribute to the risk of ESRD. This possibility, which would appear to be a mechanism different from that of nephron loss, warrants further investigation of potential mechanisms that are common to the multiple categories of childhood kidney injury enumerated in our study.

Recent guidelines on the evaluation and care of living kidney donors indicate the need for renal imaging before kidney donation and, in cases of asymmetry in kidney size, the need for differential estimation of the glomerular filtration rate. If asymmetry in renal function between the two kidneys is detected, then the one with the worse function is to be donated. However, in general, the guidelines do not point to resolved childhood kidney disease as a consideration in kidney donation.5 Although our study was not designed to address the specific question posed by Delmonico, our findings do suggest the need for thoughtful consideration of the history of resolved childhood kidney disease in the future refinement of guidelines on criteria for the selection of kidney donors.

Ronit Calderon-Margalit, M.D., M.P.H.
Hadassah–Hebrew University, Jerusalem, Israel

Karl Skorecki, M.D.
Technion–Israel Institute of Technology, Haifa, Israel

Asaf Vivante, M.D., Ph.D.
Sheba Medical Center, Tel Hashomer, Israel

Since publication of their article, the authors report no further potential conflict of interest.

  1. 1. Boubred F, Daniel L, Buffat C, et al. The magnitude of nephron number reduction mediates intrauterine growth-restriction-induced long term chronic renal disease in the rat: a comparative study in two experimental models. J Transl Med 2016;14:331331.

  2. 2. Lackland DT, Bendall HE, Osmond C, Egan BM, Barker DJ. Low birth weights contribute to high rates of early-onset chronic renal failure in the Southeastern United States. Arch Intern Med 2000;160:14721476.

  3. 3. Eriksson JG, Salonen MK, Kajantie E, Osmond C. Prenatal growth and CKD in older adults: longitudinal findings from the Helsinki Birth Cohort Study, 1924-1944. Am J Kidney Dis 2018;71:2026.

  4. 4. Vikse BE, Irgens LM, Leivestad T, Hallan S, Iversen BM. Low birth weight increases risk for end-stage renal disease. J Am Soc Nephrol 2008;19:151157.

  5. 5. Lentine KL, Kasiske BL, Levey AS, et al. KDIGO clinical practice guideline on the evaluation and care of living kidney donors. Transplantation 2017;101:Suppl 1:S1S109.

Source: Massachusetts Medical Society: New England Journal of Medicine: Table of Contents