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take prompt, corrective action before the agency Disclosure forms provided by the authors are available with
the full text of this letter at NEJM.org.
initiates an enforcement action.3
The FDA is dedicated to improving the over- This letter was updated on September 22, 2017, at NEJM.org.
sight of postmarketing requirements and com-
mitments, updating the public regularly, and 1. Woloshin S, Schwartz LM, White B, Moore TJ. The fate of
FDA postapproval studies. N Engl J Med 2017;377:1114-7.
improving the clarity of our reporting. We think 2. Guidance for industry:reports on the status of postmarket-
that it is reassuring that as of fiscal year 2015, a ing study commitments implementation of section 130 of the
total of 88% of postmarketing requirements over- Food and Drug Administration Act of 1997. Rockville, MD:Food
and Drug Administration, February 2006 (https://w ww.fda.gov/
all and 89% of FDAAA postmarketing require- downloads/Drugs/GuidanceComplianceRegulatoryInformation/
ments were progressing according to their origi- Guidances/UCM080569.pdf).
nal schedules.4 3. Food and Drug Administration. Inspections, compliance,
enforcement, and criminal investigations (https://w ww.fda.gov/
Mwango Kashoki, M.D., M.P.H. ICECI/EnforcementActions/WarningLetters/ucm278624.htm).
Cathryn Lee, M.S.N. 4. Food and Drug Administration. Report on the performance
of drug and biologics firms in conducting postmarketing require-
Peter Stein, M.D.
ments and commitments; availability. Fed Regist 2016;81(228):
Food and Drug Administration 85573-9 (https://www.federalregister.gov/d/2016-28442).
Silver Spring, MD
mwango.kashoki@fda.hhs.gov DOI: 10.1056/NEJMc1709185
hyperfiltration play a role in the progression of Moreover, the predominantly white study co-
kidney disease. hort resided in Minnesota, where the sodium
In the study conducted by Denic et al., an ele- intake during the period of donor enrollment
vated single-nephron GFR was associated with (2000 through 2011) was considerably higher
risk factors for disease progression, including than the recommended intake, as shown in the
obesity, a family history of end-stage kidney dis- Minnesota Heart Survey.2 The study cited by the
ease, and more glomerulosclerosis, findings that authors shows that the single-nephron GFR de-
suggest compensation in the remaining neph- pends not only on the location of the nephron in
rons to maintain the total GFR. The authors sug- the cortex but also on the dietary sodium intake.3
gest that enlarged glomeruli might be a benefi- High sodium intake significantly increases the
cial adaptation; we suspect that it may not. single-nephron GFR in superficial nephrons
Enlarged glomeruli are exposed to increased and concomitantly decreases it in juxtamedullary
physical stress because of the greater glomerular- nephrons.3 Such evidence is relevant to the calcu-
wall tension with greater capillary radius, as lation of the single-nephron GFR.
predicted by Laplaces law.2 Bigger glomeruli SotiriosG. Zarogiannis, Ph.D., M.P.H.
may outstrip the capacity of podocytes to cover University of Thessaly
the enlarged surface. Such diminutions in podo- Larissa, Greece
cyte density have been associated with adverse szarog@med.uth.gr
disease, and mild hypertension), but we believe As discussed by Zarogiannis et al., the single-
that this finding is misleading. The problem is nephron GFR may be higher in the deep (juxta-
that the single-nephron GFR was calculated di- medullary) glomeruli than in the more superfi-
rectly from the number of nephrons (specifically, cial glomeruli in humans, as has been observed
the total GFR divided by the number of neph- in studies in animals. Estimates of the single-
rons), and thus, the measurement error with the nephron GFR cannot be calculated separately for
number of nephrons will alone result in a nega- deep and superficial nephrons in humans by the
tive correlation between the single-nephron GFR method we used. Since varying the dietary so-
and the number of nephrons. A sophisticated dium intake in healthy humans does not change
statistical simulation with ideally more measure- the total GFR,5 it is also unlikely that the mean
ment-error data than we had may help clarify the single-nephron GFR varies according to the level
biologic correlation. of sodium intake.
In general, we agree with Rosenberg and Aleksandar Denic, M.D., Ph.D.
Hostetter that glomerular enlargement might be Mayo Clinic
considered harmful. We have found that aging Rochester, MN
alone does not lead to glomerular hypertrophy, RichardJ. Glassock, M.D.
despite a considerable decline in the number of David Geffen School of Medicine at the University of Califor-
nephrons. However, certain risk factors for nia, Los Angeles
Los Angeles, CA
chronic kidney disease, such as obesity and fam-
ily history of end-stage renal disease, are associ- AndrewD. Rule, M.D.
ated with glomerular enlargement and an ele- Mayo Clinic
Rochester, MN
vated single-nephron GFR. Nonetheless, kidney rule.andrew@mayo.edu
donation itself leads to glomerular enlargement Since publication of their article, the authors report no fur-
with increased single-nephron GFR in the remain- ther potential conflict of interest.
ing kidney but without evidence of glomerular
1. Hughson M, Farris AB III, Douglas-Denton R, Hoy WE, Ber-
hypertension,2 and progressive chronic kidney tram JF. Glomerular number and size in autopsy kidneys: the
disease rarely occurs after kidney donation. relationship to birth weight. Kidney Int 2003;63:2113-22.
2. Lenihan CR, Busque S, Derby G, Blouch K, Myers BD, Tan JC.
There may be a tipping point at which glomeru-
Longitudinal study of living kidney donor glomerular dynamics
lar enlargement becomes maladaptive. Atubular after nephrectomy. J Clin Invest 2015;125:1311-8.
glomeruli were not assessed in our study, because 3. Marcussen N. Atubular glomeruli in renal artery stenosis.
we analyzed only two consecutive 3-m kidney- Lab Invest 1991;65:558-65.
4. Kremers WK, Denic A, Lieske JC, et al. Distinguishing age-
biopsy sections, which limited our ability to related from disease-related glomerulosclerosis on kidney biopsy:
assess the entire glomerulus. Atubular glomeruli the Aging Kidney Anatomy study. Nephrol Dial Transplant 2015;
are often ischemic-appearing,3 and ischemic- 30:2034-9.
5. Mallamaci F, Leonardis D, Bellizzi V, Zoccali C. Does high
appearing glomeruli account for only 0.6% of salt intake cause hyperfiltration in patients with essential hyper-
the nonsclerosed glomeruli in this healthy popu- tension? J Hum Hypertens 1996;10:157-61.
lation.4 DOI: 10.1056/NEJMc1709128