commentary

acute kidney injury: an update. Ann Intensive 9. Poukkanen M, Wilkman E, Vaara ST, et al., GFR). As they report in this issue of Kidney
Care. 2015;5:51. FINNAKI Study Group. Hemodynamic variables
8. Lankadeva YR, Kosaka J, Evans RG, et al. and progression of acute kidney injury in
International, Klessens et al.3 (2016)
Intrarenal and urinary oxygenation during critically ill patients with severe sepsis: data examined and graded the renal histologic
norepinephrine resuscitation in ovine septic from the prospective observational FINNAKI findings at autopsy from a large cohort of
acute kidney injury. Kidney Int. 2016;90:100–108. study. Crit Care. 2013;17:R295.
decedents with diabetes and correlated
them with the clinical manifestations of
DN. Despite the few limitations inherent
Silent diabetic nephropathy to autopsy studies—such as the reliance in
some cases on urine dipstick testing
Samar M. Said1 and Samih H. Nasr1 instead of 24-hour urine tests to measure
the albumin excretion rate and the un-
Moderately increased albuminuria is widely accepted as the first clinical availability in some cases of adequate data
sign of diabetic nephropathy. However, previous morphometric studies on the use of angiotensin-converting
enzyme inhibitors—this study has
and the autopsy study by Klessens et al. have clearly demonstrated 2 important advantages over prior biopsy-
that by the time moderately increased albuminuria is evident, the based studies. First, it analyzed renal
kidneys in some diabetic patients have already undergone glomerular morphology regardless of duration or
and tubulointerstitial damage, which indicates that it is not a sensitive severity of DM, degree of proteinuria, or
marker for diabetic nephropathy. Hence, there is a need for new GFR, which provided a more accurate
biomarkers of early diabetic nephropathy. representation of those with diabetes
mellitus. Second, it provided the oppor-
Kidney International (2016) 90, 24–26; http://dx.doi.org/10.1016/j.kint.2016.02.042
tunity to study more than 100 glomeruli
Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
per decedent, which is w10 more than the
see clinical investigation on page 149 average number of glomeruli usually
sampled in routine clinical kidney biopsy.3

D
iabetic nephropathy (DN) is the
leading cause of end-stage renal
disease (ESRD) in developed
countries. It is characterized clinically by
albuminuria, a progressive decrease in
glomerular filtration rate (GFR), and
increased blood pressure. Histologically,
there is a unique constellation of patho-
logic findings, including mesangial scle-
rosis, which can be diffuse, nodular, or
both, glomerular basement membrane
and tubular basement membrane thick-
ening, and exudative lesions (inframem-
branous, subcapsular, and arteriolar
hyalinosis). The earliest detectable
glomerular lesion is thickening of the
glomerular basement membrane, which
can be observed as early as 2 years after
the onset of type 1 diabetes mellitus
(T1D). Mesangial expansion, mostly due
to an increase in mesangial matrix, de-
velops later—5 or more years after the
onset of T1D. The onset of these lesions
in patients with type 2 diabetes mellitus
1 pancreatic transplant (and, hence, the pa-
Department of Laboratory Medicine and
Pathology, Mayo Clinic, Rochester, Minnesota, USA
Correspondence: Samih H. Nasr, Division of
Anatomic Pathology, Mayo Clinic, 200 First Street
SW, Rochester, Minnesota 55905, USA. E-mail:
nasr.samih@mayo.edu
(T2D) is more variable, partly because
the time of biologic onset of T2D is
frequently unknown. In normal human
kidney, the mesangium occupies approxi-
mately 14% of the glomerular volume. In
contrast, in patients with clinically evident
DN, the mesangium occupies 30% or
more of the glomerular volume.1 The vol-
ume fraction of mesangium (i.e., mesan-
gial volume/tuft volume) inversely
correlates with peripheral capillary
filtering surface area and GFR.2 In patients
with T1D, mesangial sclerosis is closely
correlated with albuminuria, hyperten-
sion, and decreasing GFR, whereas the de-
gree of glomerular basement membrane
thickening is correlated with albuminuria
but not with GFR or hypertension.1
Most prior clinicopathologic and
morphometric studies on DN were biopsy
based. Patient cohorts included in these
studies were not totally representative of a
cross section of patients with diabetes. Bi-
opsies in these studies generally were per-
formed either as part of the work-up for
tients most likely had difficult-to-control
DN or severe complications) or in pa-
tients with diabetes with an atypical clinical
course (e.g., acute kidney injury, hematu-
ria, or nephrotic syndrome with normal
In the study by Klessens et al.,3 in which
most of the decedents were Caucasians and
had T2D, the prevalence of histologically
diagnosed DN in those with diabetes was
63% (106/168), which is much higher than
the reported prevalence of clinically diag-
nosed DN (<30%) in Caucasians with
T2D.4 Of note, 19% (20/106) of those with
histologically diagnosed DN in this study
did not have moderately increased albu-
minuria (previously called “micro-
albuminuria”) or proteinuria before death,
which is consistent with silent DN.
Furthermore, there was no significant
correlation between the albumin excretion
rate and the presence of DN histologically.
These findings agree with those of previous
biopsy-based structural–functional studies
by Fioretto and colleagues5 and Caramori
and colleagues6 who illustrated the pres-
ence of morphometric glomerular mea-
sures characteristic of DN in a proportion
of patients with T1D who had normoal-
buminuria. Thus, it is clear that moder-
ately increased albuminuria, which is
currently widely accepted as the first
clinical sign of DN, is not a sensitive
marker for the development of DN. By the
time moderately increased albuminuria
presents, the kidneys in some diabetic
patients have already sustained glomerular

24 Kidney International (2016) 90, 16–30


• Glomerular hyperfiltration and hypertrophy
• Normoalbuminuria (<30 mg/g)
Hyperfiltration • GFR increased
• Mild GBM thickening and focal mesangial sclerosis
• Normoalbuminuria (<30 mg/g)
Silent • GFR normal
• Mild to moderate GBM thickening and variable mesangial sclerosis
• Moderately increased albuminuria (30–300 mg/g)
Incipient • GFR normal or mildly decreased
• Marked GBM thickening and diffuse mesangial sclerosis
(with or without nodules)
• Severely increased albuminuria (>300 mg/g)
Overt • GFR decreased
• Hypertension
• Diffuse global glomerulosclerosis
• Decreasing albuminuria
ESRD • GFR < 15 ml/min
• Hypertension
Figure 1 | Stages of diabetic nephropathy. The figure illustrates the 5 stages of diabetic
nephropathy and the likely renal pathologic and functional alterations in each stage. ESRD,
end-stage renal disease; GBM, glomerular basement membrane; GFR, glomerular filtration rate.
and tubulointerstitial damage (Figure 1). a need for new, less invasive biomarkers of
Furthermore, progression of moderately early diabetic kidney disease to facilitate
increased albuminuria to overt DN is early diagnosis and guide therapeutic stra-
not inevitable. In a study of 386 patients tegies. Recently proposed potential bio-
with T1D and persistent moderately markers include urinary markers of
increased albuminuria for 2 years, the tubulointerstitial injury (such as liver-type
6-year cumulative incidence of regression fatty acid–binding protein, retinol bind-
of moderately increased albuminuria ing protein, N-acetyl-b-D-glucosamini-
was 58%.7 dase, kidney injury molecule-1, and heme
Caramori et al.6 recently reported a oxygenase-1), urine proteome analysis,
structural–functional study of 94 patients extracellular matrix–related proteins
with long-standing T1D and normoalbu- (such as urinary type IV collagen excre-
minuria who volunteered for research tion), and oxidative stress markers (such
kidney biopsy and had more than 5 years of as 7,8-dihydro-8-oxo-20 -deoxyguanosine)
follow-up. In this cohort, higher glomer- (reviewed by Tramonti and Kanwar9).
ular basement membrane thickness Validation of these potential markers is
and higher level of hemoglobin A1c were needed before use in clinical practice.
independent predictors of progression to In the study by Klessens et al.,3 the his-
proteinuria, ESRD, or both. The morpho- tologic features of silent “underdiagnosed”
metric measures of mesangial expansion DN were generally qualitatively no different
and glomerular filtration surface density, from those of clinical “diagnosed” DN. This
markers of progression in more advanced implies that silent DN is largely driven by
stages of DN, did not correlate with glycemia (in genetically predisposed pa-
outcome. Although the effect of better tients), whereas other previously proposed
glycemic control on the risk of proteinuria pathomechanisms for early DN, such as
and ESRD in diabetic patients with nor- increased blood pressure, hyperfiltration
moalbuminuria has not yet been studied, injury, and glomerular hemodynamic per-
there is evidence that sustained improve- turbations, may not be as important. The
ment in hemoglobin A1c levels decreases glomerular lesions in clinical and silent DN,
the risk of ESRD in patients with T1D and however, were somewhat quantitatively
proteinuria.8 Considering the challenges of different. In particular, the percentage of
adopting protocol kidney biopsy (i.e., glomeruli with nodular mesangial sclerosis
regardless of the presence of clinical DN) in was significantly lower in silent DN (11%,
the clinical care of diabetic patients, there is vs. 24% in clinical DN; P ¼ 0.03). It is quite
Kidney International (2016) 90, 16–30
commentary
possible that in the earliest stage of DN,
only a small percentage of glomeruli is
affected, even by significant mesangial
sclerosis including mesangial nodules, and
that clinical DN does not develop until a
certain percentage of glomeruli become
damaged. In our clinical experience, it is
not uncommon to find rare glomeruli with
well-developed Kimmelstiel–Wilson nod-
ules in autopsy specimens of diabetic per-
sons without proteinuria or decreased GFR.
In these cases, the remaining glomeruli
typically show no or minimal mesangial
sclerosis. Another, not mutually exclusive,
possibility is that in early DN the tubules are
healthy and able to reabsorb the leaked al-
bumin from the damaged glomeruli, which
thus contributes to the lack of detection of
albuminuria. In short, the clinical mani-
festations of DN most likely develop only
when the extent and severity of pathologic
lesions exceed the kidneys’ compensatory
capacity. The occasional observation of
histologically proven DN without albu-
minuria led to the widespread adoption of
the term “diabetic glomerulosclerosis”
instead of “diabetic nephropathy” by renal
pathologists in clinical practice. Regardless
of the term used by the renal pathologist,
the treating nephrologist and endocrinol-
ogist may consider more stringent glycemic
control in patients with histologically
proven DN, irrespective of the degree of
proteinuria or renal function.
Finally, although the prevalence of DN
in patients with diabetes is decreasing—
most likely a result of improved glycemic
control, aggressive blood pressure reduc-
tion, and the use of angiotensin-
converting enzyme inhibitors—the study
by Klessens et al.3 revealed that nearly two-
thirds of decedents with diabetes have
histologic evidence of DN, and half have
moderately increased albuminuria or
overt proteinuria. Considering the
worldwide increasing incidence and
prevalence of T2D, DN will continue to be
a major cause of ESRD. This highlights the
importance of both continued explora-
tion of the pathogenesis of DN and the
future development of more effective
drugs for treatment of diabetes mellitus.
DISCLOSURE
All the authors declared no competing
interests.
25
commentary

REFERENCES with various levels of albuminuria. Diabetes. and found that that the KDPI scores
1. Mauer SM, Steffes MW, Ellis EN, et al. 1994;43:1358–1364.
Structural-functional relationships in diabetic 6. Caramori ML, Parks A, Mauer M. Renal lesions
were lower (i.e., higher quality) for
nephropathy. J Clin Invest. 1984;74:1143–1155. predict progression of diabetic nephropathy kidneys discarded on weekends versus
2. Ellis EN, Steffes MW, Goetz FC, et al. Glomerular in type 1 diabetes. J Am Soc Nephrol. 2013;24: weekdays. Significant geographical varia-
filtration surface in type I diabetes mellitus. 1175–1181.
tion was seen in the proportion of
Kidney Int. 1986;29:889–894. 7. Perkins BA, Ficociello LH, Silva KH, et al.
3. Klessens CQF, Woutman TD, Veraar KAM, et al. Regression of microalbuminuria in type 1 kidney transplantations performed on the
An autopsy study suggests that diabetic diabetes. N Engl J Med. 2003;348:2285–2293. weekend versus weekdays, and the
nephropathy is underdiagnosed. Kidney Int. 8. Skupien J, Warram JH, Smiles A, et al. increased odds of kidney discard on week-
2016;90:149–156. Improved glycemic control and risk of ESRD in
4. Adler AI, Stevens RJ, Manley SE, et al. Development patients with type 1 diabetes and proteinuria. ends was present irrespective of the year of
and progression of nephropathy in type 2 diabetes: J Am Soc Nephrol. 2014;25:2916–2925. kidney procurement across the study
the United Kingdom Prospective Diabetes Study 9. Tramonti G, Kanwar YS. Review and discussion period. In the current era of trans-
(UKPDS 64). Kidney Int. 2003;63:225–232. of tubular biomarkers in the diagnosis and
5. Fioretto P, Steffes MW, Mauer M. Glomerular management of diabetic nephropathy.
plantation, where organ demand continues
structure in nonproteinuric IDDM patients Endocrine. 2013;43:494–503. to exceed supply, the discard of potentially
transplantable organs is of considerable
importance. Depending on the type and
The weekend effect: quality of deceased donor kidneys, reported
transplantation is not “immune” kidney discard rates in the literature
range from 28% to 51% (Figure 1).4–8 In
addition, it has been shown that discard
Sunita K.S. Singh1,3 and S. Joseph Kim1,2,3
rates vary widely by donor service area and
transplant center, suggesting differences in
The “weekend effect” has been widely studied in various health care
thresholds for organ acceptance among
settings, but it has received less attention in the field of transplantation. transplant clinicians.
The study by Mohan et al. reveals that this phenomenon exists in Although, a major component of the
discard rates for deceased donor kidneys in the United States. These decision to accept an organ for trans-
findings emphasize the importance of reducing unexplained variations plantation is based on an assessment of
in kidney discard rates, especially in light of the ongoing shortage of donor quality, the findings of Mohan
et al.3 suggest that this decision may also
transplantable organs.
be influenced by other factors. Despite
Kidney International (2016) 90, 26–28; http://dx.doi.org/10.1016/j.kint.2016.05.005
adjustment for donor quality (as
Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
measured by the KDPI), an increase in the
see clinical investigation on page 157 relative odds of kidney discard on week-
ends versus weekdays persisted. Further-

T
he “weekend effect,” which de-
scribes an increase in patient mor-
tality (or adverse outcomes) on
weekends when compared with week-
days, has been well described in medical
publications.1 A number of reasons have
been postulated to explain this phenome-
non including a reduction in hospital
staffing and resources, admission of pa-
tients with more acute, life-threatening
illnesses, and differences in the delivery
1 Mohan et al.3 (2016) explore the relation
Division of Nephrology and the Kidney Trans-
plant Program, Toronto General Hospital, Uni-
versity Health Network, Toronto, Ontario, Canada;
2
Division of Nephrology and the Renal Transplant
Program, St. Michael’s Hospital, Toronto, Ontario,
Canada; and 3Institute of Health Policy, Man-
agement and Evaluation, University of Toronto,
Toronto, Ontario, Canada
Correspondence: S. Joseph Kim, Toronto Gen-
eral Hospital, University Health Network, 585
University Avenue, 11-PMB-129, Toronto, Ontario,
Canada M5G 2N2. E-mail: joseph.kim@uhn.ca
or quality of care. Interestingly, the week-
end effect has not been shown for out-
comes of kidney transplant recipients. In
fact, existing studies demonstrate no dif-
ference in patient and graft survival
in recipients transplanted on the week-
end versus weekdays.2 Although these
findings are reassuring, they beg
the question whether other domains
of transplantation medicine may be sub-
ject to weekday versus weekend variations.
In this issue of Kidney International,
between the day of the week when deceased
donor kidneys are procured and the utili-
zation of these kidneys for transplantation
in the United States. In this study, the in-
vestigators found a 16% increase in the
odds of discard when a kidney is procured
on a weekend (a Friday or Saturday) as
compared to a weekday. Furthermore, the
investigators measured kidney quality using
the Kidney Donor Profile Index (KDPI)
more, kidney discard rates on weekends
were lower in larger transplant centers
when compared with smaller transplant
centers, and kidneys transplanted on
weekends had shorter cold ischemia
times. Clinicians may perceive weekends
to be a higher risk period due to staffing
reductions (i.e., fewer transplant surgeons
available) or the potential lack of resources
to deal with complications that may arise
after transplantation (e.g., initiation of
dialysis for delayed graft function) and as
such, resource availability may influence
the decision to accept kidneys for trans-
plantation. Paradoxically, certain re-
sources may be more available on
weekend days, such as operating rooms,
due to a reduction in elective surgeries.
However, many centers, particularly
smaller ones, may not have adequate
staffing of these operating rooms and/or
the postoperative recovery areas during
weekends. Additionally, in multiorgan

26 Kidney International (2016) 90, 16–30