See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/260431525

American Society of Nephrology Quiz and Questionnaire 2013:

Glomerulonephritis

Article  in  Clinical Journal of the American Society of Nephrology · February 2014

DOI: 10.2215/CJN.11571113 · Source: PubMed

CITATION READS

1 149

3 authors, including:

Fernando Fervenza Mark A Perazella

Mayo Foundation for Medical Education and Research Yale University
298 PUBLICATIONS   11,927 CITATIONS    281 PUBLICATIONS   8,534 CITATIONS   

SEE PROFILE SEE PROFILE

All content following this page was uploaded by Mark A Perazella on 21 April 2014.

The user has requested enhancement of the downloaded file.

 CJASN ePress. Published on February 27, 2014 as doi: 10.2215/CJN.11571113
Special Feature

American Society of Nephrology Quiz and

Questionnaire 2013: Glomerulonephritis
Fernando C. Fervenza,* Mark A. Perazella,† and Michael Choi‡

Abstract
The Nephrology Quiz and Questionnaire (NQ&Q) remains an extremely popular session for attendees of the
Annual Meeting of the American Society of Nephrology. As in past years, the conference hall of the 2013 meeting
*Division of
was overflowing with interested audience members. Topics covered by expert discussants included electrolyte Nephrology and
and acid-base disorders, glomerular disease, ESRD/dialysis, and transplantation. Complex cases representing each Hypertension, Mayo
of these categories, along with single best answer questions, were prepared by a panel of experts. Before the Clinic, Rochester,
meeting, program directors of United States nephrology training programs answered questions through an Minnesota;
†
Internet-based questionnaire. A new addition to the NQ&Q was participation in the questionnaire by nephrology Department of
Internal Medicine,
fellows. To review the process, members of the audience test their knowledge and judgment on a series of case- Yale University School
oriented questions prepared and discussed by experts. Their answers are compared in real time using audience of Medicine, New
response devices with the answers of nephrology fellows and training program directors. The correct and in- Haven, Connecticut;
correct answers are then briefly discussed after the audience responses and the results of the questionnaire are and ‡Division of
Nephrology,
displayed. This article recapitulates the session and reproduces its educational value for CJASN readers. Enjoy the Department of
clinical cases and expert discussions. Medicine, Johns
Clin J Am Soc Nephrol ▪: ccc–ccc, 2014. doi: 10.2215/CJN.11571113 Hopkins University,
Baltimore, Maryland

Introduction: Mark A. Perazella and Michael
Choi (Comoderators)
For most American Society of Nephrology (ASN)
Kidney Week attendees, case-based clinical nephrol-
ogy talks are the most exciting venues of the meeting.
The Nephrology Quiz and Questionnaire (NQ&Q) is
the essence of clinical nephrology and represents
what drew many of us into the field of nephrology.
The 2013 NQ&Q in Atlanta, with full-house atten-
dance, was no exception. Each of the discussants pre-
pared vignettes of puzzling cases, each illustrating
some topical, challenging, or controversial aspect of
the diagnosis or management of various areas of ne-
phrology. These eight interesting cases were presented
and eloquently discussed by our four expert ASN fac-
ulty. Subsequently, each discussant prepared a man-
uscript summarizing his or her discussion of the cases,
which serves as the main text of this article.
In this NQ&Q, Dr. Fernando Fervenza presents his
two challenging cases of glomerular disease and dis-
cusses the appropriate diagnosis and management of
these cases. The audience responses are reviewed
along with the training program director and ne-
phrology fellow responses obtained before the meet-
ing, giving an interesting perspective into the thought
processes of nephrologists with varying levels of
training and experience. Dr. Fervenza reviews essen-
tial clinical, laboratory, and renal pathology data and
walks the reader through the diagnosis and appropri-
ate management of two complicated and challenging
glomerular disorders. Overall, this event was an ed-
ucational experience for all who participated. We
Correspondence:
hope that this “distillate” from Atlanta will serve Dr. Fernando C.
CJASN readers well and provide some fresh insights Fervenza, Division of
into the complexity and vibrancy of clinical nephrol- Nephrology and
ogy for those who were unable to attend the meeting. Hypertension, Mayo
Clinic College of
Medicine, 200 First
GN Case 1: Fernando C. Fervenza (Discussant) Street, SW, Rochester,
A 45-year-old man with a history of hypothyroid- MN 55901. Email:
ism, primary sclerosing cholangitis, and ulcerative fervenza.fernando@
mayo.edu
colitis, and a baseline creatinine of 1.0 mg/dl was
evaluated in July 2007 for sudden onset of nephrotic
syndrome (NS). A kidney biopsy was performed and
showed minimal change disease (MCD) and acute
tubular necrosis. After the biopsy, the serum creati-
nine concentration continued to rise to 5.8 mg/dl, and
the patient was started on dialysis. Methylpredniso-
lone (1 g, twice intravenously) was initiated followed
by 1 mg/kg per day of prednisone orally. After two
dialysis sessions, kidney function started to recover.
Prednisone was tapered and discontinued by Novem-
ber 2007. Urine protein excretion fell to ,100 mg/24
h. In February 2008, the patient relapsed with pro-
teinuria of 9.7 g/24 h. Remission was induced with
oral prednisone and the patient was started on cyclo-
sporine with a plan to wean off steroids. However, he
could not tolerate cyclosporine because of a severe
headache despite dose reduction, and it was discon-
tinued in April 2009. In May 2009, the patient devel-
oped another acute relapse with proteinuria of 12.1 g/
24 h and his serum creatinine increased to 3.1 mg/dl. A
repeat kidney biopsy showed only MCD and acute tu-
bular necrosis. Renewed treatment with high-dose ste-
roids induced remission but was complicated by the

www.cjasn.org Vol 0 ▪▪▪, 2014 Copyright © 2014 by the American Society of Nephrology 1
2 Clinical Journal of the American Society of Nephrology
development of diabetes mellitus. The patient was then started
on 150 mg/d oral cyclophosphamide for 3 months with
steroid tapering. Cyclophosphamide was discontinued in
January 2010, but was followed by a relapse 2 weeks later.
The patient was instructed to return to the previous regi-
men of 150 mg/d oral cyclophosphamide and oral predni-
sone, resulting in a complete remission. In April 2011,
cyclophosphamide was stopped. However, in December
2011, the patient had another relapse with proteinuria 7.8
g/24 h. His serum creatinine was 1.1 mg/dl.
Question 1
Once remission has been induced with high-dose pred-
nisone, which of the following would give this patient the
best chance for sustained remission without corticoste-
roids?
A. Cyclophosphamide 1 mg/kg per day for 3 months
B. Cyclophosphamide 2 mg/kg per day for 6 months
C. Sirolimus 5 mg/d adjusting dose for whole blood trough
concentration of 16–24 ng/ml
D. Mycophenolate mofetil (MMF) 1000 mg twice daily,
orally
E. Rituximab 1 g intravenously on day 1 and day 15
Discussion of Case 1
The patient in this case has MCD with frequent relapses.
Of the options provided, treatment with rituximab pro-
vides the greatest likelihood of sustained remission without
continued glucocorticoid therapy while minimizing the
risks of complication from treatment (choice E is correct)
(Figure 1).
MCD accounts for the majority of cases of idiopathic NS
in children and up to 20% of cases of idiopathic NS in
Caucasian adults (1). Corticosteroid therapy is the treat-
ment of choice, leading to complete remission of protein-
uria in .90% of cases (2). However, .50% of patients who
responded to corticosteroids will have a relapse, and up to
Figure 1. | Question 1: Distribution of answers from fellows in training, training program directors (TPD) and audience members at the
Kidney Week meeting. The correct answer is E.
25%–30% of patients will have frequent relapses or become
steroid dependent (3,4). Some patients without significant
corticosteroid-related toxicity may be maintained in remis-
sion with low-dose prednisone (e.g., 15 mg every other
day). For patients who cannot tolerate continued cortico-
steroid therapy, alternatives include the use of alkylating
agents, antimetabolites, and calcineurin inhibitors. Al-
though these agents may be beneficial, some patients re-
spond poorly or not at all. In addition, the use of these
agents may be complicated by the development of signif-
icant side effects, especially when these agents are used in
combination, as discussed below. As such, alternative ther-
apies that can induce long-term remission with a favorable
safety profile have been sought.
Rituximab, a chimeric mAb directed against the B
lymphocyte–restricted cell-surface protein CD20, has
been successfully used in the treatment of a number of
autoimmune renal diseases affecting the kidney, including
ANCA-associated vasculitis and membranous nephropa-
thy (5). Two case reports—one by Gilbert et al. (6), of a 15-
year-old girl with high-dose steroid-dependent MCD and
one by Francois et al. (7), of a 22-year-old woman with
multirelapsing MCD—showed that rituximab can be effec-
tive in steroid-dependent and/or frequent-relapsing MCD.
These initial findings were corroborated by a number of
other case reports and retrospective and prospective
studies (8–23). Rituximab generally induced sustained re-
mission allowing for a marked reduction or discontinua-
tion of corticosteroids and/or immunosuppressive drugs
in patients with MCD who were steroid dependent or fre-
quent relapsers (24). Rituximab appears to be more effec-
tive when given to patients in complete remission, but a
few nephrotic patients also responded (18). It also appears
to be beneficial to patients who are steroid resistant
(10,11,25).
The beneficial effect of rituximab was confirmed in two
recent studies (26,27). Bruchfeld et al. reported the long-
term follow-up of 16 patients (9 women, 7 men; aged 19–
73 years) with frequent-relapsing, steroid-dependent
Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2014
(prednisone 5 and 20 mg/d), or steroid-resistant MCD
treated with rituximab (26). Patients had experienced 3
to .20 relapses despite previous immunosuppressive ther-
apy, including cyclophosphamide, calcineurin inhibitors,
azathioprine, MMF, chlorambucil, and/or levamisole. The
majority of the patients were nephrotic or near-nephrotic
before rituximab treatment. Thirteen patients (81%) re-
sponded to therapy with complete remission. Two pa-
tients had a 50% and 70% reduction in proteinuria,
respectively. One patient did not respond. Follow-up
was 12–70 months (median 44 months) and seven patients
relapsed after 9–28 months. Relapses coincided with re-
covery of circulating B cells, but not all patients relapsed
upon B-cell reconstitution. Four patients were retreated
with rituximab and went back into remission. In three
patients, relapses were minor and responded to a reintro-
duction of low-dose corticosteroids. Adverse events were
limited and infusion-related. At the latest follow-up, 66%
of the patients that responded to rituximab were no longer
taking any maintenance immunosuppressive therapy.
Ruggenenti et al. evaluated the effect of rituximab fol-
lowed by withdrawal of maintenance immunosuppres-
sion in 10 children and 20 adults with MCD/mesangial
proliferative GN (n=22) or FSGS (n=8) who had suffered
$2 relapses over the previous 12 months and were in
steroid-induced remission since 1 month. Participants re-
ceived one (n=28) or two doses (n=2) of rituximab (375
mg/m2 each) (27). At 1 year, all patients were in remis-
sion: 18 were treatment free and 15 had never relapsed.
The total number of relapses and the per-patient median
number of relapses decreased from 88 to 22 and from 2.5
to 0.5 after rituximab treatment, respectively, regardless of
age or histologic diagnosis. The per-patient steroid main-
tenance median dose also decreased from 0.27 mg/kg
(range, 0.19–0.60) to 0 mg/kg (range, 0–0.23) and the me-
dian cumulative dose to achieve relapse remission de-
creased from 19.5 mg/kg (range, 13.0–29.2) to 0.5 mg/kg
(range, 0–9.4). No adverse events were reported in children
but eight serious adverse events occurred in six adults. All
events occurred in patients during concomitant therapy with
steroids or other immunosuppressive medications and the
patients recovered fully.
Taken together, these studies reinforce the role of
rituximab as a corticosteroid-sparing agent in patients
with challenging frequently relapsing/steroid-dependent
MCD. However, a number of questions remain to be
answered. (1) Who is a candidate for rituximab? (2) What
is the optimal dosing strategy (e.g., the “autoimmune pro-
tocol” of 1 g rituximab twice, 2 weeks apart; the “lym-
phoma protocol” of 375 mg/m2 rituximab weekly for
4 weeks; or the B cell–driven approach of 375 mg/m2 rit-
uximab once)? In some studies, the duration of B-cell de-
pletion is not different in patients receiving one or two
rituximab infusions versus those receiving three or four
rituximab infusions (22,25), but others found longer B-
cell depletion with larger doses (19). (3) Should the initial
rituximab treatment be given after remission is induced or
during a relapse? Some studies suggest that rituximab is
more effective when given to patients in remission (22);
however, in a study by Bruchfeld et al., the majority of
patients were nephrotic and yet responses were high
(26). (4) Who should be retreated? In some patients,
Nephrology Quiz and Questionnaire 2013, Fervenza et al. 3
remission is long lasting so scheduled retreatment would
be unnecessary. (5) When should a relapse after rituximab
treatment be retreated? Should it be treated at the first sign
of B-cell recovery? Or should it be scheduled (e.g., every 6
months regardless of B-cell count)? B-cell reconstitution
can occur without triggering a clinical relapse but relapses
have been documented in patients who are still B-cell
depleted (15,22). Although the majority of relapses have
concurred with B-cell recovery (9,11,14,18,23), no B-cell
threshold for relapse has been identified. B-cell numbers
at the time of relapse varied greatly between individuals.
In one study, age at diagnosis was the strongest predictor
of drug-free remission for 6 and 12 months (19). Ravani
et al. reported that each year of age was associated with a
71% greater probability of prednisone-free and 31% of cal-
cineurin inhibitor–free remission for 6 and 12 months, re-
spectively (19), but results differ (27).
How rituximab works in MCD is unknown. A number of
clinical observations suggest that MCD is mediated by
T-cell abnormalities (28,29). On the other hand, a number
of clinical and immunologic findings suggest that B cells
are also involved in MCD (30). Patients with SLE, a B cell–
related autoimmune disease, may develop MCD, which
further supports a role for B cells in MCD. Cyclophospha-
mide, which will be discussed below, has important effects
on B-cell function and suppresses the secretion of Igs.
However, a role for T cells cannot be discarded because
rituximab may affect T-cell function. Rituximab has been
approved by the US Food and Drug Administration (FDA)
for the treatment of rheumatoid arthritis, a classic T cell–
mediated disease. Furthermore, a small population of T
cells do express CD20 (31). Finally, increased expression
of CD80 on podocytes has been associated with develop-
ment of proteinuria (32). CD80 is expressed on antigen-
presenting cells, natural killer cells, and B cells and
provides a costimulatory signal for T cells by binding to
the T-cell receptor CD28. In patients with MCD, there is
podocyte induction of CD80, and impaired downregula-
tion of CD80 expression may result in persistent CD80
expression due to an abnormal CTLA-4 response by regula-
tory T cells, resulting in foot process fusion and proteinuria.
B cells are important in the induction of inflammatory
cytokines; antigen presentation to T cells, dendritic cells,
and macrophages; T-cell activation; and generation of ec-
topic lymphogenesis (33). Treatment with rituximab may
directly or indirectly restore T-cell function in patients
with MCD.
Although the side effect profile of rituximab has been
remarkably good, a number of potential complications
should be considered. Patients treated with rituximab can
develop Pneumocystis jiroveci pneumonia (PCP) and the in-
fection has a high mortality rate (about 30%) (34). A recent
study from the Mayo Clinic evaluating patients treated
with rituximab from 1998 to 2011 reported that 30 of 230
patients developed PCP (35). Green et al. advocate routine
prophylaxis in patient populations in which the overall
incidence of PCP exceeds 3.5% (36). Although the true in-
cidence of PCP in patients receiving rituximab is un-
known, I argue that the risk is real and is associated
with a high mortality rate, and physicians should use their
judgment while carefully weighing the risk of the prophy-
laxis regimens against the potential risks of PCP while
4 Clinical Journal of the American Society of Nephrology
these patients remain B-cell depleted. Progressive multi-
focal leukoencephalopathy (PML), a fatal neurologic condi-
tion, has been reported in two patients with SLE treated
with rituximab, resulting in an official boxed warning
from the FDA. No case of PML has been reported in pa-
tients with MCD treated with rituximab, whereas .24
cases of PML are known in patients with SLE and
ANCA-associated vasculitis who have never received
rituximab (37). Nevertheless, the risk of PML is real and
needs to be discussed with the patient before initiating
treatment with rituximab. There is also a risk for hepatitis
B reactivation that led to a black box warning by the FDA.
Hepatitis B status should be checked in every candidate for
rituximab (38).
Regarding the use of cyclophosphamide, a number of
observational studies suggest that approximately 75% of
adults with frequently relapsing steroid-dependent MCD
will achieve sustained remission with the use of this
medication (3,39–41). The recommended dosage of cyclo-
phosphamide is 2 mg/kg per day orally for 12 weeks
because a shorter course has been associated with an in-
creased rate of relapse (40,42). Intravenous cyclophospha-
mide is less effective in inducing long-term remission (43).
Remission should first be induced with corticosteroids fol-
lowed by cyclophosphamide and a steroid taper. How-
ever, cyclophosphamide is associated with significant
short- and long-term side effects, including bone marrow
suppression, leukopenia, infection, malignancy, and infer-
tility. It is therefore prudent that all patients taking cyclo-
phosphamide have complete blood work performed once
per week. The dose of cyclophosphamide should be ad-
justed to maintain a total white blood cell count .3500/mm3
and an absolute neutrophil count .1500/mm3. In addition,
to prevent infection with P. jiroveci, all patients should receive
prophylaxis with either sulfamethoxazole/trimethoprim or
an alternative agent.
The long-term risk of malignancy with cyclophospha-
mide is substantial and is commensurate with the cumu-
lative dose and duration of therapy. Faurschou et al.
reported on the incidence of malignancies associated
with cyclophosphamide exposure in a cohort of 293 pa-
tients with granulomatosis with polyangiitis (44). The
risk of malignancy was not increased in patients who
never received cyclophosphamide or were treated with
cumulative cyclophosphamide doses #36 g. By contrast,
a high risk of leukemia (standardized incidence ratio, 59.0;
95% confidence interval, 12 to 172) and bladder cancer
(standardized incidence ratio, 9.5; 95% confidence inter-
val, 2.6 to 24) was observed in patients treated with cu-
mulative cyclophosphamide doses .36 g. Another major
concern limiting cyclophosphamide utility is related to its
gonadal toxicity. Data indicate that ovarian failure is seen
in female patients of any age receiving a cumulative dose
of as little as 28 g of cyclophosphamide (45). Although
male infertility is harder to assess, studies have demon-
strated that doses .7.5 g/m2 of cyclophosphamide can
result in permanent oligospermia (46). Both female and
male patients of child-bearing age should be offered cryo-
preservation of ova and sperm before treatment with cy-
clophosphamide. For these reasons, prolonged therapy
(.12 weeks) or .2 courses of cyclophosphamide should
be avoided.
The calcineurin inhibitors cyclosporine or tacrolimus are
alternatives for patients who are steroid dependent, relapse
after cyclophosphamide, or have contraindications for
cyclophosphamide (39,47–52). Approximately 70%–90%
of patients with MCD who are frequent relapsers or are
steroid dependent can be maintained in partial or complete
remission with calcineurin inhibitors (53). Cyclosporine at
a dosage of 3.5–5 mg/kg per day orally (microemulsion
preparation of cyclosporine may allow for lower doses)
or tacrolimus at a dosage of 0.1 mg/kg per day orally
can be considered (49). In the case of tacrolimus, I would
like to point out that I never start patients on that dose
because of concerns with acute nephrotoxicity. Instead, I
give two-thirds of the target dose initially and then adjust
the dose to target every 7–14 days while monitoring for
side effects, and I recommend the same precautions with
cyclosporine (i.e., start at the lower dose with subsequent
adjustments). Some authors recommend concomitant
use of low-dose prednisone; however, in my opinion,
cyclosporine or tacrolimus can be used as monotherapy.
Unfortunately, .50% of the patients who respond to cyclo-
sporine or tacrolimus will relapse once the calcineurin in-
hibitor is discontinued. Relapses are more commonly
observed if cyclosporine is used for short intervals
(39,48), whereas sustained remission is more likely in pa-
tients treated for 1 year or longer (47). Therefore, the rec-
ommendation is to maintain cyclosporine or tacrolimus
therapy for at least 1 to 2 years followed by a gradual taper.
Nevertheless, some patients will relapse and steroid depen-
dence may be replaced by calcineurin inhibitor dependence
requiring years of treatment and the associated risk of
nephrotoxicity (4). Although the risk of nephrotoxicity
can be minimized by lowering the maintenance dose of
cyclosporine (47), it still can occur even with the use of
low cyclosporine doses (54,55).
MMF may also be beneficial in frequent relapsers or in
patients with steroid-dependent MCD (3,56–62). Choi et al.
retrospectively reviewed the outcome in seven adults with
MCD who were steroid and/or cyclosporine dependent
and had been treated with MMF for 6–26 months (56).
One patient was resistant to MMF, four patients had sus-
tained remission off steroids, and two patients relapsed. In
children, Bagga et al. prospectively examined the efficacy
of long-term therapy with MMF as a steroid-sparing agent
in children with MCD (n=10) or FSGS (n=3) who were
steroid dependent (58). Patients were administered MMF
and decreasing doses of alternate-day prednisolone for
a mean of 11.8 months. After a mean follow-up of
17 months, relapse rates decreased from 6.6 to 2 episodes
per year during MMF treatment. Treatment with MMF
resulted in a reduction of the mean prednisolone dose
from 0.7 to 0.3 mg/kg per day. Fourteen patients
showed a $50% reduction in relapse rates and predniso-
lone therapy could be discontinued for $6 months in eight
patients. After discontinuation of MMF, 68.4% of patients
had an increased frequency of relapses and recurrence of
steroid dependence, requiring other medications. The ma-
jority of the data originate from studies in children; there-
fore, extrapolation of the findings to the adult population
should be done with caution.
In the present case, the patient had two previous
courses of cyclophosphamide and additional courses of
Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2014
cyclophosphamide (the dose in choice A is inadequate and
the course in choice B is too long) that would likely add to
long-term toxicity. Sirolimus (choice C) should not be used in
patients with proteinuria due to the risk of nephrotoxicity
and AKI in these patients (63,64). MMF (choice D) is the
second-line agent in children and can certainly be consid-
ered in an adult, although a great number of patients need
concomitant low-dose corticosteroid maintenance therapy to
remain in remission. Data obtained on .250 patients treated
with rituximab demonstrate that this drug represents a new
therapeutic option. Recent Kidney Disease: Improving
Global Outcomes (KDIGO) clinical practice guidelines rec-
ommend that rituximab be considered in children who are
steroid dependent or frequent relapsers despite optimal
maintenance therapy and/or have developed significant im-
munosuppression side effects (2). However, the KDIGO
guidelines do not mention the use of rituximab in the treat-
ment of adults with frequent relapsing or steroid-dependent
MCD. Part of the problem is that the KDIGO guidelines
were published in June 2012, but the actual document
was finalized much earlier (thus, at a time when the
majority of the information regarding the use of rituximab
in MCD was not available to KDIGO members). The case is
similar to the KDIGO recommendations for ANCA-associated
vasculitis; the Rituximab versus Cyclophosphamide for
ANCA-Associated Vasculitis trial and the Randomised
Trial of Rituximab versus Cyclophosphamide for
ANCA-Associated Renal Vasculitis had not yet been pub-
lished, and the Kidney Disease Outcomes Quality Initia-
tive (KDOQI) panel comments on the discrepancies of
KDIGO recommendations in the face on current knowl-
edge (65). Considering that the patient in the above-
described case is an adult, I would argue that the number
of adult MCD patients who have been treated with
rituximab in the published literature vastly outnumbers
those treated with MMF. In fact, the KDOQI discussion of
therapy of adults states the following: “MMF in this set-
ting is supported only by limited case reports” (65). This
does not void the fact that prospective controlled studies
and long-term follow-up are required to confirm the effi-
cacy and safety of rituximab in the treatment of patients
with MCD.
Figure 2. | Light microscopy examination for the patient in case 2. (A) A perihilar segmental scar. (B) Electron microscopy showing focal foot
process effacement. Original magnification, 340 in A; 38000 in B. Courtesy of Dr. Sanjeev Sethi, Department of Laboratory Medicine and
Pathology, Mayo Clinic, Rochester, Minnesota.
Nephrology Quiz and Questionnaire 2013, Fervenza et al. 5
GN Case 2: Fernando C. Fervenza (Discussant)
A 66-year-old Caucasian man was referred for 3+ pro-
teinuria and hematuria found by dipstick urinalysis on a
routine preoperative evaluation before elective orthopedic
surgery. His past medical history included hypertension,
hyperlipidemia, and gout. Several members of his family
are hypertensive, and at least one brother has impaired
kidney function. His medications included 25 mg oral
hydrochlorothiazide once a day and 20 mg oral simvastatin
once a day. He does not smoke. On physical examination,
the patient looks healthy. His BP is 140/80 mmHg and
his pulse rate is 70 bpm. The patient’s body mass index is
29 kg/m2. The head and neck examination are normal. The
patient’s chest is clear to auscultation; a first and second
heart sounds are present with normal rate and rhythm. His
abdomen shows no hepatosplenomegaly or masses. There
is no peripheral edema.
The patient’s laboratory results are as follows: hemoglo-
bin, 14.7 g/dl; leukocytes, 6.03109/L; platelets, 2253109/L;
serum creatinine, 1.52 mg/d; eGFR, 47 ml/min per
1.73 m2(calculated by the Chronic Kidney Disease in Epide-
miology Collaboration equation); electrolyte panel, normal;
glucose, 93 mg/dl; serum albumin, 4.4 g/dl; total choles-
terol, 200 mg/dl; LDL cholesterol, 122 mg/dl; serum protein
immunofixation, negative for monoclonal proteins, HIV and
hepatitis B and C serology, negative; ANCA, negative; and
C3 and C4 complement levels, normal. Urinalysis shows
protein (3+), with positive blood. Sediment shows 3–10 red
blood cells per high-power field (.25% dysmorphic) and 1–
3 white blood cells per high-power field (with occasional
fatty casts). Proteinuria is 6.5 g/24 h. A kidney biopsy is
performed and the results are shown in Figures 2 and 3.
Question 2A
Which ONE of the following is the MOST likely lesion
accounting for the clinical picture?
A. MCD
B. Membranous nephropathy
C. FSGS
D. C3 GN
E. Mesangial proliferative GN
6 Clinical Journal of the American Society of Nephrology
Figure 3. | Immunofluorescence examination showing negative
glomerular C3 staining for the patient in case 2. Courtesy of Dr.
Sanjeev Sethi, Department of Laboratory Medicine and Pathology,
Mayo Clinic, Rochester, Minnesota.
Discussion of Case 2, Question 2A
The presence of a sclerotic lesion on light microscopy
(LM), together with presence of focal foot process efface-
ment on electron microscopy (EM), points to the diagnosis
of a FSGS lesion (choice C is correct), whereas the presence
of a segmental scar on LM excludes MCD (choice A is
incorrect). Immunofluorescence shows negative C3 stain-
ing and EM does not show subepithelial deposits so it
cannot be MN (choice B is incorrect). IgG staining was not
shown but it would be positive in MN. C3 GN is
characterized by predominant C3 staining on immunoflu-
orescence with little or no Igs. Negative C3 staining on
immunofluorescence rules out this option (choice D is
incorrect). The absence of mesangial proliferation, negative
immunofluorescence, and no deposits on EM also rules out
mesangial proliferative GN (choice E is incorrect) (Figure 4).
Figure 4. | Question 2A: Distribution of answers from fellows in training, training program directors (TPD) and audience members at the
Kidney Week meeting. The correct answer is C.
Question 2B
In this patient, which of the following therapies would
you recommend?
A. Losartan 50 mg/d, orally
B. Prednisone 1 mg/kg per day, orally for .4 months
C. Cyclosporine 3.5–5 mg/kg per day orally, with trough
blood levels of 125–175 ng/ml
D. MMF 1g, orally, twice a day
E. Sirolimus 5 mg/d, orally, with trough blood levels 12–20
ng/ml
Discussion of Case 2, Question 2B
In this patient, the absence of NS and focal foot process
effacement on EM makes FSGS most likely to be secondary
and should be treated conservatively, aiming to control BP
and reduce proteinuria using inhibitors of the renin-
angiotensin system rather than immunosuppressive ther-
apy. For this reason, treatment with losartan is the most
appropriate of the options given (choice A is correct)
(Figure 5).
Focal sclerosis is a pattern of glomerular injury defined
histologically by the presence of sclerosis in parts (seg-
mental) of some (focal) glomeruli (FSGS). FSGS is a lesion
and not a disease; the finding of an FSGS lesion is the start
of an exploratory process leading to a diagnosis, and is not
an end in itself. Recognizing this fact, FSGS has been
traditionally divided into primary and secondary (adap-
tive) FSGS. Primary FSGS should be considered the result
of direct damage to the podocyte due to a putative “per-
meability factor,” viral infections (e.g., HIV), or drugs (66).
As such, primary FSGS is a podocytopathy, akin to MCD,
with patients presenting with NS and widespread foot
process effacement on EM. This is supported by the fact
that in recurrent FSGS, glomerular foot process effacement
after kidney transplantation is the first morphologic
change (67,68).
Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2014
Figure 5. | Question 2B: Distribution of answers from fellows in training, training program directors (TPD) and audience members at the
Kidney Week meeting. The correct answer is A.
On the other hand, secondary FSGS can occur due to a
genetic mutation or as a result of functional and structural
glomerular adaptation to glomerular hypertension and/or
hyperfiltration because of a reduced number of healthy
nephrons (e.g., unilateral renal agenesis) or hemodynamic
stress on an initially normal nephron population (e.g., mor-
bid obesity, reflux nephropathy) (69). The ability to differ-
entiate primary from secondary FSGS is crucial because
patients with primary FSGS may respond to immunosup-
pressive treatments, whereas those with secondary FSGS
should be treated conservatively aiming to control BP and
reduce proteinuria. Many patients with an FSGS lesion
undergo unnecessary immunosuppression due to failure
to recognize secondary FSGS. Part of the problem derives
from the lack of realization that nephrotic-range protein-
uria (.3.5 g/24 h) and NS (.3.5 g/24 h and serum albu-
min,3.5 g/dl) are not necessarily synonymous. This issue
is particularly relevant in FSGS in which nephrotic-range
proteinuria without NS is more likely due to a secondary
process, whereas NS will more likely be the clinical pre-
sentation of a primary form. The Columbia classification,
which is based on LM, classifies FSGS as follows: not oth-
erwise specified (NOS) or perihilar, cellular, tip, or collaps-
ing variants (70,71). Although patients with a tip variant
or collapsing FSGS are likely to have NS, the majority of
patients have FSGS NOS; in my experience, FSGS NOS can
be seen in primary as well as secondary cases. Similarly,
although the finding of collapsing FSGS may be enough to
decide on immunosuppressive therapy, I believe that in
other cases the histologic diagnosis is not enough, and
additional clinical information (i.e., presence or absence
of NS is needed in order to make this decision). Indeed,
there are many patients with massive proteinuria that do
not develop hypoalbuminemia (72). This is especially true
in patients with secondary FSGS (73). Praga et al. reviewed
the clinical data in patients diagnosed with FSGS and pro-
teinuria.3.5 g/24 h and classified them according to the
presence or absence of NS (73). Of the 18 patients with
nephrotic-range proteinuria but without NS, these authors
Nephrology Quiz and Questionnaire 2013, Fervenza et al. 7
found that FSGS was due to massive obesity, vesicoureteral
reflux, and renal mass reduction in 16 of these patients.
Only two patients in this group were considered to have
idiopathic FSGS. On the other hand, NS was present in 19
patients and they all had primary FSGS. The authors con-
cluded that patients with secondary FSGS may develop
massive proteinuria but not NS. This is particularly impor-
tant when we consider that the majority of cases of adults
with FSGS secondary to a genetic mutation do not have NS.
Although in a great number of secondary FSGS foot pro-
cess effacement is variable and relatively mild, the cause is
not obvious with our current investigative tools in many
cases. However, as our knowledge expands, more causes of
secondary FSGS will be added to the current list (e.g., obe-
sity, renal mass reduction, and genetic mutations).
Another important difference between primary and
secondary FSGS is the degree of foot process effacement
on EM examination. Tip, cellular, and collapsing FSGS
usually have widespread foot process effacement, whereas
foot process effacement is variable is relatively mild in the
perihilar subtype effacement and focal in FSGS NOS (74).
Because of the adaptive origin of the lesion in secondary
FSGS, patients are more likely to have mild foot process
effacement and present with subnephrotic-range protein-
uria, whereas patients with primary (or idiopathic) FSGS
are more likely to resemble MCD by the presence of wide-
spread foot process effacement and NS, as discussed
above.
In the present case, the absence of NS and partial foot
process effacement on EM point to secondary FSGS. As
such, the finding of FSGS on a renal biopsy represents only
the beginning of the diagnostic process. Establishing the
correct etiologic diagnosis avoids unnecessary and poten-
tially harmful immunosuppressive treatments. Secondary
FSGS should be considered in all patients with proteinuria,
including nephrotic-range proteinuria, that do not have
hypoalbuminemia and in which EM examination shows
only segmental foot process effacement. In secondary
FSGS, the relative preservation of the foot process contrasts
8 Clinical Journal of the American Society of Nephrology
with the findings in a primary podocytopathy such as
MCD or primary FSGS, even in patients with nephrotic-
range proteinuria. Patients with secondary FSGS should be
treated conservatively, aiming to maximize BP control with
the use of angiotensin II blockade, a low-salt diet (,4 g/d), a
low-protein diet (0.8–1 g/kg per day), lipid control with the
use of a statin, smoking cessation, weight control, and
avoidance of nephrotoxic medications. It should not be for-
gotten that one should try to find the etiology of the sec-
ondary FSGS and correct it as well. The correct answer to
question 3 is choice A. All other choices (e.g., D and E)
include immunosuppressive therapy that may be consid-
ered in cases of primary FSGS (except choice E: sirolimus,
for reasons discussed above) but not in secondary FSGS.
Disclosures
F.C.F. has received unrestricted research grants from Genentech,
Inc., the manufacturer of rituximab.
References
1. Haas M, Meehan SM, Karrison TG, Spargo BH: Changing etiol-
ogies of unexplained adult nephrotic syndrome: A comparison of
renal biopsy findings from 1976-1979 and 1995-1997. Am J
Kidney Dis 30: 621–631, 1997
2. Kidney Disease Improving Global Outcomes (KDIGO) Glomer-
ulonephritis Work Group: KDIGO Clinical Practice Guideline
for Glomerulonephritis. Kidney Int 2: 139–274, 2012
3. Waldman M, Crew RJ, Valeri A, Busch J, Stokes B, Markowitz G,
D’Agati V, Appel G: Adult minimal-change disease: Clinical
characteristics, treatment, and outcomes. Clin J Am Soc Nephrol
2: 445–453, 2007
4. Kyrieleis HA, Löwik MM, Pronk I, Cruysberg HR, Kremer JA,
Oyen WJ, van den Heuvel BL, Wetzels JF, Levtchenko EN: Long-
term outcome of biopsy-proven, frequently relapsing minimal-
change nephrotic syndrome in children. Clin J Am Soc Nephrol
4: 1593–1600, 2009
5. Kattah AG, Fervenza FC, Roccatello D: Rituximab-based novel
strategies for the treatment of immune-mediated glomerular
diseases. Autoimmun Rev 12: 854–859, 2013
6. Gilbert RD, Hulse E, Rigden S: Rituximab therapy for steroid-
dependent minimal change nephrotic syndrome. Pediatr Neph-
rol 21: 1698–1700, 2006
7. Francois H, Daugas E, Bensman A, Ronco P: Unexpected efficacy
of rituximab in multirelapsing minimal change nephrotic syn-
drome in the adult: First case report and pathophysiological
considerations. Am J Kidney Dis 49: 158–161, 2007
8. Hofstra JM, Deegens JK, Wetzels JF: Rituximab: Effective treat-
ment for severe steroid-dependent minimal change nephrotic
syndrome? Nephrol Dial Transplant 22: 2100–2102, 2007
9. Guigonis V, Dallocchio A, Baudouin V, Dehennault M, Hachon-
Le Camus C, Afanetti M, Groothoff J, Llanas B, Niaudet P, Nivet
H, Raynaud N, Taque S, Ronco P, Bouissou F: Rituximab treat-
ment for severe steroid- or cyclosporine-dependent nephrotic
syndrome: A multicentric series of 22 cases. Pediatr Nephrol 23:
1269–1279, 2008
10. Yang T, Nast CC, Vo A, Jordan SC: Rapid remission of steroid and
mycophenolate mofetil (MMF)-resistant minimal change ne-
phrotic syndrome after rituximab therapy. Nephrol Dial Trans-
plant 23: 377–380, 2008
11. Kamei K, Ito S, Nozu K, Fujinaga S, Nakayama M, Sako M, Saito
M, Yoneko M, Iijima K: Single dose of rituximab for refractory
steroid-dependent nephrotic syndrome in children. Pediatr
Nephrol 24: 1321–1328, 2009
12. Kurosu N, Sugiura H, Iwasaki C, Asamiya Y, Kojima C, Moriyama
T, Itabashi M, Tsukada M, Takei T, Ogawa T, Yoshida T, Uchida K,
Tsuchiya K, Nitta K: Successful use of single-dose rituximab for
the maintenance of remission in a patient with steroid-resistant
nephrotic syndrome. Intern Med 48: 1901–1904, 2009
13. Sawara Y, Itabashi M, Kojima C, Tabata H, Kamei D, Kawanishi K,
Moriyama T, Sugiura H, Tsukada M, Takei T, Ogawa T, Yoshida T,
Arai J, Uchida K, Tsuchiya K, Nitta K: Successful therapeutic use
of a single-dose of rituximab on relapse in adults with minimal
change nephrotic syndrome. Clin Nephrol 72: 69–72, 2009
14. Fujinaga S, Hirano D, Nishizaki N, Kamei K, Ito S, Ohtomo Y,
Shimizu T, Kaneko K: Single infusion of rituximab for persistent
steroid-dependent minimal-change nephrotic syndrome after
long-term cyclosporine. Pediatr Nephrol 25: 539–544, 2010
15. Hoxha E, Stahl RA, Harendza S: Rituximab in adult patients with
immunosuppressive-dependent minimal change disease. Clin
Nephrol 76: 151–158, 2011
16. Sugiura H, Takei T, Itabashi M, Tsukada M, Moriyama T, Kojima
C, Shiohira T, Shimizu A, Tsuruta Y, Amemiya N, Ogawa T,
Uchida K, Tsuchiya K, Nitta K: Effect of single-dose rituximab on
primary glomerular diseases. Nephron Clin Pract 117: c98–
c105, 2011
17. Kisner T, Burst V, Teschner S, Benzing T, Kurschat CE: Rituximab
treatment for adults with refractory nephrotic syndrome: A
single-center experience and review of the literature. Nephron
Clin Pract 120: c79–c85, 2012
18. Takei T, Itabashi M, Moriyama T, Kojima C, Shiohira S, Shimizu A,
Tsuruta Y, Ochi A, Amemiya N, Mochizuki T, Uchida K,
Tsuchiya K, Nitta K: Effect of single-dose rituximab on steroid-
dependent minimal-change nephrotic syndrome in adults.
Nephrol Dial Transplant 28: 1225–1232, 2013
19. Ravani P, Ponticelli A, Siciliano C, Fornoni A, Magnasco A, Sica F,
Bodria M, Caridi G, Wei C, Belingheri M, Ghio L, Merscher-
Gomez S, Edefonti A, Pasini A, Montini G, Murtas C, Wang X,
Muruve D, Vaglio A, Martorana D, Pani A, Scolari F, Reiser J,
Ghiggeri GM: Rituximab is a safe and effective long-term
treatment for children with steroid and calcineurin inhibitor-
dependent idiopathic nephrotic syndrome. Kidney Int 84: 1025–
1033, 2013
20. Kemper MJ, Gellermann J, Habbig S, Krmar RT, Dittrich K,
Jungraithmayr T, Pape L, Patzer L, Billing H, Weber L, Pohl M,
Rosenthal K, Rosahl A, Mueller-Wiefel DE, Dotsch J: Long-term
follow-up after rituximab for steroid-dependent idiopathic ne-
phrotic syndrome. Nephrol Dial Transplant 27: 1910–1915,
2012
21. Smith GC: Is there a role for rituximab in the treatment of idio-
pathic childhood nephrotic syndrome? Pediatr Nephrol 22: 893–
898, 2007
22. Sellier-Leclerc AL, Baudouin V, Kwon T, Macher MA, Guerin V,
Lapillonne H, Deschenes G, Ulinski T: Rituximab in steroid-
dependent idiopathic nephrotic syndrome in childhood–
follow-up after CD19 recovery. Nephrol Dial Transplant 27:
1083–1089, 2012
23. Munyentwali H, Bouachi K, Audard V, Remy P, Lang P, Mojaat R,
Deschênes G, Ronco PM, Plaisier EM, Dahan KY: Rituximab is an
efficient and safe treatment in adults with steroid-dependent
minimal change disease. Kidney Int 83: 511–516, 2013
24. Fervenza FC, Sethi S: Frequent-relapsing, steroid-dependent
minimal change disease: Is rituximab the answer? [published
online ahead of print September 11, 2013]. Nephrol Dial
Transplant doi:10.1093/ndt/gft366
25. Gulati A, Sinha A, Jordan SC, Hari P, Dinda AK, Sharma S,
Srivastava RN, Moudgil A, Bagga A: Efficacy and safety of treat-
ment with rituximab for difficult steroid-resistant and -dependent
nephrotic syndrome: Multicentric report. Clin J Am Soc Nephrol
5: 2207–2212, 2010
26. Bruchfeld A, Benedek S, Hilderman M, Medin C, Snaedal-
Jonsdottir S, Korkeila M: Rituximab for minimal change disease in
adults: Long-term follow-up [published online ahead of print
October 11, 2013]. Nephrol Dial Transplant doi:10.1093/ndt/
gft312
27. Ruggenenti P, Ruggiero B, Cravedi P, Massella L, Marasa M,
Chianca A, Rubis N, Ene-Iordache Rudnicki M, Pollastro R,
Pisani AB, Emma F, Remuzzi G: Rituximab in steroid-dependent
or frequently-relapsing idiopathic nephrotic syndrome. J Am Soc
Nephrol (in press)
28. Shalhoub RJ: Pathogenesis of lipoid nephrosis: A disorder of T-
cell function. Lancet 2: 556–560, 1974
29. Karras A, de Montpreville V, Fakhouri F, Grunfeld JP, Lesavre P:
Renal and thymic pathology in thymoma-associated nephropa-
thy: Report of 21 cases and review of the literature. Nephrol
Dial Transplant 20: 1075–1082, 2005
Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2014
30. Kemper MJ, Meyer-Jark T, Lilova M, Müller-Wiefel DE: Combined
T- and B-cell activation in childhood steroid-sensitive nephrotic
syndrome. Clin Nephrol 60: 242–247, 2003
31. Hultin LE, Hausner MA, Hultin PM, Giorgi JV: CD20 (pan-B cell)
antigen is expressed at a low level on a subpopulation of human T
lymphocytes. Cytometry 14: 196–204, 1993
32. Ishimoto T, Shimada M, Araya CE, Huskey J, Garin EH, Johnson
RJ: Minimal change disease: A CD80 podocytopathy? Semin
Nephrol 31: 320–325, 2011
33. Martin F, Chan AC: Pathogenic roles of B cells in human auto-
immunity; insights from the clinic. Immunity 20: 517–527, 2004
34. Tsai MJ, Chou CW, Lin FC, Chang SC: Pneumocystis jiroveci
pneumonia in patients with systemic lupus erythematosus after
rituximab therapy. Lupus 21: 914–918, 2012
35. Martin-Garrido I, Carmona EM, Specks U, Limper AH: Pneu-
mocystis pneumonia in patients treated with rituximab. Chest
144: 258–265, 2013
36. Green H, Paul M, Vidal L, Leibovici L: Prophylaxis of Pneumo-
cystis pneumonia in immunocompromised non-HIV-infected
patients: Systematic review and meta-analysis of randomized
controlled trials. Mayo Clin Proc 82: 1052–1059, 2007
37. Calabrese LH, Molloy ES, Huang D, Ransohoff RM: Progressive
multifocal leukoencephalopathy in rheumatic diseases:
Evolving clinical and pathologic patterns of disease. Arthritis
Rheum 56: 2116–2128, 2007
38. Tsutsumi Y, Kanamori H, Mori A, Tanaka J, Asaka M, Imamura M,
Masauzi N: Reactivation of hepatitis B virus with rituximab. Ex-
pert Opin Drug Saf 4: 599–608, 2005
39. Ponticelli C, Edefonti A, Ghio L, Rizzoni G, Rinaldi S, Gusmano
R, Lama G, Zacchello G, Confalonieri R, Altieri P, Bettinelli A,
Maschio G, Cinotti GA, Fuiano G, Schena FP, Castellani A, Delia
Casa-Alberighi O: Cyclosporin versus cyclophosphamide for
patients with steroid-dependent and frequently relapsing idio-
pathic nephrotic syndrome: A multicentre randomized con-
trolled trial. Nephrol Dial Transplant 8: 1326–1332, 1993
40. Nolasco F, Cameron JS, Heywood EF, Hicks J, Ogg C, Williams
DG: Adult-onset minimal change nephrotic syndrome: A long-
term follow-up. Kidney Int 29: 1215–1223, 1986
41. Mak SK, Short CD, Mallick NP: Long-term outcome of adult-
onset minimal-change nephropathy. Nephrol Dial Transplant 11:
2192–2201, 1996
42. Oemar BS, Brodehl J; Writing Committee of the Arbeitsgemein-
schaft für Pädiatrische Nephrologie: Cyclophosphamide treat-
ment of steroid dependent nephrotic syndrome: Comparison of
eight week with 12 week course. Report of Arbeitsgemeinschaft
für Pädiatrische Nephrologie. Arch Dis Child 62: 1102–1106,
1987
43. Donia AF, Gazareen SH, Ahmed HA, Moustafa FE, Shoeib AA,
Ismail AM, Khamis S, Sobh MA: Pulse cyclophosphamide in-
adequately suppresses reoccurrence of minimal change ne-
phrotic syndrome in corticoid-dependent children. Nephrol Dial
Transplant 18: 2054–2058, 2003
44. Faurschou M, Sorensen IJ, Mellemkjaer L, Loft AG, Thomsen BS,
Tvede N, Baslund B: Malignancies in Wegener’s granulomatosis:
Incidence and relation to cyclophosphamide therapy in a
cohort of 293 patients. J Rheumatol 35: 100–105, 2008
45. Pendse S, Ginsburg E, Singh AK: Strategies for preservation of
ovarian and testicular function after immunosuppression. Am J
Kidney Dis 43: 772–781, 2004
46. Meistrich ML, Wilson G, Brown BW, da Cunha MF, Lipshultz LI:
Impact of cyclophosphamide on long-term reduction in sperm
count in men treated with combination chemotherapy for Ewing
and soft tissue sarcomas. Cancer 70: 2703–2712, 1992
47. Meyrier A, Noël LH, Auriche P, Callard P; Collaborative Group of
the Société de Néphrologie: Long-term renal tolerance of cy-
closporin A treatment in adult idiopathic nephrotic syndrome.
Kidney Int 45: 1446–1456, 1994
48. Meyrier A: Treatment of idiopathic nephrosis by immunophillin
modulation. Nephrol Dial Transplant 18[Suppl 6]: vi79–vi86,
2003
49. Cattran DC, Alexopoulos E, Heering P, Hoyer PF, Johnston A,
Meyrier A, Ponticelli C, Saito T, Choukroun G, Nachman P, Praga
M, Yoshikawa N: Cyclosporin in idiopathic glomerular disease
associated with the nephrotic syndrome : Workshop recom-
mendations. Kidney Int 72: 1429–1447, 2007
Nephrology Quiz and Questionnaire 2013, Fervenza et al. 9
50. Westhoff TH, Schmidt S, Zidek W, Beige J, van der Giet M:
Tacrolimus in steroid-resistant and steroid-dependent nephrotic
syndrome. Clin Nephrol 65: 393–400, 2006
51. Sinha MD, MacLeod R, Rigby E, Clark AG: Treatment of severe
steroid-dependent nephrotic syndrome (SDNS) in children with
tacrolimus. Nephrol Dial Transplant 21: 1848–1854, 2006
52. Li X, Li H, Chen J, He Q, Lv R, Lin W, Li Q, He X, Qu L, Suya W:
Tacrolimus as a steroid-sparing agent for adults with steroid-
dependent minimal change nephrotic syndrome. Nephrol Dial
Transplant 23: 1919–1925, 2008
53. Hogan J, Radhakrishnan J: The treatment of minimal change
disease in adults. J Am Soc Nephrol 24: 702–711, 2013
54. Isnard Bagnis C, Tezenas du Montcel S, Beaufils H, Jouanneau C,
Jaudon MC, Maksud P, Mallet A, LeHoang P, Deray G: Long-
term renal effects of low-dose cyclosporine in uveitis-treated
patients: Follow-up study. J Am Soc Nephrol 13: 2962–2968,
2002
55. Fujinaga S, Hirano D, Murakami H, Ohtomo Y, Shimizu T,
Kaneko K: Nephrotoxicity of once-daily cyclosporine A in min-
imal change nephrotic syndrome. Pediatr Nephrol 27: 671–674,
2012
56. Choi MJ, Eustace JA, Gimenez LF, Atta MG, Scheel PJ,
Sothinathan R, Briggs WA: Mycophenolate mofetil treatment for
primary glomerular diseases. Kidney Int 61: 1098–1114, 2002
57. Briggs WA, Choi MJ, Scheel PJ Jr: Successful mycophenolate
mofetil treatment of glomerular disease. Am J Kidney Dis 31:
213–217, 1998
58. Bagga A, Hari P, Moudgil A, Jordan SC: Mycophenolate mofetil
and prednisolone therapy in children with steroid-dependent
nephrotic syndrome. Am J Kidney Dis 42: 1114–1120, 2003
59. Dorresteijn EM, Kist-van Holthe JE, Levtchenko EN, Nauta J, Hop
WC, van der Heijden AJ: Mycophenolate mofetil versus cyclo-
sporine for remission maintenance in nephrotic syndrome. Pe-
diatr Nephrol 23: 2013–2020, 2008
60. Fujinaga S, Ohtomo Y, Hirano D, Nishizaki N, Someya T,
Ohtsuka Y, Kaneko K, Shimizu T: Mycophenolate mofetil therapy
for childhood-onset steroid dependent nephrotic syndrome after
long-term cyclosporine: Extended experience in a single center.
Clin Nephrol 72: 268–273, 2009
61. Gellermann J, Querfeld U: Frequently relapsing nephrotic syn-
drome: Treatment with mycophenolate mofetil. Pediatr Nephrol
19: 101–104, 2004
62. Pesavento TE, Bay WH, Agarwal G, Hernandez RA Jr, Hebert LA:
Mycophenolate therapy in frequently relapsing minimal
change disease that has failed cyclophosphamide therapy.
Am J Kidney Dis 43: e3–e6, 2004
63. Fervenza FC, Fitzpatrick PM, Mertz J, Erickson SB, Liggett S,
Popham S, Wochos DN, Synhavsky A, Hippler S, Larson TS,
Bagniewski SM, Velosa JA: Acute rapamycin nephrotoxicity in
native kidneys of patients with chronic glomerulopathies.
Nephrol Dial Transplant 19: 1288–1292, 2004
64. Cho ME, Hurley JK, Kopp JB: Sirolimus therapy of focal segmental
glomerulosclerosis is associated with nephrotoxicity. Am J Kid-
ney Dis 49: 310–317, 2007
65. Beck L, Bomback AS, Choi MJ, Holzman LB, Langford C, Mariani
LH, Somers MJ, Trachtman H, Waldman M: KDOQI US com-
mentary on the 2012 KDIGO clinical practice guideline for
glomerulonephritis. Am J Kidney Dis 62: 403–441, 2013
66. Meyrier A: Focal and segmental glomerulosclerosis: Multiple
pathways are involved. Semin Nephrol 31: 326–332, 2011
67. D’Agati VD: Podocyte injury in focal segmental glomerulo-
sclerosis: Lessons from animal models (a play in five acts). Kidney
Int 73: 399–406, 2008
68. Chang JW, Pardo V, Sageshima J, Chen L, Tsai HL, Reiser J, Wei C,
Ciancio G, Burke GW 3rd, Fornoni A: Podocyte foot process ef-
facement in postreperfusion allograft biopsies correlates with
early recurrence of proteinuria in focal segmental glomerulo-
sclerosis. Transplantation 93: 1238–1244, 2012
69. Rennke HG, Klein PS: Pathogenesis and significance of non-
primary focal and segmental glomerulosclerosis. Am J Kidney
Dis 13: 443–456, 1989
70. Thomas DB, Franceschini N, Hogan SL, Ten Holder S, Jennette
CE, Falk RJ, Jennette JC: Clinical and pathologic characteristics of
focal segmental glomerulosclerosis pathologic variants. Kidney
Int 69: 920–926, 2006
 10 Clinical Journal of the American Society of Nephrology
71. Stokes MB, Valeri AM, Markowitz GS, D’Agati VD: Cellular focal
segmental glomerulosclerosis: Clinical and pathologic features.
Kidney Int 70: 1783–1792, 2006
72. Praga M, Borstein B, Andres A, Arenas J, Oliet A, Montoyo C,
Ruilope LM, Rodicio JL: Nephrotic proteinuria without hypo-
albuminemia: Clinical characteristics and response to angiotensin-
converting enzyme inhibition. Am J Kidney Dis 17: 330–338, 1991
73. Praga M, Morales E, Herrero JC, Perez Campos A, Dominguez-
Gil B, Alegre R, Vara J, Martinez MA: Absence of hypo-
View publication stats
albuminemia despite massive proteinuria in focal segmental
glomerulosclerosis secondary to hyperfiltration. Am J Kidney Dis
33: 52–58, 1999
74. D’Agati VD, Kaskel FJ, Falk RJ: Focal segmental glomerulo-
sclerosis. N Engl J Med 365: 2398–2411, 2011
Published online ahead of print. Publication date available at www.
cjasn.org.