CJASN ePress. Published on May 24, 2010 as doi: 10.2215/CJN.
00540110
Special Feature
Nephrology Quiz and Questionnaire: 2009
Richard J. Glassock (Moderator)*; Participants: Joanne M. Bargman,† Biff F. Palmer,‡
Millie Samaniego,§ and Fernando C. Fervenza储
*Department of Medicine, Geffen School of Medicine at UCLA, Los Angeles, California; †Department of Medicine,
Toronto General Hospital, Toronto, Ontario, Canada; ‡Department of Internal Medicine, University of Texas
Southwestern Medical Center, Dallas, Texas; §Division of Nephrology, Department of Medicine, University of Michigan
Medical School, Ann Arbor, Michigan; and 储Division of Nephrology and Hypertension, Mayo Clinic, Rochester,
Minnesota
Clin J Am Soc Nephrol 5: 1141–1160, 2010. doi: 10.2215/CJN.00540110
T
he Nephrology Quiz and Questionnaire returns to the
pages of CJASN after an absence of 3 years, but it still
remains one of the most popular sessions at the annual
meeting of the American Society of Nephrology. The meeting in
2009 in San Diego was no exception, with a full-house atten-
dance, estimated at more than 800 eager nephrologists. Eight
challenging and educational cases were presented and dis-
cussed by four able and skilled experts. The discussants were
asked to prepare vignettes of puzzling cases, each illustrating
some topical, challenging, or controversial aspect of diagno-
sis or management of ESRD and dialysis (Dr. Bargman), fluid
and electrolytes (Dr. Palmer), kidney transplantation (Dr.
Samaniego), and glomerular disease (Dr. Fervenza). One or two
single best answers questions followed each case presentation,
which were addressed by the audience in a live electronic
response system. In addition, several weeks before the meeting,
the cases and questions (without the answers) were sent to all
of the US nephrology training program directors as a question-
naire. Their responses to the questions were tallied and pre-
sented after the audience response but before the answers to the
quiz and the analyses of the cases were given by the discus-
sants.
Each discussant prepared a manuscript summarizing his or
her discussion of the cases, an edited version of which serves as
the main text of this article. We hope that this “distillate” from
San Diego will serve the subscribers to CJASN well and provide
some fresh insights into the complexity and vibrancy of clinical
nephrology for those who were unable to attend (Richard J.
Glassock, MD, Moderator).
Case 1: Joanne M. Bargman
The patient was a 59-year-old man from North Africa. A diag-
nosis of ankylosing spondylitis was made in 1980 and was
treated with anti-inflammatory agents. In 2002, he was noted to
have significant proteinuria and microscopic hematuria. A re-
nal biopsy demonstrated AA amyloidosis. He had slowly pro-
Published online ahead of print. Publication date available at www.cjasn.org.
Correspondence: Dr. Richard J. Glassock, 8 Bethany, Laguna Niguel, CA 92677.
Phone: 949-388-8885; Fax: 949-388-8882; E-mail: glassock@cox.net
Copyright © 2010 by the American Society of Nephrology
gressive renal impairment. In 2005, he underwent nephrectomy
for renal cell carcinoma. This resulted in worsening nephrotic
syndrome and stage 5 chronic kidney disease. A peritoneal
dialysis (PD) catheter was inserted in July 2005, and the patient
started on continuous ambulatory PD, 3 ⫻ 2 L exchanges
during the day and icodextrin exchanges overnight. He devel-
oped anuria over the subsequent 2 months. Peritonitis was
diagnosed on September 10, 2006, when he presented with
abdominal pain and cloudy drainage fluid.
Examination of the PD drainage fluid revealed a white blood
cell count of 1870 ⫻ 106/L, 90% neutrophils. He was started on
empiric therapy with intraperitoneal cefazolin and ceftazidime.
Culture and sensitivity of the PD fluid revealed Acinetobacter
calcoaceticus-baumanii complex that was resistant to cefazolin.
He was continued on intraperitoneal ceftazidime. Fungal pro-
phylaxis was given with oral mycostatin.
Subsequent PD fluid cell counts were as follows:
• September 12: ⬍100/L
• September 14: ⬍100/L
• September 16: ⬍100/L
• September 20: 1360 ⫻ 106/L, 96% neutrophils
Question 1
With respect to the increase in cell count on day 10 (September
20) of therapy, which ONE of the following statements is MOST
correct (Figure 1)?
A. It is unlikely to be fungal because of the prophylaxis with
mycostatin.
B. The most likely cause is that the patient stopped taking his
intraperitoneal antibiotic.
C. The causative organism became resistant to the antibiotic.
D. The icodextrin has led to a chemical peritonitis via contam-
ination with peptidoglycans.
E. The blood levels of ceftazidime became subtherapeutic.
Discussion of Case 1 (Question 1)
The best answer is choice C: The causative organism became
resistant to the antibiotic. Acinetobacter calcoaceticus-baumanii
belongs to the SPICE group of organisms. This is an acronym
for a group of bacteria that have chromosomally mediated
ISSN: 1555-9041/506 –1141
1142 Clinical Journal of the American Society of Nephrology
Figure 1. Answers from the membership, question 1.
activity that induces resistance to antibiotics (1). Although this
group of organisms may be reported as sensitive to cephalo-
sporins upon initial testing, they can quickly undergo genetic
mutation with selection pressure for ␤-lactamase–producing
mutants and become resistant to this class of antibiotic. Bacteria
included in the SPICE category include
Serratia
Pseudomonas/Providencia
Indole-positive Proteus/Acinetobacter/Morganella
Citrobacter
Enterobacter
The initial response of the patient’s peritonitis to the cepha-
losporin-based therapy speaks to the initial sensitivity of the
Acinetobacter to these antibiotics; however, by the 10th day of
treatment, the peritonitis relapsed because of the resistance that
supervened. Fortunately, the organism remained sensitive to
aminoglycoside, his antibiotics were adjusted accordingly, and
the peritonitis was cured. For serious infections caused by
SPICE or extended-spectrum ␤-lactamase organisms, the anti-
biotics of choice are the carbapenems (2).
The incidence of inducible resistance to antibiotics varies in
different parts of the world and these bacteria may also possess
factors that confer resistance to other antibiotics such as the
fluoroquinolones and aminoglycosides (3). It is important to be
aware of this activity in the SPICE group of bacteria. Otherwise,
for example, the peritonitis in the patient discussed may have
been considered resistant to treatment and his PD catheter
removed. Several methods are available to detect extended-
spectrum ␤-lactamase activity, but they may be confounded by
other factors that contribute to ␤-lactam resistance, such as
production of Amp-C ␤-lactamase by Enterobacteriaceae (4). For
this and many other reasons, it is helpful to have an infectious
disease specialist with an interest in PD peritonitis work in
conjunction with a PD program.
Fungal peritonitis is a very serious complication in PD and is
associated with technique failure and death (5). Patients who
are especially at risk for this type of peritonitis include the
elderly, patients with diabetes, and those who are receiving
Clin J Am Soc Nephrol 5: 1141–1160, 2010
immunosuppressive drugs. Perhaps the greatest risk for yeast
or fungal peritonitis is the use of broad-spectrum antibiotics,
especially when instilled in the peritoneal cavity (6). It is pos-
tulated that the antibiotics disturb the usual balance between
bacteria and fungi within the bowel lumen, allowing for over-
growth of the fungi. Consequently, the extra burden of intralu-
minal fungi leads to migration of these organisms across the
bowel wall and into the peritoneal cavity. Although there are
anecdotal reports of eradication of these infections with anti-
fungal agents, this is a rare event, and, in most cases, the
catheter must be removed to treat the infection (7). After a
period off PD, usually ⱖ6 weeks, another catheter can be re-
inserted; however, fungal peritonitis is often associated with
the formation of intraperitoneal adhesions that may prevent the
successful resumption of PD. Unfortunately, it is difficult to
predict who will develop adhesions, and they cannot be im-
aged, so it is impossible to know whether another catheter can
be inserted successfully until the time of the procedure. The use
of antifungal prophylaxis concurrent with broad-spectrum an-
tibiotics has been advocated to reduce the fungal overgrowth
and thus reduce the risk for a secondary fungal peritonitis.
Results of studies using this approach have been variable, but
in centers where there is a higher baseline rate of fungal peri-
tonitis, the use of prophylaxis seems to reduce this complica-
tion (8,9). Given that a regimen such as oral mycostatin is
associated with few complications, it may be worthwhile to
co-administer oral mycostatin at the same time as the patient is
taking antibiotics, given the poor outcomes that are associated
with fungal peritonitis. Although answer A addresses the re-
duction in risk for fungal peritonitis because of the prophylaxis,
it is an overstatement to say that this complication is “unlikely”
because of it. Certainly with a “relapse” during antibiotic ther-
apy, fungal peritonitis must be considered a possibility. An-
swer B is not likely. First, the time to relapse in this case is
particularly short for someone who stopped taking antibiotic.
Second, it is underappreciated how painful peritonitis is (10),
and so a home dialysis patient, who already undergoes dialysis
autonomously, will be motivated to continue the antibiotic
therapy.
Icodextrin is a starch-based polymer that is used as an alter-
native to dextrose solutions for ultrafiltration in PD. The dex-
trins of dispersed molecular weight exert an oncotic pressure
across the peritoneal capillary network, resulting in slow but
sustained ultrafiltration. In patients who are rapid transporters
and have early dissipation of the glucose-based osmotic gradi-
ent and loss of ultrafiltration over the long dialysis dwells,
icodextrin has proved very helpful. Adverse effects are mini-
mal, although skin rashes have been reported as a reaction to
this solution (11). Several years ago, several cases of culture-
negative peritonitis were described with the use of icodextrin.
This peritoneal reaction was found to be related to contamina-
tion of the solution by peptidoglycans that originated in the
starch product, and modification in the production of this
solution has resulted in a reduction in this complication (12).
That is why answer D is not the best choice. In addition, the
chemical peritonitis that is associated with the peptidoglycans
Clin J Am Soc Nephrol 5: 1141–1160, 2010
typically manifests with a lower peritoneal cell count with less
neutrophilic predominance.
Finally, with instillation of high dosages of antibiotics into
the peritoneal cavity, there will be equilibration of these agents
with the blood compartment. Re-diffusion of the antibiotic into
the peritoneal cavity with subsequent PD exchanges will bring
more antibiotic into the peritoneal fluid; however, the principal
bacterial killing occurs with the very high dosages of antibiotic
that is usually given on a daily basis in the treatment of PD
peritonitis (13); therefore, answer E, which suggests that blood
concentration of antibiotic (rather than intraperitoneal concen-
tration) is important in treating the peritonitis, is not correct.
Case 2: Joanne M. Bargman
A 55-year-old right-handed woman with type 2 diabetes and
progressive diabetic nephropathy has been followed in a mul-
tidisciplinary predialysis clinic for 2 years. She has received
education on options for renal replacement therapy. There are
no candidates to donate a kidney, and she declines home PD.
She undergoes left radiocephalic fistula creation, but the fistula
fails to mature. She is assessed for fistula creation on the right
arm, but venous studies demonstrate in the right innominate
vein a stenosis that is believed to be a sequela of a previous
central line during an intensive care unit admission for urosep-
sis.
While she is waiting to be reassessed by the vascular sur-
geon, she has another episode of urosepsis and develops symp-
tomatic uremia and volume overload. She is admitted to hos-
pital, and a tunneled cuffed catheter is placed via the left
internal jugular vein. She is started on hemodialysis (HD) three
times a week.
After 1 month of HD, there is no evidence of return of renal
function. She is reluctant to proceed with creation of another
fistula. In the sixth week of therapy, she develops fever and
chills on dialysis. There is no evidence of infection at the exit
site and no hemodynamic compromise. There is no other ob-
vious source of infection. A presumptive diagnosis of line
sepsis is made, and she is treated as an outpatient with intra-
venous cefazolin and gentamicin. Blood cultures grow coagu-
lase-negative Staphylococcus that is sensitive to cephalosporins.
She is prescribed cefazolin at each HD session for 3 weeks.
Three days later at the HD unit, she has had no fever and does
not develop fever or chills during the dialysis run.
Question 2
At this point, which ONE of the following is the BEST approach
to her subsequent treatment (Figure 2)?
A. Continue the intravenous cefazolin for 3 weeks total, and
change the dialysis line over a guidewire.
B. Discontinue the intravenous cefazolin after 1 week, and
switch to oral therapy for 2 weeks.
C. Continue the intravenous cefazolin for 3 weeks total, mon-
itor the exit site, but change the line only if there is evidence
of infection at the exit site.
D. Continue the intravenous cefazolin for 3 weeks, and re-site
the tunneled venous catheter to the femoral vein.
Nephrology Quiz and Questionnaire: 2009 1143
Figure 2. Answers from the membership, question 2.
E. Continue the intravenous cefazolin for 3 weeks, do not
change or re-site the tunneled internal jugular line, and
institute an antibiotic lock.
Discussion of Case 2 (Question 2)
The correct answer is A: Continue the intravenous cefazolin for
3 weeks total, and change the dialysis line over a guidewire.
The use of tunneled subclavian catheters and, more recently,
tunneled internal jugular catheters, has made it possible to have
immediate venous access for urgent or emergent HD and al-
lows the patient to leave hospital and await a more permanent
vascular access. Unfortunately, the permanent (and superior)
form of vascular access, such as an arteriovenous fistula, often
never is established. First, the patient may become comfortable
with the internal jugular line, both because it avoids needle
stick and because of a reluctance to undergo more procedures.
Second, the patient may agree to creation of an arteriovenous
fistula but that surgery is not successful or the fistula is created
but does not develop sufficiently to support the HD blood
flows. According to recent data from the US Renal Data System,
a majority of patients start HD with “temporary” venous ac-
cess, and even many months later, half or more of these patients
still have a catheter.
Catheter-related bacteremia (CRB) is a frequent complication
of indwelling HD catheters and is associated with a number of
serious complications, including septicemia, hospitalization,
metastatic infection, and death. Indeed, the increased risk for
mortality that results from an episode of CRB does not dissipate
with treatment of infection but instead is associated with an
ongoing increased death risk for several years (14).
CRB that is associated with ongoing septic symptoms, in-
cluding fever and hypotension, is usually treated with antibi-
otics, systemic support, and removal of the dialysis catheter.
Similarly, the catheter is removed when there is CRB in asso-
ciation with infection at the exit site. What is unclear is whether
the catheter has to be removed when there is an “uncompli-
cated” CRB—that is, unassociated with hemodynamic compro-
mise or exit-site infection.
1144 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 5: 1141–1160, 2010

Unfortunately, most studies to date have suggested that an- a relatively newer procedure, however, I am reserving judg-
tibiotic therapy alone without removal or exchange of the HD ment and suggest that option A is the better one. Of course,
catheter is associated with an unacceptable rate of relapse of the from the vantage of the patient, an antibiotic lock would be
bacteremia. Only one third of catheters could be “salvaged” preferable to a line change.
with this approach, and, in the majority, the infection recurred
such that the catheter eventually had to be removed (15,16). Case 3: Biff F. Palmer
Moreover, there seems to be a higher incidence of metastatic A 33-year-old black woman is admitted with right flank pain
infection compared with those who undergo immediate re- radiating to the groin in association with gross hematuria. Her
moval of the infected line (17,18). A recent study from the history is noteworthy for one previous episode of nephrolithi-
United Kingdom reported a salvage rate in two thirds of bac- asis 6 months before. The patient works as a fashion model and
teremias, but this entailed 6 weeks of parenteral antibiotics, as such has always been concerned about her body weight. She
including the use of two antibiotics for Gram-positive organ- admits to use of diuretics in the past but denies recent use of
isms (19). This kind of prolonged, intensive regimen may in- diuretic, laxatives, or vomiting. Physical examination shows a
crease the chances of antibiotic-associated adverse effects and BP of 122/78 mmHg with no orthostatic changes. The remain-
perhaps bacterial resistance. Because catheter salvage with an- der of the examination is normal. Laboratory data are given in
tibiotics alone for 3 weeks will not be successful in the majority Table 1.
of cases, answers B and C (switch to oral antibiotics) are not the
best choices. Question 3
If a more definitive approach is to remove the dialysis cath- Which ONE of the following can BEST account for the clinical
eter, then this can be accomplished in two ways: The first findings in this patient (Figure 3)?
option is to remove the catheter, leave the patient without
A. Surreptitious vomiting
access for a day or two, and then re-insert a new catheter at the B. Surreptitious laxative abuse
original or at another site. This approach subjects the patients to C. Bartter syndrome
two procedures. Furthermore, in those with tenuous vascular D. Sjögren syndrome
access, there is a possibility that venous access will not be E. Surreptitious diuretic abuse
re-established at the re-insertion of the catheter. Patients may
also have to be hospitalized to expedite the two interventions. Discussion of Case 3 (Question 3)
Another approach is to remove the catheter but replace it over Surreptitious laxative abuse (B) is the best explanation for the
a guidewire at the same procedure (20). This both avoids an- findings in this case. The prevalence of this disorder has been
other intervention and preserves the same venous access. The estimated to be between 4 and 26% of patients with chronic
guidewire-exchange approach has been demonstrated to be as
efficacious as the two-step procedure (21–23) and does not
seem to leave the patient more vulnerable to metastatic infec-
Table 1. Laboratory data for case 3
tion (23). More recently, however, Mokrzycki et al. (24) sug-
gested that the guidewire exchange may not be as successful for Parameter Value
CRB that is caused by Staphylococcus aureus. In the case in
question, the causative organism was coagulase-negative Creatinine (mg/dl) 1.1
Staphylococcus, so answer A, guidewire exchange and 3 weeks BUN (mg/dl) 14
of parenteral antibiotics, is correct. Option D is partially correct, Serum electrolytes
insofar as the catheter could be removed and re-sited; however, (mEq/L)
this patient had limited vascular access, and re-siting a catheter Na⫹ 139
to the femoral vein would be less preferable and associated K⫹ 2.3
with a higher risk for complications. Cl⫺ 92
The final consideration is alluded to in option E, whether the HCO3 34
catheter could be kept in situ without a guidewire exchange by Urine electrolytes
using an antibiotic lock in the catheter lumen to kill the organ- (mEq/L):
isms in the bacterial biofilm. Very high concentrations of anti- Na⫹ 10
biotic are instilled into each port at the end of each HD session K⫹ 15
and left there until the beginning of the next session, when the
Cl⫺ 80
antibiotic solution is aspirated. This approach has salvaged
Urinalysis and urine Specific gravity 1.024, pH 6.8,
catheters in two thirds or more of CRB without the need for
culture ⫹ blood on dipstick, 20
guidewire exchange or catheter replacement (25,26); however,
RBC/hpf, 5 to 10 WBC/
once again, infection with Staphylococcus aureus seems to be
hpf; urine culture: no
resistant to this approach, with a low salvage rate and an
growth
unacceptable complication rate (26,27). In this case of CRB
Stone analysis Ammonium urate
caused by coagulase-negative Staphylococcus, however, option E BUN, blood urea nitrogen; hpf, high-power field; RBC, red
is an acceptable alternative to guidewire exchange. Because it is blood cells; WBC, white blood cells.
Clin J Am Soc Nephrol 5: 1141–1160, 2010
Figure 3. Answers from the membership, question 3.
diarrhea (28). Although one typically associates diarrhea with
the development of a normal anion gap metabolic acidosis,
hypokalemic metabolic alkalosis can be the dominant acid-base
disturbance in these patients.
Acid-base disturbances that result from diarrhea can vary
depending on the site of origin of the diarrhea, whether the
diarrhea is secretory or osmotic, the duration of the disorder,
and the degree of K⫹ deficiency (29). Under normal circum-
stances, stool electrolyte content is such that the sum of Na⫹
and K⫹ exceeds the concentration of Cl⫺. The resultant anion
gap can be accounted for by stool HCO3 and a variety of
organic anions, many of which are derived from bacterial me-
tabolism of dietary carbohydrates. These organic anions are
absorbed and subsequently metabolized into HCO3 and there-
fore represent a potential source of alkali. In the setting of acute
diarrhea, particularly of small bowel origin, there is a signifi-
cant loss of alkali from the body in the form of both HCO3 and
potential HCO3 as a result of loss of organic acids. Despite the
development of systemic acidosis, the stool pH is typically
acidic as a result of the high concentration of these acids.
Surreptitious laxative abuse typically involves drugs that are
stimulants of the colon. Because colonic fluid has a high K⫹
content, patients who abuse these drugs tend to develop sig-
nificant total body K⫹ depletion (30). Hypokalemia can con-
tribute to the development of metabolic alkalosis in several
ways. First, the movement of K⫹ from the intracellular to
extracellular space in response to K⫹ depletion will be accom-
panied by movement of H⫹ into cells, resulting in intracellular
acidosis. The decrease in cell pH will serve as a stimulus for H⫹
secretion in the distal nephron of the kidney. Hypokalemia also
leads to increased expression of the H⫹-K⫹-ATPase in the distal
nephron. In the proximal tubule cell, acidification serves as a
major stimulus for increased synthesis of ammonia. The in-
crease in availability of ammonia to act as a urinary buffer
combined with an increase in H⫹ secretion by the distal
nephron leads to the generation of a metabolic alkalosis. The
urinary anion gap is negative in this situation as a result of the
large increase in urinary NH4Cl excretion. Renal net acid ex-
Nephrology Quiz and Questionnaire: 2009 1145
cretion exceeds the loss of actual or potential base in the stool so
that the net effect is development of metabolic alkalosis.
The large increase in urinary ammonium concentration can
predispose to the development of ammonium urate stones as
was seen in this patient. Dick et al. (31) described nine women
with laxative abuse complicated by ammonium urate calculi.
Measurement of urinary electrolytes in these patients showed
low values for Na⫹ and K⫹ but increased urinary Cl⫺ (negative
urinary anion gap), consistent with increased urinary ammo-
nium excretion. Intracellular acidosis as a cause of increased
renal ammoniagenesis was inferred by the finding of low uri-
nary citrate levels because intracellular acidosis stimulates
proximal citrate resorption. The authors postulated the low
urinary Na⫹ concentration that results from mild volume con-
traction allows for urate to bind to the abundant ammonium
ion and predispose to ammonium urate stone formation.
A similar mechanism may be responsible for endemic am-
monium urate bladder stones described in children from third-
world countries (32). These patients have an acidogenic diet
that is low in phosphate as a result of the high cereal content
and lack of animal protein intake. Increased ammonia is the
primary buffer for H⫹ secretion, particularly because urinary
phosphate excretion is low as a result of low animal protein
intake. The frequent occurrence of diarrhea predisposes these
patients to low urinary volumes and low urine Na⫹ concentra-
tion. As in patients with laxative abuse, urate in the urine is free
to bind to the high concentrations of ammonium, leading to the
formation of ammonium urate calculi (Figure 4).
For years, the most commonly abused laxative was phenol-
phthalein. Patients who used this laxative could be detected by
alkalinizing a sample of urine or stool and looking for the
development of a strong violet color change. Several years ago,
the drug was reclassified by the Food and Drug Administration
so that it is no longer available as an over-the-counter agent.
The two most frequently abused laxatives today are bisaco-
dyl and anthraquinones (28). Bisacodyl is the active ingredient
in Ex-Lax, Correctol, and Dulcolax. The most commonly used
anthraquinone is senna, which is the active ingredient in Seno-
kot, Castoria, and Black Draft. Use of these laxatives can be
detected in either stool or urine samples using thin-layer chro-
matography.
Figure 4. Proposed mechanism for ammonium urate renal
stone formation in a patient with long-term laxative abuse.
1146 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 5: 1141–1160, 2010

Specimens that are submitted for laxative screening in the sion are normal. Right-sided pyelonephritis is diagnosed. The
United States are directed to a single reference laboratory. In patient is treated with intravenous ticarcillin/clavulanate, gen-
this regard, Shelton et al. (33) submitted stool and urine samples tamicin, and tetracycline, and the patient’s clinical condition
that were taken from normal volunteers in which diarrhea was gradually improves over the next several days. After a 2-week
induced by ingestion of either bisacodyl or senna to verify the course of parenteral antibiotics, she is discharged on no medi-
sensitivity and specificity of the assay used in this reference cations. One week after discharge, the patient presents with the
laboratory. Interestingly, the tests were reported as negative in complaint of weakness and paresthesias. Physical examination
all samples of urine and stool taken from the participants with shows downward beat nystagmus, and carpal pedal spasm is
senna-induced diarrhea. Testing of samples that were taken elicited. An electrocardiogram showed prominent U waves and
from participants with bisacodyl-induced diarrhea was more Q-T prolongation. Laboratory data are given in Table 2.
accurate but had sensitivity of only 73 and 91% and specificity
of 91 and 96% for the urine and stool samples, respectively. This Question 4
study suggests that testing for laxative abuse as currently prac- Which ONE of the following is the MOST likely cause of the
ticed can produce misleading results with a high frequency of electrolyte abnormalities in this patient (Figure 5)?
false-positive tests for bisacodyl and false-negative results for
A. Complication of ticarcillin/clavulanate
senna. It is important for clinicians to be aware of these limi-
B. Surreptitious diuretic use
tations in testing, because they evaluate patients with suspected
C. Tetracycline nephrotoxicity
laxative abuse.
D. Aminoglycoside nephrotoxicity
Vomiting (A) can certainly present as hypokalemic metabolic
E. Gitelman syndrome
alkalosis and should be suspected in a patient with possible
bulimia; however, the urine electrolytes would argue against
this diagnosis, and vomiting cannot account for the history of Discussion of Case 4 (Question 4)
ammonium urate nephrolithiasis. Vomiting leads to a contrac- Aminoglycoside nephrotoxicity (D) is the correct answer. This
tion of extracellular fluid volume, and loss of gastric acid gen- patient presents with the development of hypokalemic meta-
erates a metabolic alkalosis. While the patient is vomiting, the bolic alkalosis with normal BP after a recent hospitalization in
plasma HCO3 exceeds the tubular maximum for bicarbonate which she was treated with a variety of antibiotics for pyelo-
resorption in the proximal tubule, which leads to renal loss of nephritis. The electrolyte disturbance is accompanied by high
NaHCO3 (further exacerbating total body salt depletion) and normal values for plasma renin activity and aldosterone. Urinary
KHCO3 (leading to K⫹ depletion). The volume depletion leads calcium is increased, and the patient has hypomagnesemia.
to an increase in aldosterone secretion, which in the setting of Many of the features in this case are consistent with Bartter
high distal Na⫹ delivery accounts for the renal K⫹ wasting. syndrome, although the abnormalities in this patient are re-
Typical urinary electrolytes in active vomiting are a urine Cl⫺
⬍15 mEq/L, in the presence of a high urine Na⫹, a high urine
K⫹, and a urine pH of 7 to 8. Table 2. Laboratory data for case 4
Bartter syndrome (C) is also not correct. Although this dis-
order is characterized by hypokalemic metabolic alkalosis, Parameter Value
urine Na⫹, K⫹, and Cl⫺ all are increased. This pattern of urine
Creatinine (mg/dl) 0.9
electrolytes is also characteristic of active loop and thiazide
BUN (mg/dl) 14
diuretic use, making choice E incorrect. In addition, Bartter
Serum electrolytes (mEq/L)
syndrome and diuretic use would not account for the develop-
Na⫹ 139
ment of the renal stone disease described in this patient.
K⫹ 2.3
The two most common renal manifestations in Sjögren syn-
Cl⫺ 92
drome are nephrogenic diabetes insipidus and type 1 distal
HCO3 34
renal tubular acidosis (RTA). Although nephrolithiasis and
Urine electrolytes (mEq/L)
nephrocalcinosis are characteristic of patients with type 1 RTA,
Na⫹ 110
the stone composition is most commonly calcium phosphate.
K⫹ 35
The type of stone and the lack of a hyperchloremic metabolic
Cl⫺ 106
acidosis make a diagnosis of Sjögren syndrome untenable (D).
Serum magnesium (mg/dl) 0.9
Spot urine Ca2⫹/creatinine 0.53
Case 4: Biff F. Palmer (mg/mg)
A 35-year-old woman is admitted with left flank pain and fever
Other testing Plasma renin activity
for 2 days. Physical examination shows a toxic-appearing thin
2.4 ng/ml per h
woman. Vital signs are significant for a temperature of 38.5°C,
(0.8 to 2.5),
BP 100/68 mmHg, pulse 110, and respiratory rate of 24. Right-
aldosterone 235
sided costovetebral tenderness is present. An ultrasound of the
ng/dl (35 to 240)
abdomen shows normal-sized kidneys and no evidence of hy-
dronephrosis. Renal function and serum electrolytes on admis- BUN, blood urea nitrogen.
Clin J Am Soc Nephrol 5: 1141–1160, 2010
Figure 5. Answers from the membership, question 4.
cently acquired as evidenced by the normal serum electrolytes
on admission to the hospital.
Bartter syndrome is a hereditary disorder characterized by
renal salt wasting and hypokalemic metabolic alkalosis resem-
bling the features of chronic loop diuretic therapy. This disease
results from gene defects that lead to decreased NaCl resorp-
tion in the thick ascending limb of Henle.
With relevance to this case, an acquired form of Bartter
syndrome can develop in association with the administration of
aminoglycoside antibiotics (34 –36). Chou et al. (36) described
four patients who presented with marked paresthesia, muscle
weakness, and tetany after gentamicin therapy with total dos-
ages ranging from 1.2 to 2.6 g. All four patients developed
hypokalemia, metabolic alkalosis, hypomagnesemia with hy-
permagnesuria, and hypercalciuria. These abnormalities even-
tually resolved over a period of 2 to 6 weeks. A similar Bartter-
like syndrome has been described in rats that were given
gentamicin. In these animals, administration of the drug leads
to increased urinary excretion of Na⫹, K⫹, Ca2⫹, and Mg2⫹
accompanied by decreased expression of the Na⫹-K⫹-2Cl⫺ co-
transporter in the thick ascending limb (37). The biochemical
findings in patients who have developed this form of nephro-
toxicity resemble those seen in patients with gain-of-function
mutations in the calcium-sensing receptor. Because gentamicin
is a divalent cation, binding and activation of the calcium-
sensing receptor may account for the development of this clin-
ical syndrome (38) (Figure 6).
Gitelman syndrome is also characterized by hypokalemic
metabolic alkalosis; however, this diagnosis (E) can be excluded
by the normal electrolytes at the time of admission to the
hospital as well as the high urinary Ca2⫹ excretion. Hypocal-
ciuria is the typical finding in patients with this disorder.
Surreptitious use of loop or thiazide diuretics can be a cause
of hypokalemic metabolic alkalosis that is intermittent in nature
and cannot be totally excluded in this case; however, there was
no history to suggest that this patient was prone to abuse of
such drugs and therefore choice B would not be the best answer
to explain the features in this case.
Nephrology Quiz and Questionnaire: 2009 1147
Figure 6. Gentamicin is a divalent cation and therefore has the
potential to bind to the basolateral Ca2⫹-sensing receptor in the
thick limb of Henle. This binding leads to inhibitory effects on
the apical transporters, thereby contributing to a Bartter-like
syndrome.
One of the antibiotics used in the treatment of this patient
was ticarcillin. A complication of this drug when given to
patients who are volume depleted is the development of hy-
pokalemic metabolic alkalosis. The drug is excreted as a Na⫹
salt and acts as a nonresorbable anion. In the setting of in-
creased aldosterone levels, the high distal Na⫹ delivery leads to
increased renal K⫹ excretion. The increase in luminal electro-
negativity in the distal nephron also stimulates H⫹ secretion,
thus leading to the generation of a metabolic alkalosis. Charac-
teristic urine electrolytes in this setting are increased urine Na⫹
and K⫹, a low urinary Cl⫺, and an acid urine pH. As long as
patients are kept euvolemic so that aldosterone levels are sup-
pressed, serum electrolytes remain normal when the drug is
given. The development of the electrolyte abnormalities well
after being exposed to the drug as well as the urinary electro-
lyte pattern in this patient exclude A.
As detailed in a recent review, tetracyclines may enter cells in
the proximal tubule through organic anion transporters from
either the apical or the basolateral side (38,39). Once inside the
cell, these drugs can produce tubular injury by inhibiting ribo-
somal protein synthesis. Such injury may result in development
of a proximal RTA usually associated with Fanconi syndrome.
The absence of hypokalemic normal gap metabolic acidosis and
other features of proximal tubular dysfunction make C incor-
rect.
One last comment about this patient has to do with the
neurologic manifestations noted on physical examination. One
of the clinical manifestation of hypomagnesemia is increased
neuromuscular irritability. In addition, hypomagnesemia is one
of the few causes of downbeat nystagmus, as was seen in this
case (40,41).
Case 5: Millie Samaniego
A previously healthy 26-year-old white woman presented with
fever, vomiting, abdominal cramping, and diarrhea. Three
weeks before this presentation, she noticed bruising over her
extremities followed by upper respiratory tract symptoms with
sore throat and rhinorrhea. Her husband and her 11-month-old
son had similar respiratory symptoms, and the husband re-
ceived a diagnosis of culture-positive streptococcal pharyngitis.
1148 Clinical Journal of the American Society of Nephrology
On presentation, the patient’s initial laboratory abnormalities
included a hemoglobin level of 6.7 g/dl, hematocrit of 18%,
platelet count of 19,000/mm3, blood urea nitrogen level of 75
mg/dl, and creatinine level of 4.6 mg/dl. Urinalysis showed 3⫹
protein and 3⫹ blood, and the urinary sediment was abnormal
with ⬎100 red blood cells per high-power field and granular
casts. A kidney biopsy showed diffuse capillary fibrin deposi-
tion and segmental staining for fibrin and IgM along the glo-
merular basement membrane (GBM), consistent with a diagno-
sis of thrombotic microangiopathy (TMA). A disseminated
intravascular coagulation workup was negative. Stool cultures
for Escherichia coli O157:H7, Salmonella, Campylobacter, Shigella
species, ova, and parasites were negative. Other relevant tests
were a C3 level of 58 mg/dl (normal range 70 to 205) and C4
level of 20 (normal range 10 to 60); negative antinuclear anti-
body (ANA) and anti-streptolysin O titers; and negative anti-
PR3, anti-myeloperoxidase, and anti-GBM antibody levels. Her
ADAMST-13 activity was 97% (normal range ⱖ67) and inhibi-
tor ⬍0.4 units (normal range ⱕ0.4).
She received a diagnosis of atypical hemolytic uremic syn-
drome (aHUS) and was treated aggressively with 41 plasma
exchange sessions, four doses of rituximab, and a single dose of
vincristine without clinical response. She presents to your office
for preemptive transplant evaluation 7 months after the onset
of disease and would like to know what the probability of
disease recurrence in the transplant is.
Question 5A
Given the clinical presentation of this patient, which ONE off the
following statements is MOST appropriate concerning the likeli-
hood of recurrence of disease in a renal allograft (Figure 7)?
A. The likelihood of recurrence is low, because the patient has
nonfamilial HUS likely as a result of streptococcal infection.
B. The likelihood of recurrence is high but will decrease with
time; therefore, delaying transplantation for 1 year is appro-
priate.
C. Additional testing is necessary to provide an accurate esti-
mate of the likelihood of recurrence.
Figure 7. Answers from the membership, question 5A.
Clin J Am Soc Nephrol 5: 1141–1160, 2010
D. Because her likelihood of recurrence is exceedingly high,
living-donor transplantation should be avoided and she
should be listed for a deceased-donor transplant.
Discussion of Case 5 (Question 5A)
The most appropriate answer to this question is C: Additional
testing is necessary to provide an accurate estimate of the
likelihood of recurrence. HUS is characterized by microangio-
pathic hemolytic anemia, thrombocytopenia, and acute kidney
injury. HUS is classified in two large categories: Diarrheal
(D⫹HUS) and nondiarrheal (D⫺HUS). Microvascular endothe-
lial cell injury underlies both forms of this disease and leads to
the loss of the endothelium anticoagulant phenotype, enhanced
platelet consumption and leukocyte trafficking, complement
activation, and disruption of the fibrinolytic pathways (42).
D⫹HUS more commonly affects children than adults, can
present in an epidemic manner, and is usually associated with
a prodrome of severe bloody diarrhea, hence its name. Endo-
thelial cell injury is caused by Shiga toxin–producing bacteria
and can be sporadic, endemic, or epidemic. Escherichia coli
O157:H7 strains are responsible for most cases of D⫹HUS. The
diarrhea in our patient is a red herring and likely represents a
nonspecific response to acute illness (42,43).
D⫺HUS, or aHUS, is more frequent in adults, can be sporadic
or familial in presentation, and is unrelated to diarrhea. The
past decade has seen the identification of mutations in the
genes for complement factor H (CFH), complement factor I
(CFI), and membrane co-factor protein (MCP; or CD46) as
predisposing factors for the development of D⫺HUS. Approx-
imately 30 to 50% of patients with D⫺HUS have genetic defect
involving the complement regulatory proteins (CRPs). A grow-
ing number of mutations and polymorphisms that alone or in
combination may lead to D⫺HUS are being identified. Some of
the less well-characterized genetic defects involve C3 and com-
plement factor B (44 – 48).
CFH is a serum glycoprotein that is synthesized by the liver
and regulates the function of the alternative pathway of com-
plement in fluid phase and on cellular surfaces. It binds to C3b,
accelerates the decay of the C3 convertase, and also acts as a
co-factor for CFI. The CFH gene is located on chromosome
1q32-q32.1 within a cluster of genes encoding regulatory com-
plement components (45). CFI is a serum regulatory serine
protease that is predominantly synthesized by the liver as a
single-chain precursor, the gene of which is located on chro-
mosome 4q25. MCP is a widely distributed C3b/C4b-binding
cell surface glycoprotein that serves as an inhibitor of comple-
ment activation via the classical and alternative pathways on
host cells. The genes for MCP are tightly clustered on chromo-
some 1 at q3.2 (46).
Deficiency or dysfunction of CRPs leads to complement-
mediated endothelial cell injury in the setting of unregulated
activity of the C3 and C5 convertases that leads to the produc-
tion of proinflammatory complement split products (C3a, iC3b,
C3dg, and C5a) and the membrane attack complex (C5b
through C9) (45).
Kidney transplantation in patients with HUS is associated
with a variable rate of disease recurrence in the transplanted
Clin J Am Soc Nephrol 5: 1141–1160, 2010
graft, yet when recurrence occurs, it usually results in the loss
of the transplant. Thus, an accurate diagnosis of the cause of
HUS must be pursued before transplantation. Table 3 shows
the various rates of HUS recurrence on the basis of its different
causes (43,45,49,50).
The diagnostic workup in this patient effectively ruled out
D⫹HUS, because stool cultures for Shiga toxin–producing bac-
teria were negative, whereas negative lupus serologies and
ADAMST-13 inhibitor and normal ADAMST-13 activity ruled
out sporadic forms of D-HUS such as systemic lupus erythem-
atosus (SLE) and familial or sporadic thrombotic thrombocyto-
penic purpura (51,52). Notably absent in the assessment of this
patient, however, was the evaluation for familial forms of
D-HUS or inhibitors of CRPs (CFH, CFI, MCH, and MCP au-
toantibodies) (44).
Several findings in this patient suggest deficiency or dysfunc-
tion of CRPs as the cause of D⫺HUS, including young age and
persistently low levels of C3 with normal C4 levels. In almost
all cases of D⫺HUS as a result of mutations in CFH and CFI, C4
levels are normal and C3 levels are low, whereas in MCP
mutations, C4 and C3 levels are normal. Because of low sensi-
tivity, the presence of normal C3 levels does not exclude mu-
tations of CRP genes (44,45).
Because patients with CRP deficiency or dysfunction lack a
classical clinical phenotype, this diagnosis is often missed
(46,49). Only in cases in which clinical suspicion prompts the
testing of serum activity and levels of CRPs as well as geno-
typing can accurate diagnosis be reached.
Choice A—the likelihood of recurrence is low because the
patient has nonfamilial HUS likely as a result of streptococcal
infection—is the wrong answer. In patients with HUS, a history
of recurrent streptococcal infections or infections with other
encapsulated microorganisms (e.g., Neisseria meningitidis, Hae-
mophilus influenzae) suggests a familial etiology, especially CFH
or CFI deficiency. In these patients, functional C3 deficiency as
a result of uncontrolled activation of the alternative pathway of
complement leads to deficient opsonization and phagocytosis
of encapsulated organisms and hence infection (46). As shown
in Table 3, CFH and CFI deficiencies are associated with high
recurrence of disease in kidney transplants and graft loss.
Choice B—the likelihood of recurrence is high but will de-
Table 3. Rates of recurrence of HUS according to cause (46,47,50,53)
HUS in Native Kidneys
Postdiarrheal HUS (D⫹HUS)
Nondiarrheal HUS (D⫺HUS) sporadic or familial forms
CFH mutation
CFI mutation
Idiopathic (unidentified genetic defect?)
MCP mutation
CFH autoantibodies
C3 and CFB deficiency
drugs, pregnancy, invasive S. pneumoniae infection
KTx, kidney transplantation.
Nephrology Quiz and Questionnaire: 2009 1149
crease with time; therefore, delaying transplantation for 1 year
is appropriate—is also incorrect. In patients with D⫹HUS or
D⫺HUS as a result of MCP deficiency or drug-induced injury
(e.g., ticlopidine, valacyclovir, clopidrogel), recurrence is negli-
gible and kidney transplantation need not to be delayed
(43,45,50).
In contrast, in patients with acquired (i.e., autoantibodies or
inhibitors) or hereditary deficiencies of CRPs, the risk for re-
currence persists throughout the life of the individual unless
the basic defect is corrected. Prevention of disease recurrence
and correction of CFH or CFI deficiency can be accomplished
with combined kidney-liver transplantation (46,53). Although
the initial three reports that described this modality for CFH-
associated HUS had poor outcome, more recent reports in
which combined kidney-liver transplantation has been per-
formed successfully in combination with pretransplantation
plasma exchange have been described (53).
Current recommendations for combined kidney-liver trans-
plantation include CFH and CFI mutations, ⬍10% normal CFH
levels in plasma, patients with identified mutations of CFH and
CFI genes with recurrence after isolated kidney transplantation, or
patients who have a family member with the same mutation and
recurrence of HUS after isolated kidney transplantation (53).
The correct answer is D: Because her likelihood of recurrence
is exceedingly high, living-donor transplantation should be
avoided and she should be listed for a deceased-donor trans-
plant. This choice is controversial. Similar to option B, the
choice of pursuing or avoiding transplantation or the use of a
deceased donor vìs a vìs a living donor depends on the cause of
HUS and the likelihood of recurrence. In a meta-analysis of 10
selected studies in 159 grafts of 127 patients with a well-docu-
mented history of HUS in native kidneys and biopsy-proven
TMA in the transplanted kidney, living-donor transplantation
was associated with an increased risk for recurrence; however,
the risk for recurrence in living-related versus -unrelated kidney
transplants was not analyzed (54).
Patients with D⫹HUS or D⫺HUS as a result of drug toxicity
should be offered living-donor transplantation. In patients with
D⫺HUS as a result of CRP deficiencies or dysfunction, living-
unrelated donor transplantation should be discouraged given
the high likelihood of recurrence and recurrence-related graft
Relative Risk of Recurrence in KTx (%)
Negligible
80
80 to 100
30 to 50
0 to 20
0
?
Negligible
1150 Clinical Journal of the American Society of Nephrology
loss. Patients with MCP deficiency or anti-CFH autoantibodies,
however, should be considered for living-unrelated kidney
transplantation. MCP has a high level of expression in kidney
tissue, and transplantation with a living-donor kidney with
normal (wild-type) MCP expression results in the cure of the
kidney disease. In patients with CFH autoantibodies, antibody-
depleting strategies in conjunction with isolated kidney trans-
plantation have been successful (46,50,53).
Many centers do not recommend living-related transplanta-
tion because of the risk for recurrence in the recipient and of de
novo disease in the donor. In four reported cases, the donors
went on to develop HUS within 1 year of donation. Genotyping
of the donor and recipient should be undertaken when living-
related donation is to be considered. This will not prevent the
risk for the donor in those with an unknown genetic basis
(46,50,53). Transplantation options for patients with aHUS are
shown in Figure 8.
One year after her first visit to your clinic, the patient received
a zero-antigen mismatch deceased-donor kidney transplant. The
immunosuppression consisted of alemtuzumab induction and
maintenance therapy with prednisone, mycophenolate mofetil,
and tacrolimus. She had excellent graft function initially with a
creatinine level of 1.1 mg/dl on discharge but on day 30 after
transplantation was admitted with a rise in serum creatinine to
1.9 mg/dl. A transplant biopsy showed TMA with many of the
19 glomeruli containing fibrin thrombi in a segmental distribu-
tion. C4d staining was negative, and the tacrolimus trough
level was 6 ng/ml. Further testing showed complement C3 of
70 (normal range 88 to 201) and C4 of 23 (normal range 16 to 47)
and ADAMST-13 activity of 94% (normal ⬎67%) and with
Figure 8. Therapeutic options for aHUS. IF, factor I; BF, factor B;
C3, complement protein 3; KTx, kidney transplantation; SKL,
simultaneous kidney-liver transplant; Eculizumab, humanized
mAb that functions as a complement inhibitor by blocking
cleavage of C5 into C5a and C5b and decreasing formation of
membrane attack complex.
Clin J Am Soc Nephrol 5: 1141–1160, 2010
quantitative factor H level of 244.9 ␮g/ml (normal range 160 to
412).
Question 5B
Which ONE of the following choices would MOST likely con-
firm the correct diagnosis (Figure 9)?
A. Response to plasma exchange
B. Donor-specific antibody (DSA) testing
C. Double-stranded DNA (dsDNA) antibodies
D. Factor I and factor H genotyping
E. Discontinuation of calcineurin inhibitor (CNI)
Discussion of Case 5 (Question 5B)
The correct answer is D: Factor I and factor H genotyping. The
current evidence suggests that all patients who have D⫺HUS
and are being considered for kidney transplantation should
undergo screening for mutations in CRPs. An initial screening
should test protein levels (either serum levels or surface expres-
sion). This offers a rapid mechanism to identify the genes
involved (44,53).
In patients with normal levels of CRPs, genetic screening
should be performed on the basis of frequency of mutation
(CFH approximately 30%; MCP approximately 10%; CFI 2 to
5%). The exons in which CRP gene mutations cluster have been
identified, and by screening these regions first, cost and detec-
tion time can be minimized (44,53). The patient presented here
was found to be heterozygous for a novel missense mutation,
Y369S, in CFI (55).
Choice A—response to plasma exchange—is incorrect. Re-
cent guidelines recommended the use of empiric plasma ther-
apy in all forms of D⫺HUS within 24 hours of diagnosis (53).
This is in contrast to previous guidelines in which the use of
plasma exchange was considered a grade C, level IV recom-
mendation given the lack of conclusive evidence of improve-
ment in outcomes (42).
Choice B—DSA testing—would not confirm the cause of this
patient’s disease. Although this patient may have been sensi-
tized against HLA antigens after receiving multiple sessions of
Figure 9. Answers from the membership, question 5B.
Clin J Am Soc Nephrol 5: 1141–1160, 2010
plasma exchange, C4 staining in the biopsy was negative, there-
fore making the diagnosis of antibody-mediated rejection
(AMR) less likely (56). It must be noted that fresh-frozen
plasma has been known to contain anti-HLA antibodies that
can lead to passive sensitization.
Choice C— dsDNA antibodies—is also incorrect. Although
active lupus can have a similar clinical presentation to D⫺HUS,
particularly in patients with antiphospholipid antibody syn-
drome, this patient does not have systemic evidence of lupus
activity (42). In lupus, both C3 and C4 levels are reduced, the
result of complement activation by autoantibodies via the clas-
sical pathway.
Choice E— discontinuation of CNI—would not lead to the
correct cause of this patient’s kidney disease. CNIs have been
identified as a cause of drug-induced HUS since the early
stages of their use in clinical transplantation. Recent studies
have now reported that some of the cases that were diagnosed
as being CNI related may have actually been caused by AMR,
or ADAMST-13 inhibitors (57–59). The recently published
guidelines from the aHUS Consensus Study Group make no
specific recommendations about use or avoidance of CNIs. The
guidelines state that D⫺HUS is not considered per se a specific
contraindication to treatment with CNIs and that initial immu-
nosuppression with mammalian target of rapamycin inhibitors
should not be encouraged (53).
Case 6: Millie Samaniego
A 55-year-old multiparous woman with type 2 diabetes re-
ceived a standard-criteria deceased-donor kidney transplant
from a 20-year-old donor with a cold ischemic time of 6 hours.
Her class I and class II flow cytometry panel-reactive antibodies
(PRA) were 65 and 80%, respectively. A donor-specific flow
cross-match was negative.
Her immunosuppressive regimen consisted of alemtuzumab
induction and maintenance therapy with cyclosporine, myco-
phenolate mofetil, and prednisone. Although urine production
was noted after the vascular anastomosis was completed, the
urine output decreased within the first 12 hours after transplan-
tation and her blood urea nitrogen and creatinine failed to
decrease. A renal transplant ultrasound showed adequate
blood flow in the renal transplant artery and vein and a resis-
tive index of 1.0. On day 2 after transplantation, the platelet
count was noted to fall from 200,000 to 90,000/mm3, and her
hemoglobin decreased from 11 to 8.5 g/dl. A repeat flow cy-
tometry cross-match was negative.
Question 6A
Concerning the cause of this patient’s transplant dysfunction, which
ONE of the following statements is MOST correct (Figure 10)?
A. Delayed graft function (DGF) is likely given the prolonged
cold ischemic time.
B. CNI-related TMA is the most likely diagnosis.
C. Antibody testing using single-antigen bead flow cytometry
should be performed emergently.
D. Observant approach is adequate because this presentation is
consistent with alemtuzumab-related side effects.
Nephrology Quiz and Questionnaire: 2009 1151
Figure 10. Answers from the membership, question 6A.
Discussion of Case 6 (Question 6A)
The correct answer is choice C: Antibody testing using single-
antigen bead flow cytometry should be performed emergently.
The patient has been sensitized to HLA antigens through mul-
tiple pregnancies. She is sensitized against class I HLA mole-
cules (i.e., PRA 20 to 79%) and highly sensitized against class II
HLA antigens (i.e., PRA ⱖ80%) and, accordingly, has a high
immunologic risk for both T cell–mediated rejection and AMR.
Patients as the one discussed with high level of HLA sensitiza-
tion are likely to develop an anamnestic DSA response after
reintroduction of antigen in the form of a transplant. In such
individuals, even if solid-phase assays such as flow-cytometry
cross-match are negative, low levels of DSA can be missed and
more sensitive solid-phase assays such as single-antigen bead
Luminex flow cytometry are usually required (60,61).
Choice A—DGF is likely given the prolonged cold ischemic
time—is incorrect. This patient received a deceased-donor
transplant from a young standard-criteria donor and a short
cold ischemia time—all factors associated with a low risk for
DGF (62,63). Although the risk for DGF increases in donors
who are older than 13 years, the donor age that is associated
with a higher risk for DGF is ⱖ50 years. Although the risk for
DGF increases with cold ischemia time ⬎12 hours, cold isch-
emia times ⬎36 (62) or ⬎40 hours (64) are associated with the
highest risk.
Choice B—CNI-related TMA is the most likely diagnosis—is
not a likely cause in this patient’s presentation. This patient has
clinical features suggestive of TMA: Acute anemia and throm-
bocytopenia in the setting of transplant dysfunction and re-
duced urine output. Although CNIs are a recognized cause of
TMA, the onset of TMA is earlier than expected— usually be-
yond day 4 after transplantation—although it can be highly
variable with a range of 4 to 2190 days after transplantation
(65). Furthermore, severe forms of AMR can lead to glomerular
fibrinoid thrombosis (56), and some patients can have a TMA-
like syndrome.
Choice D— observant approach is adequate because this pre-
sentation is consistent with alemtuzumab-related side ef-
1152 Clinical Journal of the American Society of Nephrology
fects—is a red herring. Alemtuzumab is an effective depleting
humanized mAb directed against CD52—a surface marker of
unknown function that is densely expressed in T and B lym-
phocytes, monocytes/macrophages, and natural killer cells. As
opposed to other depletional biologics, alemtuzumab is not
associated with anemia or thrombocytopenia, yet, in some pa-
tients, the effect of alemtuzumab on CD52—a glycosylphos-
phatidylinositol-anchored protein—translates to other glyco-
sylphosphatidylinositol proteins such as the CRPs CD55 and
CD59. The dysfunction of CRPs results in complement-depen-
dent intravascular hemolysis and thrombocytopenia, and case
reports of HUS-like syndrome and TMA in alemtuzumab-treated
patients have been published (66,67). Regardless of its cause, TMA
in native or transplanted kidneys is an emergency, and observant
management is not indicated (42).
Single-antigen bead flow cytometry testing showed high lev-
els of DSAs against class II antigen DR7, and a kidney trans-
plant biopsy confirmed the presence of DSA. The patient re-
sponded favorably to aggressive therapy with plasmapheresis,
intravenous gammaglobulin, and intravenous steroids and was
discharged 2 weeks later with a serum creatinine level of 1.4
mg/dl. At month 7 after transplantation, she presents to the
clinic with a serum creatinine level of 2.5 mg/dl (compared
with 1.8 mg/dl the previous month) and a urine protein-to-
creatinine ratio of 3.5 (compared with 1.0 the previous month).
Question 6B
Which ONE of the following choices is the MOST likely diag-
nosis for her proteinuria (Figure 11)?
A. De novo membranous nephropathy
B. Recurrent diabetic nephropathy
C. Transplant glomerulopathy (TG)
D. De novo FSGS
E. Acute T cell–mediated rejection
Discussion of Case 6 (Question 6B)
The correct choice is C: Transplant glomerulopathy. TG is a
condition that is associated with poor outcome and is charac-
Figure 11. Answers from the membership, question 6B.
Clin J Am Soc Nephrol 5: 1141–1160, 2010
terized by duplication of the GBMs, mesangial matrix expan-
sion, and mesangial cell interposition (Figure 12). Originally
classified as a variant of chronic allograft nephropathy of un-
known cause, TG is now recognized with increased frequency
in patients with a history of AMR and is also associated with
deposition of the complement split product C4d, suggesting
that TG may be one manifestation of AMR (68,69). Gloor et al.
(70) reported a cumulative incidence of TG at 5 years of 20%
and a strong association with anti-HLA antibodies especially
anti– class II, with the risk increasing when the antibodies were
donor specific. Approximately 60% of patients with TG have
proteinuria ⬎500 mg/d at the time of diagnosis, and, with
disease progression, patients can develop nephrosis, like the
patient described here. Per each 1-g increase in proteinuria, the
hazard ratio of death-censored graft survival is 1.56 (95% con-
fidence interval 1.3 to 1.8; P ⬍ 0.0001) (68,70).
The remaining choices are incorrect. Although de novo mem-
branous nephropathy, de novo FSGS, and recurrent diabetic
nephropathy can result in nephrotic-range proteinuria, these
diseases usually present late in the natural history of kidney
transplantation. De novo membranous nephropathy occurs ap-
proximately 49.27 ⫾ 32.71 months after transplantation, with a
cumulative incidence of 5.3% at 8 years after transplantation,
and 62% of patients have nephrosis at the time of diagnosis. De
novo FSGS was observed in 30% of kidney transplant recipients
Figure 12. Transplant glomerulopathy. (A) Global and severe
duplication of capillary walls with minimal, segmental mesan-
gial expansion (silver-stained section). (B) Mesangial prolifera-
tion, segmental endocapillary proliferation, cellular interposi-
tion, and global duplication of capillary walls (periodic acid-
Schiff–stained section). (C) Extensive remodeling of the GBM
with extensive reduplication of the GBM (electron microscopy).
(D) C4d-stained section in a biopsy with chronic active AMR
with positive peritubular capillaries and global glomerular cap-
illary wall staining. Magnification, ⫻400.
Clin J Am Soc Nephrol 5: 1141–1160, 2010 Nephrology Quiz and Questionnaire: 2009 1153

during a mean follow-up of 57 months, and 24% of patients

exhibited nephrotic syndrome at the time of diagnosis (71).
Virtually 100% of patients with type 2 diabetes will develop
recurrence of diabetic nephropathy in the kidney transplant
with an average time to onset of de novo diabetic nephropathy
of 10 years (72). Finally, patients with acute T cell–mediated
rejection usually present with nonproteinuric or non-nephrotic
acute kidney transplant dysfunction. Of note, TG can be T cell
mediated, yet TG is a chronic, not an acute, histologic or clinical
cause of transplant dysfunction. That this patient had received
a diagnosis of AMR early in the course of her transplant makes
TG the most likely diagnosis, decreasing the likelihood of the
other options.

Case 7: Fernando C. Fervenza

In February 2009, a 64-year-old white woman was evaluated for
nephrotic syndrome. Serum creatinine level was 1.6 mg/dl and
proteinuria was 11 g/24 h. Tests for hepatitis B and C, cryo-
globulins, serum protein electrophoresis, ANCA, and comple-
ment levels were either negative or within normal range. ANA
test was 1:80. A renal biopsy showed a membranoproliferative
glomerulonephritis (MPGN) pattern of injury on light micros-
copy (Figure 13). On immunofluorescence, there was granular
capillary wall and mesangial staining for IgG (3⫹), IgM (2⫹),
C1q (1⫹), C3 (3⫹), ␬ (3⫹), and ␭ (trace) but no IgA (Figure 14).
Therapy with an angiotensin-converting enzyme inhibitor
(ACEI), aspirin, dipyridamole, and prednisone at 60 mg/d was
started with the dosage tapered during the subsequent 3
months. Despite the treatment, renal function continued to
deteriorate, and on June 21, serum creatinine had increased to
4.2 mg/dl. She was then referred for further evaluation and a

Figure 14. Immunofluorescence microscopy. (A and B) Granu-

Figure 13. MPGN. The glomerulus shows mesangial expansion
with increase in mesangial matrix and cellularity, mostly as a
result of mononuclear cells, as well as endocapillary prolifera-
tion. Capillary walls are thickened, and many loops show sub-
endothelial expansion and new basement membrane forma-
tion, resulting in double contours and lobular accentuation of
the glomerular tuft. Extracapillary proliferation, resulting in the
formation of a small cellular crescent, is also present (silver
stain). Magnification, ⫻400.
lar staining for IgG (A) and ␬ (B) along the capillary walls. (C) ␭
light chain staining is negative.
second opinion. On physical examination, BP was 139/82
mmHg, and, apart from peripheral edema, the physical exam-
ination was unremarkable.
Laboratory evaluation showed hemoglobin level of 11.7 g/dl,
leukocytes of 15.1 ⫻ 109/L, platelet count of 356 ⫻ 109/L,
albumin level of 2.3 g/dl, and serum creatinine level of 4.5
1154 Clinical Journal of the American Society of Nephrology
mg/dl. Urinalysis showed ⬎100 red blood cells per high-power
field, ⬎25% dysmorphic, four to 10 white blood cells per high-
power field, and a predictive 24-hour urine protein excretion of
17 g by urine protein-creatinine ratio. Serum protein electrophore-
sis found no monoclonal protein, but immunofixation revealed a
low-level monoclonal IgM ␭ plus a monoclonal IgG ␬. Free ␬ light
chain was 4 mg/dl (0.33 to 1.95), free ␭ light chain was 5.65 mg/dl
(0.57 to 2.63), and ␬-␭ ratio was 0.7 (0.26 to 1.65). Serum C3 and C4
complement levels were normal. An anti-dsDNA antibody was
negative. A repeat renal biopsy is performed.
Question 7
Which ONE of the following is the MOST likely diagnosis
(Figure 15)?
A. Necrotizing and crescentic glomerulonephritis, pauci-im-
mune
B. Cryoglobulinemic glomerulonephritis
C. MPGN secondary to a monoclonal gammopathy
D. C1q nephropathy
E. Diffuse proliferative lupus nephritis (class IV)
Discussion of Case 7 (Question 7)
The correct answer is C. MPGN, or mesangiocapillary glomer-
ulonephritis, refers to a specific histologic pattern of glomerular
injury characterized by massive mesangial hypercellularity,
mesangial matrix expansion, and thickening of the GBM with
the appearance of “double contours.” The duplicated or split
basement membranes is the result of new basement membrane
formation caused by the interposition of the mesangial cell and
mesangial matrix along the subendothelial side of the lamina
densa. The proliferation in the mesangial region and mesangial
matrix expansion often has a lobular appearance. MPGN can be
idiopathic or secondary to a variety of diseases (Table 4). Sys-
temic conditions that are associated with MPGN include auto-
immune diseases (e.g., SLE) and chronic infections (e.g., hepa-
titis C). Less widely known, however, is the association of
MPGN with monoclonal gammopathy. Monoclonal gammopa-
thy is defined as an excessive production of an Ig or its subunits
Figure 15. Answers from the membership, question 7.
Clin J Am Soc Nephrol 5: 1141–1160, 2010
Table 4. Conditions associated with an MPGN pattern
of injury
Chronic infections
viral: Hepatitis C, hepatitis B (rarely)
bacterial: Endocarditis, infected ventriculo-atrial
shunt, visceral abscesses, leprosy, meningococcal
meningitis
protozoa/other infections: Malaria, schistosomiasis,
mycoplasma, leishmaniasis
Autoimmune diseases
SLE
Sjögren syndrome
rheumatoid arthritis
C2 deficiency and SLE-like disease
Inherited complement deficiencies (e.g., CFH, CFI, C3
deficiency)
Monoclonal gammopathies
Other neoplasias (e.g., lung cancer, lymphoma)
Chronic and healed TMAs
healing phase of HUS/TTP
antiphospholipid (anticardiolipin) antibodies
syndrome
radiation nephritis
nephropathy associated with bone marrow
transplantation
drug-associated thrombotic angiopathies
sickle cell anemia and polycythemia
dysfibrinogenemia and other prothrombotic states
TG
POEMS syndrome
Idiopathic forms of MPGN
MPGN type I
MPGN type II or dense-deposit disease
MPGN type III/IV (Strife and Burkholder variants)
TTP, thrombotic thrombocytopenic purpura.
that arises from a clonal proliferation of plasma cells or B
lymphocytes. The majority of kidney diseases that are associ-
ated with monoclonal gammopathy are secondary to deposi-
tion of light chains (␬ or ␭) and not heavy chains or intact Igs
(73). These include myeloma kidney (cast nephropathy), Ig
light chain (AL) amyloidosis, and light chain deposition disease
(74). The spectrum of renal lesions that are associated with
monoclonal gammopathy is extensive and depends on the
physiochemical properties of the Ig produced (75). It should be
pointed out that whereas light chain deposition with an MPGN
pattern of injury is a widely known entity, MPGN secondary to
intact monoclonal Igs is less frequently recognized.
We recently analyzed renal biopsies of patients who received
a diagnosis of MPGN at the Mayo Clinic during a 6-year period
from 2001 through 2006 (76). Among the 65 patients with
hepatitis-negative MPGN, we identified 28 (43.1%) patients
who were positive for monoclonal/biclonal Igs. Immunofluo-
rescence microscopy showed granular immune deposits in the
mesangium and/or along the capillary walls, consisting of IgM
Clin J Am Soc Nephrol 5: 1141–1160, 2010
␬ (n ⫽ 11), IgG ␬ (n ⫽ 4), IgG only (n ⫽ 2), IgG ␭ (n ⫽ 1), IgM
␭ (n ⫽ 1), and IgG/IgM ␭ (n ⫽ 1). These results correlated with
immunofixation results (in two cases, IgG was noted in the
mesangium and along capillary walls, but light chain restriction
was not documented). In most biopsies, the deposits were more
prominent along the capillary walls than in the mesangium,
whereas in a few others the reverse was true. Three biopsies did
not contain glomeruli or contained only globally sclerotic glo-
meruli, and in five biopsies, significant immune deposits were
not noted; however, three of the five negative cases showed C3
along the capillary walls. On electron microscopy examination,
there was thickening of the capillary walls with subendothelial
deposits in all cases. Cellular interposition and new basement
membrane formation with double contours were also seen. The
deposits were granular, and substructures were typically ab-
sent. In four biopsies, scattered subepithelial deposits could be
identified. The mesangium also contained electron-dense de-
posits in 21 cases. Podocytes showed segmental effacement of
the foot processes, and many of the capillary loops showed
leukocyte infiltration. Tubuloreticular structures were absent in
the endothelial cells.
Sixteen of the 28 patients had a normal bone marrow biopsy
and were classified as having a monoclonal gammopathy of
unknown significance (MGUS). The diagnosis of MGUS re-
quires a serum monoclonal paraprotein band of ⬍30 g/L; a
bone marrow biopsy that shows ⬍10% plasma cells; and ab-
sence of end organ damage such as lytic bone lesions, anemia,
hypercalcemia, and kidney failure. It is the most common
plasma cell disorder recognized and is a potential precursor for
multiple myeloma (77,78). Thus, the important finding of this
study is the association of MPGN with MGUS. This study also
shows that in addition to MGUS, a membranoproliferative
pattern of injury can be seen in the setting of conditions that are
associated with a monoclonal gammopathy, such as B cell
lymphomas, chronic lymphocytic leukemia, and multiple my-
eloma. In one case, serum protein electrophoresis studies were
negative even though the renal biopsy suggested an MPGN
secondary to monoclonal gammopathy. A few months after the
biopsy, serum immunofixation results turned positive for a
monoclonal gammopathy. Thus, MPGN may often be the first
sign of the underlying lymphoplasmacytic disorder. Although
a direct relationship between the presence of a monoclonal
protein and the development of an MPGN remains to be
proved, these observations point in that direction.
Recently, Nasr et al. (79) described an entity of proliferative
glomerulonephritis associated with IgG deposition. That study,
however, differs from our observations in that the deposits
were composed exclusively of monoclonal IgG and thus may
belong to a subgroup of patients with monoclonal IgG. Bone
marrow biopsy was performed in 22 of 37 patients, only one of
whom showed multiple myeloma. Because a monoclonal gam-
mopathy was identified in only 30% of the cases, the authors
did not associate the lesions with MGUS, lymphoproliferative
disease, or multiple myeloma.
In this case, a repeat renal biopsy was performed at presen-
tation to our institution and showed glomeruli with mesangial
expansion, increased cellularity, and endocapillary prolifera-
Nephrology Quiz and Questionnaire: 2009 1155
tion and capillary walls with double contours. In three glomer-
uli, extracapillary proliferation resulted in the formation of
cellular crescents with fibrinoid necrosis. Immunofluorescent
histology showed granular staining for IgG (2⫹), IgM (1 to 2⫹),
C1q (1 to 2⫹), C3 (3⫹), and ␬ light chain (3⫹) along the
capillary walls. ␭ light chain and IgA were negative. Electron
microscopy showed no tubuloreticular structures and no mes-
angial deposits. These findings led us to make the diagnosis of
an MPGN secondary to a monoclonal gammopathy.
A pauci-immune crescentic glomerulonephritis (A) is the
most common cause of rapidly progressive glomerulonephritis
in patients who are older than 60 years (80). In these cases,
ANCA is present in ⬎90% of patients at initial presentation
(81). Although nephrotic-range proteinuria can occur in the
setting of ANCA-associated vasculitis, the absence of ANCA
together with massive proteinuria makes this diagnosis un-
likely. Cryoglobulinemic glomerulonephritis (B) can present as
part of a renal-dermatologic small-vessel vasculitis syndrome.
Cryoglobulinemic glomerulonephritis is typically associated
with positive hepatitis C serology, positive cryoglobulins, and
low C4, all of which were absent in this case. C1q nephropathy
(D) is a glomerulonephritis that is characterized by predomi-
nant mesangial C1q deposition but with other histologic fea-
tures resembling lupus nephritis (e.g., capillary wall thickening
recognizable as “wire loops,” a “full house” on immunofluo-
rescence microscopy, and electron-dense deposits in mesangial
and subendothelial locations) (82). Clinical features of SLE are
absent at presentation, although some patients may develop
positive lupus serology and overt clinical lupus on follow-up.
In this case, renal biopsy showed no features suggestive of
lupus nephritis or C1q predominance, making this diagnosis
unlikely. In diffuse proliferative lupus nephritis (E) a positive
ANA is present in ⬎95% of patients; however, ANA lacks
specificity and can occur, usually in low titers, as a result of
cross-reactivity with other autoantibodies. Hematuria and pro-
teinuria in the setting of lupus nephritis are usually associated
with low complement levels, and anti-dsDNA antibodies are
strongly positive. This patient had normal complement levels
and negative anti-dsDNA, making the diagnosis of lupus ne-
phritis less likely.
There is no standard treatment for patients with MPGN
associated with a monoclonal gammopathy. Conservative as
well as immunosuppressive therapy with the use of corticoste-
roids (alone or in combination with an alkylating agent), tha-
lidomide, bortezomib (Velcade), mycophenolate mofetil, cyclo-
sporine, and rituximab have been used in a small number of
patients with variable outcomes (79). Prospective, controlled
studies of larger cohorts of patients with MPGN and monoclo-
nal gammopathy are needed to ascertain optimal therapy. At
present, treatment decisions will have to be made purely on the
basis of clinical experience. In this case, the patient was treated
with two pulses of methylprednisolone (1 g each) followed by
prednisone 60 mg/d, tapered down to 40 mg/d at 4 weeks,
with subsequent tapering by 10 mg every 2 weeks until discon-
tinuation. The patient also received concomitant treatment with
cyclophosphamide (1 mg/kg per day, orally) for 3 months. Oral
sulfamethoxazole-trimethoprim was used for Pneumocystis ji-
1156 Clinical Journal of the American Society of Nephrology
roveci pneumonia prophylaxis. When last seen in October 2009,
serum creatinine level was 1.8 mg/dl, proteinuria had come
down to 4.3 g/24 h, and urinary sediment was inactive.
In summary, many patients with an MPGN pattern of injury
on renal biopsy have an underlying monoclonal gammopathy,
and renal biopsies should be analyzed with anti–light chain
antibodies to detect a possible underlying monoclonal gam-
mopathy. Similarly, all patients with MPGN should undergo a
full workup for gammopathies, which should include serum
and urine immunofixation studies. When positive, a bone mar-
row biopsy should also be performed. As it stands, “idiopathic”
MPGN seems to be a vanishing disease and a possible under-
lying cause is likely to be found in the majority of cases of
MPGN.
Case 8: Fernando C. Fervenza
A 60-year-old man with a history of hypertension and type 2
diabetes for 10 years was evaluated for sudden onset of massive
proteinuria (45 g/d). Renal biopsy showed 24 glomeruli, six of
which were totally sclerotic. All of the glomeruli showed mes-
angial expansion with formation of homogeneous acellular pe-
riodic acid-Schiff– and silver-negative nodules. Congo red
stains were positive and showed reddish brown material that
showed apple green birefringence under polarized light. Im-
munofluorescence study showed glomerular staining for IgG
(1⫹), IgA (trace to 1⫹), IgM (2 to 3⫹), C3 (2⫹), C1q (2⫹), fibrin
(2 to 3⫹), ␬ (trace to 1⫹), and ␭ (1⫹). Electron microscopy
showed mesangial expansion with amyloid fibrils. Staining for
serum amyloid protein (SAP) was positive, but staining for
serum amyloid A (SAA) protein was negative. Serum immuno-
fixation was negative, whereas urine immunoelectrophoresis
showed polyclonal ␬ and ␭ light chains. Bone marrow biopsy
was negative for monoclonal plasma cells.
Question 8
Which ONE of the following is the MOST appropriate next step
(Figure 16)?
A. Proceed with high-dosage melphalan followed by autolo-
gous stem cell transplantation (ASCT).
B. Begin treatment with vincristine, adriamycin, and dexa-
methasone for three cycles, then proceed with high-dosage
melphalan and ASCT.
C. Conduct scintigraphy with labeled SAP component.
D. Conduct genetic testing for hereditary amyloid variants.
E. Start oral colchicine and an ACEI.
Discussion of Case 8 (Question 8)
Conduct genetic testing for hereditary amyloid variants (D) is
the correct answer. The diagnosis of amyloidosis is usually
based on positive Congo red and/or Thioflavin T stain. Routine
subtyping of amyloidosis into AL amyloidosis (light chain–
associated amyloid) and AA amyloidosis (secondary amyloid)
is then done by immunochemistry staining for ␭ and ␬ light
chains, SAP, and SAA protein. In AL amyloidosis, the amyloid
stains for SAP and either ␬ or ␭ light chain. In case of AA
amyloidosis, the amyloid stains for SAP and SAA protein but is
Clin J Am Soc Nephrol 5: 1141–1160, 2010
Figure 16. Answers from the membership, question 8.
negative for either light chain. In this case, the renal biopsy
finding are not compatible with the diagnosis of AL amyloid or
AA amyloid. If the amyloid protein cannot be typed into AL or
AA subtypes, then it should raise suspicion for a hereditary
amyloidosis and the diagnosis of a hereditary form should be
pursued by serum isoelectric focusing, DNA sequencing,
and/or mass spectrometry of the amyloid protein (83) (Table 5).
Hereditary systemic amyloidoses are usually derived from
genetic variants of transthyretin (familial amyloid polyneurop-
athy), apolipoprotein AI, apolipoprotein AII, lysozyme, cysta-
tin C, gelsolin, TNF receptor, or fibrinogen A ␣-chain (AFib)
(84). These diseases all are inherited in an autosomal dominant
manner with variable penetrance. Variations in the gene muta-
tions result in clinical amyloidosis syndromes that differ with
respect to clinical presentation, age of onset, organ distribution,
rate of progression, and prognosis. Of these conditions, the
most common is caused by mutations in the transthyretin gene.
Patients usually have a family history of progressive peripheral
and autonomic neuropathy secondary to amyloid, although
involvement of the heart or kidneys is variable. Conversely, the
kidney is usually involved in amyloidosis caused by mutations
in the genes that encode lysozyme, apolipoproteins AI and AII,
or AFib (84); however, these autosomal dominant conditions
are generally not considered in the differential diagnosis for
patients without a relevant family history. Lachmann et al. (85)
reported on 350 patients who had systemic amyloidosis and for
whom a diagnosis of AL amyloidosis had been made on the
basis of clinical and laboratory findings and by the absence of
a family history. Testing these patients for amyloidogenic mu-
tations showed that mutations were present in 34 (9.7%) of the
350 patients, most often in the genes that encode AFib (18
patients) and transthyretin (13 patients). In all 34 of these
patients, the diagnosis of hereditary amyloidosis was con-
firmed by additional investigations. Of note, a low-grade
monoclonal gammopathy (⬍0.2 g/dl) was detected in eight
(24%) of the 34 patients, but in none of these patients were free
light chains detected in the urine. Because MGUS can be found
in 3.2% of individuals who are 50 years of age and increases to
5.3% among individuals who are aged ⱖ70 years (77), the
Clin J Am Soc Nephrol 5: 1141–1160, 2010
Table 5. Causes of systemic amyloidosis
Amyloid Protein Precursor
ALa Ig light chain
AHa Ig heavy chain
A␤2Ma ␤2-microglobulin
ATTR Transthyretin
AA (Apo) serum AA
AApoAI Apolipoprotein AI
AApoAIV Apolipoprotein AIV
AGel Gelsolin
ALys Lysozyme
AFib Fibrinogen ␣-chain
ACys Cystatin C
ABri ABriPP
a
Can be localized/organ restricted.
detection of a monoclonal protein in a patient with the diagno-
sis of amyloidosis may result in misleading the diagnosis as AL
amyloidosis. In the report by Lachmann et al. (85), four of the 18
patients with AFib mutation had a monoclonal gammopathy;
the presence of these monoclonal gammopathies reinforced the
initial misdiagnosis of AL amyloidosis, and three of the four
patients received cytotoxic chemotherapy. Thus, it is important
that the diagnosis of hereditary amyloidosis be considered for all
patients who receive a diagnosis of amyloidosis but for whom
biopsy stains are negative for the reactive systemic amyloid AA
type and confirmation of the AL type cannot be obtained.
In this case, subsequent DNA sequencing showed a mutation
in valine 526 position of the AFib, leading to a diagnosis of
hereditary AFib amyloidosis. Hereditary AFib amyloidosis has
been the subject of a number of publications (86 –90). Patients
with AFib amyloidosis typically present in middle age with
proteinuria, hypertension, and progressive renal failure that
reaches ESRD within 4 to 8 years (87). A family history of renal
disease is frequently absent. Renal biopsy often shows massive
accumulation of amyloid in the glomeruli but little or no inter-
stitial or vascular amyloid. The most common amyloidogenic
mutation in the fibrinogen gene is the single-base substitution
of glutamic acid to valine in the codon at position 526 (as was
noted in our patient). Other mutations at codons 552, 540, 538,
and 525 have also been described (87). In patients with AFib
amyloidosis, clinical manifestations are typically restricted to
the kidney, with significant extrarenal disease being very rare.
In the report by Gillmore et al. (87), median time from presen-
tation to ESRD was 4.6 years, and the estimated median patient
survival was 15.2 years. Among 44 patients who reached ESRD,
median survival was 9.3 years. Kidney transplantation alone
has been performed in a number of patients with AFib amy-
loidosis, and in the series by Gillmore et al., 12 kidney trans-
plants survived for a median of 6.0 years (range 0.0 to 12.2
years), whereas seven grafts failed after a median follow-up
from transplantation of 5.8 years; however, unless the supply of
the abnormal amyloidogenic protein could be reduced, AFib
amyloidosis will recur after a kidney transplant and may result
in allograft loss (76,87). Combined kidney liver transplantation
Nephrology Quiz and Questionnaire: 2009 1157
Syndrome or Involved Tissue
Primary; myeloma-associated
Primary; myeloma-associated
Hemodialysis-associated; joints
Familial; senile systemic
Secondary, reactive
Familial
Sporadic, associated with aging
Familial (Finnish)
Familial
Familial
Familial
Familial dementia, British
has been attempted as a way to prevent recurrence from he-
reditary AFib amyloidosis with some success (87,91). Liver
transplantation removes the source of the circulating fibrinogen
variant. Combined kidney-liver transplantation has also been
done in a case with no evidence of recurrence of AFib amyloid-
osis (92); however, it has been argued that because recurrent
AFib amyloidosis develops slowly, liver transplantation should
be considered only for patients or families in whom fast recur-
rence has resulted in accelerated loss in a first kidney transplant
or when the involved mutation is known to result in fast
recurrence in the graft (91).
Light chain amyloidosis (AL), formerly known as primary
amyloidosis, is the most common form of amyloidosis and can
respond to therapy that is directed at the underlying plasma
cell dyscrasia (93–95). Thus, high-dosage melphalan followed
by ASCT (A) would be appropriate if the patient had AL
amyloidosis. In this case, the absence of a monoclonal protein
on serum and urine immunofixation studies together with a
bone marrow biopsy showing no monoclonal plasma cells rules
out the diagnosis of AL amyloidosis. The use of vincristine,
adriamycin, and dexamethasone for induction before ASCT (B)
had been tested in 28 patients with AL amyloidosis (96). In this
study, four patients died before ASCT (two from progression,
two from treatment). No additional benefits were found in
comparison with ASCT alone; therefore, induction chemother-
apy before ASCT is not recommended.
Scintigraphy with labeled SAP component (C) has been used
to quantify imaging of amyloid deposits in vivo but is nonspe-
cific for any particular type of amyloidosis (97). Similarly, ther-
apy with colchicine and an ACEI would be appropriate for
patients with a diagnosis of familiar Mediterranean fever
(FMF). FMF usually occurs during childhood, with 60% of
patients showing first symptoms before the age of 10 years (98).
FMF is clinically characterized by bouts of fever and serositis
(peritonitis, synovitis, or pleuritis) that last 1 to 3 days (99). Skin
involvement is also common, generally as an erysipela-like rash
that occurs most frequently on the shins and dorsum of the
foot. AA amyloidosis can develop in a significant percentage of
1158 Clinical Journal of the American Society of Nephrology
patients with FMF. None of these findings was present in this
case, and stain for AA amyloid was negative.
Disclosures
None.
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