NephSAP Volume 17, Number 4, September 2018

Secondary Glomerular Diseases

Answers and Explanations

x link alph 5 type 4 collagen

Question 1
Answer D: The fellow tells the patient that his kidney disease is caused by a mutation in the
gene that encodes the alpha-5 chain of type IV collagen
Educational objective: Know that thin glomerular basement membrane disease and autosomal
dominant Alport syndrome are due to mutations in the COL4A3 and A4 genes
This patient most likely has thin glomerular basement membrane disease. Thin glomerular basement
membrane disease and autosomal dominant Alport syndrome are due to mutations in the COL4A3 and
A4 genes, whereas X-linked Alport syndrome is due to mutations in the gene that encodes the alpha-5
chain of type IV collagen (COL4A5). Therefore, the fellow was incorrect in identifying mutations in the
gene that encodes the alpha-5 chain of type IV collagen as the cause of this patient’s kidney disease;
hence, option D is the answer to this question. In X-linked disorders, there is no male-to-male
transmission. Because the patient’s father also had hematuria, the patient’s mother is healthy, and a
son is affected, the disease is not X-linked, but probably autosomal dominant (option A is true and is
not the answer to the question). Option B is not the answer to this question because thin basement
membrane disease carries a good long-term prognosis for most patients. A small number of patients
with thin glomerular basement membrane disease develop proteinuria and can have a progressive
decline in kidney function, sometimes leading to end-stage kidney disease, especially at an older age.
Therefore, it is important to monitor kidney function over time in affected individuals. The fellow is
correct in telling the patient that a biopsy would most likely show alterations in the thickness of the
glomerular basement membrane. Thus, option C is not the answer to this question.
• Weber S, Strasser K, Rath S, Kittke A, Beicht S, Alberer M, Lange-Sperandio B, Hoyer PF,
Benz MR, Ponsel S, Weber LT, Klein HG, Hoefele J: Identification of 47 novel mutations in
patients with Alport syndrome and thin basement membrane nephropathy. Pediatr Nephrol 31:
941-955, 2016
• Nabais Sa MJ, Storey H, Flinter F, Nagel M, Sampaio S, Castro R, Araujo JA, Gaspar MA,
Soares C, Oliveira A, Henriques AC, da Costa AG, Abreu CP, Ponce P, Alves R, Pinho L, Silva
SE, de Moura CP, Mendonca L, Carvalho F, Pestana M, Alves S, Carvalho F, Oliveira JP:
Collagen type IV-related nephropathies in Portugal: pathogenic COL4A3 and COL4A4
mutations and clinical characterization of 25 families. Clin Genet 88: 456-461, 2015
• Papazachariou L, Papagregoriou G, Hadjipanagi D, Demosthenous P, Voskarides K, Koutsofti
C, Stylianou K, Ioannou P, Xydakis D, Tzanakis I, Papadaki A, Kallivretakis N, Nikolakakis N,

NSAP Secondary GN Answers and Explanations-September 2018: Page 1 of 25

 Perysinaki G, Gale DP, Diamantopoulos A, Goudas P, Goumenos D, Soloukides A, Boletis I,
Melexopoulou C, Georgaki E, Frysira E, Komianou F, Grekas D, Paliouras C, Alivanis P,
Vergoulas G, Pierides A, Daphnis E, Deltas C: Frequent COL4 mutations in familial
microhematuria accompanied by later-onset Alport nephropathy due to focal segmental
glomerulosclerosis. Clin Genet 92: 517-527, 2017

Question 2
Answer A: Genetic analysis for hereditary forms of FSGS
Educational objective: Appropriately recommend genetic testing in a relatively young person
with steroid-resistant focal and segmental glomerulosclerosis and a family history of kidney
disease
Although this patient has adult-onset steroid resistant nephrotic syndrome, she appears to have a
family history of kidney disease. Hence, the likelihood of her having a genetic form of focal and
segmental glomerulosclerosis (FSGS) is increased. In adults, hereditary FSGS is usually due to
dominant mutations, often with incomplete penetrance. Other family members, although healthy-
appearing, may harbor the mutation and should be excluded from kidney donation. Option A is correct
because it will inform planning for future transplantation. Option B in incorrect because it is not clear
what new information will be gained from a repeat biopsy. The patient had a histologic diagnosis of
FSGS and progression in the setting of ongoing proteinuria and poorly controlled blood pressure is not
unexpected. Although the patient is obese, she does not appear to have a secondary form of FSGS
given her presentation with nephrotic syndrome and extensive foot process effacement on kidney
biopsy (option C is incorrect). FSGS frequently recurs in kidney transplants, but usually not if the FSGS
is monogenic in origin, as is likely in this patient. Even if the patient has immune-mediated FSGS, this
would not be a reason to exclude the possibility of a first kidney transplant with appropriate monitoring
and response for disease recurrence. Hence, option D is incorrect.
• Sen ES, Dean P, Yarram-Smith L, Bierzynska A, Woodward G, Buxton C, Dennis G, Welsh GI,
Williams M, Saleem MA: Clinical genetic testing using a custom-designed steroid-resistant
nephrotic syndrome gene panel: analysis and recommendations. J Med Genet 54: 795-804,
2017
• Mallett AJ, McCarthy HJ, Ho G, Holman K, Farnsworth E, Patel C, Fletcher JT, Mallawaarachchi
A, Quinlan C, Bennetts B, Alexander SI: Massively parallel sequencing and targeted exomes in
familial kidney disease can diagnose underlying genetic disorders. Kidney Int 92: 1493-1506,
2017
• Sethi S, Glassock RJ, Fervenza FC: Focal segmental glomerulosclerosis: towards a better
understanding for the practicing nephrologist. Nephrol Dial Transplant 30: 375-384, 2015

NSAP Secondary GN Answers and Explanations-September 2018: Page 2 of 25

 • Bierzynska A, McCarthy HJ, Soderquest K, Sen ES, Colby E, Ding WY, Nabhan MM, Kerecuk
L, Hegde S, Hughes D, Marks S, Feather S, Jones C, Webb NJ, Ognjanovic M, Christian M,
Gilbert RD, Sinha MD, Lord GM, Simpson M, Koziell AB, Welsh GI, Saleem MA: Genomic and
clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine
approach to disease management. Kidney Int 91: 937-947, 2017

Question 3
Answer A: The IgG in the kidney biopsy may be monoclonal
Educational objective: Recognize clinical features of atypical anti-GBM disease
Recently, patients with atypical anti-GBM disease have been described with a less aggressive form of
glomerulonephritis. These “atypical patients” were diagnosed mainly by linear glomerular basement
membrane (GBM) immunoglobulin staining seen on immunofluorescence microscopy. About half of the
reported atypical anti-GBM patients show monoclonal IgG or light chain restriction on kidney biopsies.
In most of these patients, a serum or urine monoclonal protein is not detected. In cases in which a
serum or urine monoclonal antibody is identified, it may not reflect the monoclonal or restricted
glomerular immunoglobulin demonstrated on biopsy (option A is correct). Although many patients with
anti-GBM disease are also ANCA positive, patients with atypical anti-GBM disease are usually not
(option B is incorrect). In contrast to typical anti-GBM disease, with its very high incidence of end-stage
kidney disease requiring dialysis or transplantation, only about 25% of atypical patients required
permanent dialysis during two years of follow-up (option C is incorrect). It should be emphasized that
only a small number of patients with atypical anti-GBM disease have been reported so far; hence, the
true prevalence remains unknown. The ideal approach to treatment has not been defined. In the
reported series, only two patients were treated as for classic anti-GBM disease with cyclophosphamide,
corticosteroids, and plasmapheresis, so the need to urgently start this level of immunosuppression is
not clear (option D is incorrect).
• Nasr SH, Collins AB, Alexander MP, Schraith DF, Herrera Hernandez L, Fidler ME, Sethi S,
Leung N, Fervenza FC, Cornell LD: The clinicopathologic characteristics and outcome of
atypical anti-glomerular basement membrane nephritis. Kidney Int 89: 897-908, 2016
• Biesenbach P, Kain R, Derfler K, Perkmann T, Soleiman A, Benharkou A, Druml W, Rees A,
Saemann MD: Long-term outcome of anti-glomerular basement membrane antibody disease
treated with immunoadsorption. PLoS One 9: e103568, 2014
• McAdoo SP, Tanna A, Hruskova Z, Holm L, Weiner M, Arulkumaran N, Kang A, Satrapova V,
Levy J, Ohlsson S, Tesar V, Segelmark M, Pusey CD: Patients double-seropositive for ANCA
and anti-GBM antibodies have varied renal survival, frequency of relapse, and outcomes
compared to single-seropositive patients. Kidney Int 92: 693-702, 2017

NSAP Secondary GN Answers and Explanations-September 2018: Page 3 of 25

 • Huart A, Josse AG, Chauveau D, Korach JM, Heshmati F, Bauvin E, Cointault O, Kamar N,
Ribes D, Pourrat J, Faguer S, French Society of H: Outcomes of patients with Goodpasture
syndrome: A nationwide cohort-based study from the French Society of Hemapheresis. J
Autoimmun 73: 24-29, 2016

Question 4
Answer B: The worsening kidney function may be due thrombotic microangiopathy from the
sunitinib, and you would like to do a kidney biopsy for diagnosis before recommending any
changes to the patient’s cancer therapy
Educational objective: Manage progressive kidney the disease in a patient undergoing therapy
with the vascular endothelial growth factor receptor inhibitor sunitinib
Sunitinib is a vascular endothelial growth factor receptor inhibitor that has been associated with
thrombotic microangiopathy (TMA) that can affect the kidney and cause acute kidney injury. The AKI
can resolve if the medication is discontinued, but before that decision is made, the TMA should be
proven. TMA in the setting of cancer therapies is often subtle and is difficult to diagnose without a
kidney biopsy. Often, the usual tests for TMA are unremarkable, including lactate dehydrogenase and
haptoglobin for hemolysis, and a peripheral smear for schistocytes. Therefore, option B is correct, and
options C and D are incorrect. Also confusing the picture is the likelihood of pre-existing diabetic
nephropathy, an unclear time course for the increase in serum creatinine, and inadequate blood
pressure control, which may suggest worsening of diabetic kidney disease. Nonetheless, it is important
to establish or reject the diagnosis of TMA as it will have therapeutic implications for the cancer
treatment, so a biopsy to establish a definitive diagnosis is important in this case. Thus, option A is not
the best answer because a TMA has not been definitively excluded.
• Noronha V, Punatar S, Joshi A, Desphande RV, Prabhash K: Sunitinib-induced thrombotic
microangiopathy. J Cancer Res Ther 12: 6-11, 2016
• Yilmaz S, Ozcakar ZB, Taktak A, Kiremitci S, Ensari A, Dincaslan H, Yalcinkaya F: Anti-VEGF-
related thrombotic microangiopathy in a child presenting with nephrotic syndrome. Pediatr
Nephrol 31: 1029-1032, 2016
• Koizumi M, Takahashi M, Murata M, Kikuchi Y, Seta K, Yahata K: Thrombotic microangiopathy
associated with cetuximab, an epidermal growth factor receptor inhibitor. Clin Nephrol 87
(2017): 51-54, 2017
• Lopez Rubio ME, Rodado Martinez R, Illescas ML, Mateo Bosch E, Martinez Diaz M, de la Vara
Inesta L, Cabezuelo B, Morales Albuja ME, Lucas Guillen E, Jimeno Garcia L: Gemcitabine-
induced hemolytic-uremic syndrome treated with eculizumab or plasmapheresis: two case
reports. Clin Nephrol 87 (2017): 100-106, 2017

NSAP Secondary GN Answers and Explanations-September 2018: Page 4 of 25

 • Murugapandian S, Bijin B, Mansour I, Daheshpour S, Pillai BG, Thajudeen B, Salahudeen AK:
Improvement in Gemcitabine-Induced Thrombotic Microangiopathy with Rituximab in a Patient
with Ovarian Cancer: Mechanistic Considerations. Case Rep Nephrol Dial 5: 160-167, 2015

Question 5
Answer D: A kidney biopsy to verify your suspicion that this patient has staphylococcal-
associated IgA GN
Educational objective: Diagnose staphylococcal-associated IgA glomerulonephritis
This patient developed AKI in the setting of an active infection, not several days after the infection.
Therefore, post-infectious glomerulonephritis is unlikely, and option A is incorrect. The AKI started
before the patient was given antibiotics and although vancomycin can be nephrotoxic, this is usually
associated with very high trough levels. These considerations suggest that option B is incorrect. In
addition to urinalysis findings consistent with acute tubular injury, the patient also has evidence of
glomerular hematuria. Her hypotension was modest at best and was easily corrected. Thus, acute
tubular necrosis alone is unlikely to entirely account for the acute kidney injury, making option C a less
appealing option. The ANCA positivity is concerning in the setting of a glomerulonephritis and rising
serum creatinine, but aggressive immunosuppression with an active infection may prove fatal.
Therefore, a firm diagnosis needs to be established in this patient before therapies other than
antibiotics are added. Option D is the best answer, and option E is incorrect. Glomerulonephritis, often
with mesangial and endocapillary hypercellularity, crescents, acute tubular necrosis, and the presence
of IgA on immunofluorescence is well known to occur with staphylococcal infections. A small but
significant percent of these patients can be ANCA positive. The infection may trigger autoantibody
production, and not just ANCA, or provoke an immune-mediated disease, like ANCA-associated
nephritis in susceptible individuals. Clinically it may be difficult to distinguish the etiology of an
individual’s glomerulonephritis, but a prudent approach is to treat the infection and determine whether
the process resolves before using immunosuppressive therapy. A kidney biopsy can help, although
about 13% of patients with staphylococcal-associated glomerulonephritis have a pauci-immune
immunofluorescence pattern.
• Satoskar AA, Suleiman S, Ayoub I, Hemminger J, Parikh S, Brodsky SV, Bott C, Calomeni E,
Nadasdy GM, Rovin B, Hebert L, Nadasdy T: Staphylococcus Infection-Associated GN -
Spectrum of IgA Staining and Prevalence of ANCA in a Single-Center Cohort. Clin J Am Soc
Nephrol 12: 39-49, 2017
• Marinozzi MC, Roumenina LT, Chauvet S, Hertig A, Bertrand D, Olagne J, Frimat M, Ulinski T,
Deschenes G, Burtey S, Delahousse M, Moulin B, Legendre C, Fremeaux-Bacchi V, Le

NSAP Secondary GN Answers and Explanations-September 2018: Page 5 of 25

 Quintrec M: Anti-Factor B and Anti-C3b Autoantibodies in C3 Glomerulopathy and Ig-Associated
Membranoproliferative GN. J Am Soc Nephrol 28: 1603-1613, 2017

Question 6
Answer D: Cryoglobulinemia can occur with hepatitis C and hepatitis B
Educational objective: Know the clinical manifestations and treatments of kidney diseases
secondary to hepatitis B and C virus infection
Although cryoglobulinemia is most frequently associated with hepatitis C, it is also commonly seen in
patients with hepatitis B virus infection; hence, option D is correct. A large study in U.S. Veterans
showed that treatment of hepatitis C with interferon-α decreased the chances of developing
cryoglobulinemia and glomerulonephritis, but this protection declined significantly if treatment was
delayed beyond 2 years after discovery of the infection. Therefore, options A and C are incorrect.
Hepatitis C virus B-cell clones that produce cryoglobulins can persist after viral eradication; thus, option
B is incorrect.
• Mahale P, Engels EA, Li R, Torres HA, Hwang LY, Brown EL, Kramer JR: The effect of
sustained virological response on the risk of extrahepatic manifestations of hepatitis C virus
infection. Gut 10.1136/gutjnl-2017-313983, 2017
• Ghosn M, Palmer MB, Najem CE, Haddad D, Merkel PA, Hogan JJ: New-onset hepatitis C
virus-associated glomerulonephritis following sustained virologic response with direct-acting
antiviral therapy. Clin Nephrol 87 (2017): 261-266, 2017
• Li SJ, Xu ST, Chen HP, Zhang MC, Xu F, Cheng SQ, Liu ZH: Clinical and morphologic
spectrum of renal involvement in patients with HBV-associated cryoglobulinaemia. Nephrology
(Carlton) 22: 449-455, 2017
• Wang C, Ye ZY, Zeng DH, Xie FL, Qu LJ, Zheng ZY: Clinicopathological features of
cryoglobulinemic glomerulonephritis associated with HBV infection: a retrospective analysis of 8
cases in China. Int J Clin Exp Pathol 8: 10475-10481, 2015
• Terrier B, Marie I, Lacraz A, Belenotti P, Bonnet F, Chiche L, Graffin B, Hot A, Kahn JE, Michel
C, Quemeneur T, de Saint-Martin L, Hermine O, Leger JM, Mariette X, Senet P, Plaisier E,
Cacoub P: Non HCV-related infectious cryoglobulinemia vasculitis: Results from the French
nationwide CryoVas survey and systematic review of the literature. J Autoimmun 65: 74-81,
2015

NSAP Secondary GN Answers and Explanations-September 2018: Page 6 of 25

Question 7
Answer D: What was the magnitude and time course of the patient’s hematologic response to
therapy
Educational objective: Determine the renal prognosis of AL amyloidosis
The traditional metrics used by nephrologists to predict long-term kidney survival when a patient is first
seen, including magnitude of proteinuria, kidney function, and chronic damage on biopsy are not the
best markers for renal outcomes in patients with AL amyloidosis. The single best predictor of dialysis-
free survival is how well therapy attenuates the monoclonal light chain causing the amyloidosis.
Decreasing the light chain burden by at least 90% within 3-6 months of beginning therapy is the best
marker of kidney survival in multivariate analysis. Patients who do not have a hematologic remission
generally do not achieve an organ response in AL amyloidosis. Therefore, option D is the superior
answer of the choices listed (options A through C are incorrect).
• Rezk T, Lachmann HJ, Fontana M, Sachchithanantham S, Mahmood S, Petrie A, Whelan CJ,
Pinney JH, Foard D, Lane T, Youngstein T, Wechalekar AD, Bass P, Hawkins PN, Gillmore JD:
Prolonged renal survival in light chain amyloidosis: speed and magnitude of light chain reduction
is the crucial factor. Kidney Int 10.1016/j.kint.2017.05.004, 2017
• Huang X, Wang Q, Chen W, Ren G, Liu Z: Bortezomib with dexamethasone as first-line
treatment for AL amyloidosis with renal involvement. Amyloid 23: 51-57, 2016

Question 8
Answer B: Serum immunofixation plus serum free light chains
Educational objective: Identify an abnormal B cell or plasma cell clone in proliferative
glomerulonephritis with monoclonal immunoglobulin deposits
Monoclonal paraproteins and abnormal clones are difficult to detect in proliferative glomerulonephritis
with monoclonal immunoglobulin deposits (PGNMID). Serum immunofixation and serum free light
chains are more sensitive than urine protein electrophoresis in identifying monoclonal paraproteins
derived from abnormal clones. If both tests are done and a monoclonal protein is identified, the
chances of finding an abnormal clone in the bone marrow increases greatly. Therefore, option B is
correct. Urine studies for monoclonal proteins are not sensitive (option A is incorrect). Serum
complement levels do not help establish or distinguish clonality, although glomerular C3 deposits may
be seen in PGNMID. Laser dissection/mass spectrometry the most accurate method of classifying the
nature of amyloid deposits and would not be the next best test to establish the presence of a
monoclonal protein.
• Bhutani G, Nasr SH, Said SM, Sethi S, Fervenza FC, Morice WG, Kurtin PJ, Buadi FK, Dingli D,
Dispenzieri A, Gertz MA, Lacy MQ, Kapoor P, Kumar S, Kyle RA, Rajkumar SV, Leung N:

NSAP Secondary GN Answers and Explanations-September 2018: Page 7 of 25

 Hematologic characteristics of proliferative glomerulonephritides with nonorganized monoclonal
immunoglobulin deposits. Mayo Clin Proc 90: 587-596, 2015
• Vignon M, Cohen C, Faguer S, Noel LH, Guilbeau C, Rabant M, Higgins S, Hummel A, Hertig A,
Francois H, Lequintrec M, Vilaine E, Knebelmann B, Pourrat J, Chauveau D, Goujon JM,
Javaugue V, Touchard G, El Karoui K, Bridoux F: The clinicopathologic characteristics of kidney
diseases related to monotypic IgA deposits. Kidney Int 91: 720-728, 2017

Question 9
Answer C: Avoid nonsteroidal anti-inflammatory drugs and proton pump inhibitors
Educational objective: Mitigate the risk of checkpoint inhibitor-related interstitial nephritis
There are no good data on how to predict or prevent kidney injury with the checkpoint inhibitors. Most
of the documented cases of kidney injury with checkpoint inhibitors have been due to interstitial
nephritis. The interstitial nephritis often occurs in individuals receiving therapy with drugs known to
cause interstitial nephritis that the patients have been taking for a long time without incident. This has
led to the idea that the checkpoint inhibitors may lower the threshold for developing interstitial nephritis
from commonly used medications. Thus, although never tested and purely speculative, it may be
worthwhile to ask the patient to avoid taking a proton pump inhibitor and NSAIDs, if possible, while
being treated with pembrolizumab. This recommendation could be extended to any medications that
put a patient at risk for interstitial nephritis. To date, glomerular injury has been infrequently reported
with checkpoint inhibitors, and there is no reason to screen for diabetes or lupus, or to begin treatment
with an ACE inhibitor in this patient without evidence of kidney disease; thus, options A, B and D are
incorrect.
• Jung K, Zeng X, Bilusic M: Nivolumab-associated acute glomerulonephritis: a case report and
literature review. BMC Nephrol 17: 188, 2016
• Cortazar FB, Marrone KA, Troxell ML, Ralto KM, Hoenig MP, Brahmer JR, Le DT, Lipson EJ,
Glezerman IG, Wolchok J, Cornell LD, Feldman P, Stokes MB, Zapata SA, Hodi FS, Ott PA,
Yamashita M, Leaf DE: Clinicopathological features of acute kidney injury associated with
immune checkpoint inhibitors. Kidney Int 90: 638-647, 2016
• Shirali AC, Perazella MA, Gettinger S: Association of Acute Interstitial Nephritis With
Programmed Cell Death 1 Inhibitor Therapy in Lung Cancer Patients. Am J Kidney Dis 68:
287-291, 2016
• Belliere J, Meyer N, Mazieres J, Ollier S, Boulinguez S, Delas A, Ribes D, Faguer S: Acute
interstitial nephritis related to immune checkpoint inhibitors. Br J Cancer 115: 1457-1461, 2016

NSAP Secondary GN Answers and Explanations-September 2018: Page 8 of 25

Question 10
Answer C: You continue treatment for anti-GBM disease with plasmapheresis, steroids, and
cyclophosphamide, and after the patient goes into remission you provide the patient with
maintenance immunosuppression
Educational objective: Manage dual positive anti-glomerular basement membrane (GBM)
disease/anti-neutrophil cytoplasmic antibody (ANCA)-associated nephritis
Patients with anti-glomerular basement membrane (GBM) disease who are also anti-neutrophil
cytoplasmic antibody (ANCA) positive have a disease course that falls somewhere in between that of
patients with anti-GBM disease alone and patients with ANCA-associated nephritis alone. Because
there are few data on the use of rituximab in anti-GBM disease, induction therapy should follow the
usual treatment protocols for anti-GBM disease and should include corticosteroids, cyclophosphamide,
and plasmapheresis. These measures remove pathogenic anti-GBM antibodies and prevent further
anti-GBM antibody production. The positive PR3-ANCA places this patient at particularly high risk for
relapse. Most physicians would place the patient on maintenance therapy as for ANCA vasculitis.
Therefore, option C is correct. Rituximab is not the best initial induction therapy for anti-GBM disease
because of the lack of controlled trial establishing efficacy; thus, option A is incorrect. Option B is
incorrect because this patient has dual ANCA/anti-GBM seropositivity. If the patient only had anti-GBM
disease, maintenance immunosuppression would not be needed as the disease rarely relapses, so
option B would be correct in that circumstance, which is not the case for this patient. Although having
two auto-antibodies that may be pathogenic and affect the kidney seems ominous, long-term kidney
survival in double-positive patients is better than patients with isolated anti-GBM disease. Hence,
discontinuing treatment is not warranted (option D is incorrect).
• McAdoo SP, Tanna A, Hruskova Z, Holm L, Weiner M, Arulkumaran N, Kang A, Satrapova V,
Levy J, Ohlsson S, Tesar V, Segelmark M, Pusey CD: Patients double-seropositive for ANCA
and anti-GBM antibodies have varied renal survival, frequency of relapse, and outcomes
compared to single-seropositive patients. Kidney Int 92: 693-702, 2017

Question 11
Answer A: A combination of low-dose tacrolimus and low-dose mycophenolate mofetil (MMF)
with prednisone
Educational objective: Manage class IV lupus nephritis in a woman who declines
cyclophosphamide therapy
Multi-target therapy with a low-dose of a calcineurin inhibitor and mycophenolate mofetil has been
shown to be more effective than cyclophosphamide in Asian patients and carries very little risk of
infertility. Therefore, option A is the best option of those listed. Azathioprine has been used for induction

NSAP Secondary GN Answers and Explanations-September 2018: Page 9 of 25

therapy for lupus nephritis in the past and could be considered if there were no other options (option B
is incorrect). Rituximab monotherapy has not been approved or recommended as initial therapy for new
class IV nephritis (option C is incorrect). Rituximab has been used in combination with other drugs for
refractory disease and in combination with MMF as a steroid sparing regimen for lupus nephritis.
Likewise, belimumab is not recommended for induction therapy for active lupus nephritis because of
the lack of data supporting efficacy for this indication.
• Liu Z, Zhang H, Liu Z, Xing C, Fu P, Ni Z, Chen J, Lin H, Liu F, He Y, He Y, Miao L, Chen N, Li
Y, Gu Y, Shi W, Hu W, Liu Z, Bao H, Zeng C, Zhou M: Multitarget therapy for induction
treatment of lupus nephritis: a randomized trial. Ann Intern Med 162: 18-26, 2015
• Zhang H, Liu Z, Zhou M, Liu Z, Chen J, Xing C, Lin H, Ni Z, Fu P, Liu F, Chen N, He Y, Liu J,
Zeng C, Liu Z: Multitarget therapy for maintenance treatment of lupus nephritis. J Am Soc
Nephrol 10.1681/ASN.2017030263, 2017
• Rathi M, Goyal A, Jaryal A, Sharma A, Gupta PK, Ramachandran R, Kumar V, Kohli HS,
Sakhuja V, Jha V, Gupta KL: Comparison of low-dose intravenous cyclophosphamide with oral
mycophenolate mofetil in the treatment of lupus nephritis. Kidney Int 89: 235-242, 2016
• Herath N, Ratnatunga N, Weerakoon K, Wazil A, Nanayakkara N: Clinicopathological findings,
treatment response and predictors of long-term outcome in a cohort of lupus nephritis patients
managed according to the Euro-lupus regime: a retrospective analysis in Sri Lanka. BMC Res
Notes 10: 80, 2017
• Weidenbusch M, Rommele C, Schrottle A, Anders HJ: Beyond the LUNAR trial. Efficacy of
rituximab in refractory lupus nephritis. Nephrol Dial Transplant 28: 106-111, 2013
• Condon MB, Ashby D, Pepper RJ, Cook HT, Levy JB, Griffith M, Cairns TD, Lightstone L:
Prospective observational single-centre cohort study to evaluate the effectiveness of treating
lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis
72: 1280-1286, 2013

mmf should be stop 6wks before conseption

Question 12
Answer C: Talk to the patient about repeating a kidney biopsy to determine if her lupus
nephritis is still active or if the proteinuria represents chronic disease and immunosuppression
can be safely tapered
Educational objective: Manage lupus nephritis in the preconception period
Option C is the best answer. A repeat kidney biopsy will definitively determine what is going on in the
kidney, as clinical data, though suggestive of quiescent disease, can be misleading. If there is no
further lupus activity, mycophenolate mofetil (MMF) can be slowly discontinued and the patient can be
observed for relapse. After she had been off mycophenolate mofetil and stable, she can work on having

NSAP Secondary GN Answers and Explanations-September 2018: Page 10 of 25

a child. Although azathioprine and tacrolimus can both be used during pregnancy, options A and B do
not answer the question of whether the lupus nephritis is active (options A and B are incorrect).
Nephritis activity within 6 months of conception is a risk factor for poor maternal and fetal outcome.
Additionally, it is not advisable to become pregnant immediately after stopping MMF, but to wait and let
the drug wash out over a period of at least six weeks. Option D is very aggressive, is based on little
evidence of active SLE or lupus nephritis and would put the patient at further risk for premature ovarian
failure by increasing lifetime burden of the alkylating agent; hence, option D is incorrect.
• Sammaritano LR, Bermas BL: Therapy: A fine conception -- BSR/BHPR guidelines on drugs in
pregnancy. Nat Rev Rheumatol 12: 197-198, 2016
• Narvaez J, Ricse M, Goma M, Mitjavila F, Fulladosa X, Capdevila O, Torras J, Juanola X, Pujol-
Farriols R, Nolla JM: The value of repeat biopsy in lupus nephritis flares. Medicine (Baltimore)
96: e7099, 2017

Question 13
Answer B: Add an antimalarial to the regimen
Educational objective: Manage class IV lupus nephritis
The RELSSER and SLICC studies both showed a lower odds ratio for end-stage renal disease in
patients with lupus nephritis receiving an antimalarial compared to those who did not receive
antimalarial therapy. This was statistically significant in the RELSSER cohort, but not in the SLICC
cohort. Nonetheless, given the other options, option B is the best answer. The multi-target trials have
shown an advantage in short-term remissions over conventional therapy, but no long-term advantage
for renal survival (option A is incorrect). There have been no studies comparing long-term kidney
survival for patients treated with conventional therapy or conventional therapy plus rituximab (option C
is incorrect). The ALMS extension trial suggested MMF was superior to azathioprine in preventing end-
stage renal disease (option D is incorrect).
• Galindo-Izquierdo M, Rodriguez-Almaraz E, Pego-Reigosa JM, Lopez-Longo FJ, Calvo-Alen J,
Olive A, Fernandez-Nebro A, Martinez-Taboada V, Vela-Casasempere P, Freire M, Narvaez FJ,
Rosas J, Ibanez-Barcelo M, Uriarte E, Tomero E, Zea A, Horcada L, Torrente V, Castellvi I,
Calvet J, Menor-Almagro R, Zamorano MA, Raya E, Diez-Alvarez E, Vazquez-Rodriguez T,
Garcia de la Pena P, Movasat A, Andreu JL, Richi P, Marras C, Montilla-Morales C, Hernandez-
Cruz B, Marenco de la Fuente JL, Gantes M, Ucar E, Alegre-Sancho JJ, Manero J, Ibanez-
Ruan J, Rodriguez-Gomez M, Quevedo V, Hernandez-Beriain J, Silva-Fernandez L, Alonso F,
Perez S, Rua-Figueroa I, Relesser Group fSSoRSADSG: Characterization of Patients With
Lupus Nephritis Included in a Large Cohort From the Spanish Society of Rheumatology Registry

NSAP Secondary GN Answers and Explanations-September 2018: Page 11 of 25

 of Patients With Systemic Lupus Erythematosus (RELESSER). Medicine (Baltimore) 95:
e2891, 2016
• Hanly JG, O'Keeffe AG, Su L, Urowitz MB, Romero-Diaz J, Gordon C, Bae SC, Bernatsky S,
Clarke AE, Wallace DJ, Merrill JT, Isenberg DA, Rahman A, Ginzler EM, Fortin P, Gladman DD,
Sanchez-Guerrero J, Petri M, Bruce IN, Dooley MA, Ramsey-Goldman R, Aranow C, Alarcon
GS, Fessler BJ, Steinsson K, Nived O, Sturfelt GK, Manzi S, Khamashta MA, van Vollenhoven
RF, Zoma AA, Ramos-Casals M, Ruiz-Irastorza G, Lim SS, Stoll T, Inanc M, Kalunian KC,
Kamen DL, Maddison P, Peschken CA, Jacobsen S, Askanase A, Theriault C, Thompson K,
Farewell V: The frequency and outcome of lupus nephritis: results from an international
inception cohort study. Rheumatology (Oxford) 55: 252-262, 2016
• Liu Z, Zhang H, Liu Z, Xing C, Fu P, Ni Z, Chen J, Lin H, Liu F, He Y, He Y, Miao L, Chen N, Li
Y, Gu Y, Shi W, Hu W, Liu Z, Bao H, Zeng C, Zhou M: Multitarget therapy for induction
treatment of lupus nephritis: a randomized trial. Ann Intern Med 162: 18-26, 2015
• Dooley MA, Jayne D, Ginzler EM, Isenberg D, Olsen NJ, Wofsy D, Eitner F, Appel GB,
Contreras G, Lisk L, Solomons N, Group A: Mycophenolate versus azathioprine as maintenance
therapy for lupus nephritis. N Engl J Med 365: 1886-1895, 2011

Question 14
Answer C: Dialysis vintage >5 years
Educational objective: Cite factors the support or refute the probability of a lupus flare in a
patient with end-stage kidney disease
Most flares in patients with systemic lupus erythematosus on dialysis occur within the first five years of
renal replacement therapy. Therefore, option C is correct (i.e., his relatively long dialysis vintage is
associated with a decreased risk that he is experiencing a lupus flare). The risk of flare is higher in men
and higher in patients who have had IgM antiphospholipid antibodies in the past. Thus, options A and B
are incorrect. The common extra-renal manifestations of lupus in patients on dialysis are hematologic,
articular, and mucocutaneous. Although this patient does have a mouth ulcer, arthralgias, and pleurisy,
these can be explained by a viral syndrome as opposed to active lupus. The low serum C4 level over
the last several months has been shown to be independently associated with an increased risk for
developing a lupus flare while on dialysis (option D is incorrect). A younger age at start of renal
replacement therapy and a history of prior hematologic manifestations of SLE are also independently
associated with developing a flare of lupus while on dialysis.
• Barrera-Vargas A, Quintanar-Martinez M, Merayo-Chalico J, Alcocer-Varela J, Gomez-Martin D:
Risk factors for systemic lupus erythematosus flares in patients with end-stage renal disease: a
case-control study. Rheumatology 55: 429-435, 2016

NSAP Secondary GN Answers and Explanations-September 2018: Page 12 of 25

Question 15
Answer D: Restart MMF and corticosteroids to treat a presumptive diagnosis of class V plus
class III or IV lupus nephritis
Educational objective: Implement appropriate therapy for a presumed flare of lupus nephritis
Patients who have had pure class V lupus nephritis (LN) and flare after successful treatment have a
high likelihood of having a component of class III or IV in addition to class V LN. While it is difficult to
predict kidney histology based on clinical findings, the presence of nephrotic syndrome is consistent
with class V and the large number of acanthocytes along with an increase in the serum creatinine level
are consistent with a component of class III or IV LN. Therefore, option D is a reasonable approach for
this person who declines kidney biopsy. Rituximab monotherapy has been used in pure class V LN, but
the studies have been small and uncontrolled. Furthermore, this patient has clinical findings suggestive
of mixed class III/IV plus class V LN, decreasing enthusiasm for rituximab monotherapy. Calcineurin
inhibitors have been used successfully for pure Class V LN and as monotherapy for patients with
proliferative LN in trials from Asia. In this patient, who likely has mixed LN, calcineurin monotherapy
(Option B) is not the best choice. Option C is incorrect because this woman has evidence of active LN
that merits immunosuppressive therapy.
• Narvaez J, Ricse M, Goma M, Mitjavila F, Fulladosa X, Capdevila O, Torras J, Juanola X, Pujol-
Farriols R, Nolla JM: The value of repeat biopsy in lupus nephritis flares. Medicine (Baltimore)
96: e7099, 2017
• Tektonidou MG, Dasgupta A, Ward MM: Risk of End-Stage Renal Disease in Patients With
Lupus Nephritis, 1971-2015: A Systematic Review and Bayesian Meta-Analysis. Arthritis
Rheumatol 68: 1432-1441, 2016
• Chavarot N, Verhelst D, Pardon A, Caudwell V, Mercadal L, Sacchi A, Leonardi C, Le Guern V,
Karras A, Daugas E, Groupe Cooperatif sur le Lupus R: Rituximab alone as induction therapy
for membranous lupus nephritis: A multicenter retrospective study. Medicine (Baltimore) 96:
e7429, 2017

Question 16
Answer C: Rituximab
Educational objective: Treat ANCA-associated vasculitis and nephritis
This patient appears to have moderate ANCA-associated vasculitis and nephritis and should be treated
with more than just corticosteroids (option A is incorrect). Although induction immunosuppression
choices include either cyclophosphamide or rituximab, rituximab is favored because the patient is PR3-
ANCA positive. Rituximab therapy may achieve remission more rapidly compared to cyclophosphamide

NSAP Secondary GN Answers and Explanations-September 2018: Page 13 of 25

in this setting. While cyclophosphamide would also likely be effective in this patient, his disease
manifestations are not sufficiently severe to warrant addition of plasmapheresis. Hence, of the choices
listed, option C is favored over option B. Mycophenolate mofetil is not generally used for induction or
maintenance in ANCA-associated nephritis.
• Hanaoka H, Ota Y, Takeuchi T, Kuwana M: Poor renal outcomes in patients with anti-neutrophil
cytoplasmic antibody-associated crescentic glomerulonephritis and normal renal function at
diagnosis. Clin Rheumatol 35: 495-500, 2016
• Unizony S, Villarreal M, Miloslavsky EM, Lu N, Merkel PA, Spiera R, Seo P, Langford CA,
Hoffman GS, Kallenberg CM, St Clair EW, Ikle D, Tchao NK, Ding L, Brunetta P, Choi HK,
Monach PA, Fervenza F, Stone JH, Specks U, Group R-IR: Clinical outcomes of treatment of
anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type. Ann
Rheum Dis 75: 1166-1169, 2016
• de Luna G, Chauveau D, Aniort J, Carron PL, Gobert P, Karras A, Marchand-Adam S, Maurier F,
Hatron PY, Mania A, le Guenno G, Bally S, Bienvenu B, Cardineau E, Goulenok T, Jourde-
Chiche N, Samson M, Huart A, Pourrat J, Tiple A, Aumaitre O, Puechal X, Heshmati F, le
Jeunne C, Mouthon L, Guillevin L, Terrier B, French Vasculitis Study G: Plasma exchanges for
the treatment of severe systemic necrotizing vasculitides in clinical daily practice: Data from the
French Vasculitis Study Group. J Autoimmun 65: 49-55, 2015.
• Solar-Cafaggi D, Atisha-Fregoso Y, Hinojosa-Azaola A: Plasmapheresis therapy in ANCA-
associated vasculitides: A single-center retrospective analysis of renal outcome and mortality. J
Clin Apher 31: 411-418, 2016

Question 17
Answer C: ANCA became undetectable after induction therapy
Educational objective: Assess the risk of relapse in ANCA-associated glomerulonephritis
Although patients with PR3-ANCA tend to relapse more frequently than patients with MPO-ANCA,
patients with MPO-ANCA do relapse. Patients who have persistently positive ANCA going into
maintenance therapy have higher rate of relapse than patients who become ANCA negative. Therefore,
option A is incorrect, and C is correct. The relapse rate of patients given intravenous cyclophosphamide
is higher than patients who were induced with oral cyclophosphamide (option B is incorrect). Treatment
with plasmapheresis is not known to influence the rate of relapse of ANCA-associated vasculitis.
Goceroglu et al. found that plasmapheresis did not significantly influence the rate of renal relapse,
although the number of patients treated with plasma exchange in this analysis was only 28 (option D is
incorrect).

NSAP Secondary GN Answers and Explanations-September 2018: Page 14 of 25

 • Murosaki T, Sato T, Akiyama Y, Nagatani K, Minota S: Difference in relapse-rate and clinical
phenotype by autoantibody-subtype in Japanese patients with anti-neutrophil cytoplasmic
antibody-associated vasculitis. Mod Rheumatol 27: 95-101, 2017
• Cordova-Sanchez BM, Mejia-Vilet JM, Morales-Buenrostro LE, Loyola-Rodriguez G, Uribe-
Uribe NO, Correa-Rotter R: Clinical presentation and outcome prediction of clinical, serological,
and histopathological classification schemes in ANCA-associated vasculitis with renal
involvement. Clin Rheumatol 35: 1805-1816, 2016
• Fussner LA, Hummel AM, Schroeder DR, Silva F, Cartin-Ceba R, Snyder MR, Hoffman GS,
Kallenberg CG, Langford CA, Merkel PA, Monach PA, Seo P, Spiera RF, William St Clair E,
Tchao NK, Stone JH, Specks U, Rituximab in A-AV-ITNRG: Factors Determining the Clinical
Utility of Serial Measurements of Antineutrophil Cytoplasmic Antibodies Targeting Proteinase 3.
Arthritis Rheumatol 68: 1700-1710, 2016
• Morgan MD, Szeto M, Walsh M, Jayne D, Westman K, Rasmussen N, Hiemstra TF, Flossmann
O, Berden A, Hoglund P, Harper L, European Vasculitis S: Negative anti-neutrophil cytoplasm
antibody at switch to maintenance therapy is associated with a reduced risk of relapse. Arthritis
Res Ther 19: 129, 2017
• Goceroglu A, Berden AE, Fiocco M, Flossmann O, Westman KW, Ferrario F, Gaskin G, Pusey
CD, Hagen EC, Noel LH, Rasmussen N, Waldherr R, Walsh M, Bruijn JA, Jayne DR, Bajema
IM, European Vasculitis S: ANCA-Associated Glomerulonephritis: Risk Factors for Renal
Relapse. PLoS One 11: e0165402, 2016
• Puechal X, Pagnoux C, Perrodeau E, Hamidou M, Boffa JJ, Kyndt X, Lifermann F, Papo T,
Merrien D, Smail A, Delaval P, Hanrotel-Saliou C, Imbert B, Khouatra C, Lambert M, Leske C,
Ly KH, Pertuiset E, Roblot P, Ruivard M, Subra JF, Viallard JF, Terrier B, Cohen P, Mouthon L,
Le Jeunne C, Ravaud P, Guillevin L, French Vasculitis Study G: Long-Term Outcomes Among
Participants in the WEGENT Trial of Remission-Maintenance Therapy for Granulomatosis With
Polyangiitis (Wegener's) or Microscopic Polyangiitis. Arthritis Rheumatol 68: 690-701, 2016

Question 18
Answer A: No need to re-induce because the patient’s kidney function is improving as
expected, and proteinuria and hematuria take longer to resolve
Educational objective: Manage ANCA-associated glomerulonephritis
The kidney injury of ANCA-associated vasculitis usually requires six months or longer to heal;
proteinuria and hematuria may persist during the healing phase after induction therapy. In this patient,
the fall in the GFR has been quite good and fairly rapid. The proteinuria and findings in the urinary
sediment are improving, and the expectation is that improvement will continue. As long as there is no

NSAP Secondary GN Answers and Explanations-September 2018: Page 15 of 25

evidence of new or worsening extra-renal vasculitis, there is no need to change therapy at this point.
Therefore, option A is correct and options B through D are incorrect.
• Oomatia A, Moran SM, Kennedy C, Sequeira R, Hamour S, Burns A, Little MA, Salama AD:
Prolonged Duration of Renal Recovery Following ANCA-Associated Glomerulonephritis. Am J
Nephrol 43: 112-119, 2016

Question 19
Answer D: Because the patient did not have lung or upper respiratory vasculitis, her chances of
disease relapse while she is using dialysis are lower
Educational objective: Counsel a patient with advanced chronic kidney disease due to ANCA-
associated nephritis about subsequent disease course, prognosis, and renal replacement
therapy
The major risk factor for ANCA–associated vasculitis relapse on hemodialysis is a history of pulmonary
involvement; thus, option D is correct. Patients with end-stage kidney disease from ANCA-associated
nephritis do as well with hemodialysis and kidney transplantation as the general population of patients
with kidney disease (options A and B are incorrect). ANCA positivity at the time of kidney transplant
was not found to be a risk factor for disease relapse and kidney transplantation should not be delayed if
no other manifestations of ANCA–associated vasculitis are manifest (option C is incorrect).
• Goceroglu A, Rahmattulla C, Berden AE, Reinders ME, Wolterbeek R, Steenbergen EJ,
Hilbrands LB, Noorlander I, Berger SP, Peutz-Kootstra CJ, Christiaans MH, van Dijk MC, de
Joode AA, Goldschmeding R, van Zuilen AD, Harper L, Little MA, Hagen EC, Bruijn JA, Bajema
IM: The Dutch Transplantation in Vasculitis (DUTRAVAS) Study: Outcome of renal
transplantation in antineutrophil cytoplasmic antibody-associated glomerulonephritis.
Transplantation 100: 916-924, 2016
• Hasegawa M, Hattori K, Sugiyama S, Asada H, Yamashita H, Takahashi K, Hayashi H, Koide S,
Sato W, Yuzawa Y: A retrospective study on the outcomes of MPO-ANCA-associated vasculitis
in dialysis-dependent patients. Mod Rheumatol 26: 110-114, 2016

Question 20
Answer D: The patient had moderately severe MPO-ANCA-associated nephritis, received
induction therapy with oral cyclophosphamide, and became ANCA negative when maintenance
therapy was initiated
Educational objective: Assess optimal duration of maintenance immunosuppressive therapy
based on risk of relapse in ANCA-associated nephritis

NSAP Secondary GN Answers and Explanations-September 2018: Page 16 of 25

The optimal duration of maintenance therapy for ANCA-associated small vessel vasculitis is not entirely
clear. Although a small prospective study suggested that prolonged maintenance therapy was
associated with significantly fewer and less severe relapses, many patients are unwilling to continue
prolonged immunosuppressive therapy. Factors associated with a high incidence of relapse include
PR3-ANCA, ANCA positivity at the time maintenance therapy is started, a rise or reappearance of
ANCA titers (especially PR3-ANCA in rituximab treated patients), and less severe kidney disease.
Options A through C include findings associated with an increased risk of relapse. Answer D describes
a patient with several attributes that suggest a low risk for relapse. These include the MPO-ANCA
subtype, disappearance of ANCA with treatment, use of oral instead of intravenous cyclophosphamide
for induction, and an initial presentation with severe kidney disease. Therefore, option D is correct.
• Karras A, Pagnoux C, Haubitz M, Groot K, Puechal X, Tervaert JWC, Segelmark M, Guillevin L,
Jayne D, European Vasculitis S: Randomised controlled trial of prolonged treatment in the
remission phase of ANCA-associated vasculitis. Ann Rheum Dis 76: 1662-1668, 2017
• Fussner LA, Hummel AM, Schroeder DR, Silva F, Cartin-Ceba R, Snyder MR, Hoffman GS,
Kallenberg CG, Langford CA, Merkel PA, Monach PA, Seo P, Spiera RF, William St Clair E,
Tchao NK, Stone JH, Specks U, Rituximab in A-AV-ITNRG: Factors determining the clinical
utility of serial measurements of antineutrophil cytoplasmic antibodies targeting proteinase 3.
Arthritis Rheumatol 68: 1700-1710, 2016
• Morgan MD, Szeto M, Walsh M, Jayne D, Westman K, Rasmussen N, Hiemstra TF, Flossmann
O, Berden A, Hoglund P, Harper L, European Vasculitis S: Negative anti-neutrophil cytoplasm
antibody at switch to maintenance therapy is associated with a reduced risk of relapse. Arthritis
Res Ther 19: 129, 2017
• Goceroglu A, Berden AE, Fiocco M, Flossmann O, Westman KW, Ferrario F, Gaskin G, Pusey
CD, Hagen EC, Noel LH, Rasmussen N, Waldherr R, Walsh M, Bruijn JA, Jayne DR, Bajema
IM, European Vasculitis S: ANCA-Associated Glomerulonephritis: Risk Factors for Renal
Relapse. PLoS One 11: e0165402, 2016
• Puechal X, Pagnoux C, Perrodeau E, Hamidou M, Boffa JJ, Kyndt X, Lifermann F, Papo T,
Merrien D, Smail A, Delaval P, Hanrotel-Saliou C, Imbert B, Khouatra C, Lambert M, Leske C,
Ly KH, Pertuiset E, Roblot P, Ruivard M, Subra JF, Viallard JF, Terrier B, Cohen P, Mouthon L,
Le Jeunne C, Ravaud P, Guillevin L, French Vasculitis Study G: Long-Term Outcomes Among
Participants in the WEGENT Trial of Remission-Maintenance Therapy for Granulomatosis With
Polyangiitis (Wegener's) or Microscopic Polyangiitis. Arthritis Rheumatol 68: 690-701, 2016
• Hanaoka H, Ota Y, Takeuchi T, Kuwana M: Poor renal outcomes in patients with anti-neutrophil
cytoplasmic antibody-associated crescentic glomerulonephritis and normal renal function at
diagnosis. Clin Rheumatol 35: 495-500, 2016

NSAP Secondary GN Answers and Explanations-September 2018: Page 17 of 25

 • Murosaki T, Sato T, Akiyama Y, Nagatani K, Minota S: Difference in relapse-rate and clinical
phenotype by autoantibody-subtype in Japanese patients with anti-neutrophil cytoplasmic
antibody-associated vasculitis. Mod Rheumatol 27: 95-101, 2017
• Gupta T, Dhiman RK, Rathi S, Agrawal S, Duseja A, Taneja S, Chawla Y: Impact of Hepatic and
Extrahepatic Insults on the Outcome of Acute-on-Chronic Liver Failure. J Clin Exp Hepatol 7:
9-15, 2017

Question 21
Answer A: His serum creatinine level at presentation is an independent predictor of dialysis
dependency at one year
Educational objective: Communicate prognosis in anti-glomerular basement membrane disease
glomerulonephritis
Huart and coworkers conducted a multicenter retrospective study on 122 subjects with anti-glomerular
basement membrane antibody disease in the registry of the French Society of Hemapheresis. Renal
survival in patients alive at 1 year was predicted when the serum creatinine was <500 μmol/L (5.65
mg/dl) at presentation. A serum creatinine level >5.65 mg/dl (>500 μmol/L) at presentation was
predictive of dialysis dependency at one year. Therefore, option A is correct. Age >60 years was an
independent predictor of death at one year but was not significantly predictive of dialysis dependency at
one year, although there was a trend toward worse renal prognosis in subjects aged >60 years (option
B is incorrect). Crescent percentage >75% trended toward decreased renal survival but was not a
statistically significant predictor of dialysis dependency at 12 months (option C is incorrect). Thirty eight
percent of subjects in this analysis did not require chronic renal replacement therapy at 12 months.
Similarly, a retrospective analysis of 123 patients from six centers worldwide by van Daalen et al.
demonstrated a 5-year kidney survival rate of 34%.
• Huart A, Josse AG, Chauveau D, Korach JM, Heshmati F, Bauvin E, Cointault O, Kamar N,
Ribes D; Pourrat J, Faguer S, French Society of H: Outcomes of patients with Goodpasture
syndrome: A nationwide cohort-based study from the French Society of Hemapheresis. J
Autoimmun 73: 24-29, 2016
• van Daalen EE, Jennette JC, McAdoo SP, Pusey CD, Alba MA, Poulton CJ, Wolterbeek R,
Nguyen TQ, Goldschmeding R, Alchi B, Griffiths M, de Zoysa JR, Vincent B, Bruijn JA, Bajema
IM: Predicting outcome in patients with anti-GBM glomerulonephritis. Clin J Am Soc Nephrol 13:
63-72, 2018

NSAP Secondary GN Answers and Explanations-September 2018: Page 18 of 25

Question 22
Answer B: Begin enzyme replacement therapy now
Educational objective: Manage Fabry disease
Nowak and coworkers modeled disease progression to evaluate the impact of enzyme replacement
therapy with agalsidase-β in 98 individuals (62% female) with genetically verified Fabry disease. Renal
events preceding enzyme replacement therapy were a significant risk factor for new renal end points.
Subjects with an eGFR >75 ml/min per 1.73 m2 had superior long-term outcomes in this analysis. The
findings of this analysis support implementation of enzyme replacement therapy early in the course of
disease in individuals with evidence of renal disease. This woman had significant proteinuria,
neurologic symptoms, and cardiac manifestations that warrant initiation of agalsidase-β therapy now.
Therefore, option B is correct, and options A, C and D are incorrect.
• Nowak A, Koch G, Huynh-Do U, Siegenthaler M, Marti HP; Pfister M: Disease Progression
Modeling to Evaluate the Effects of Enzyme Replacement Therapy on Kidney Function in Adult
Patients with the Classic Phenotype of Fabry Disease. Kidney Blood Press Res 42: 1-15, 2017
• Desnick RJ, Brady R, Barranger J, Collins AJ, Germain DP, Goldman M, Grabowski G,
Packman S, Wilcox WR: Fabry disease, an under-recognized multisystemic disorder: expert
recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern
Med 138: 338-346, 2003

Question 23
Answer C: COL4 (type IV chain of collagen)
Educational objective: Know that heterozygous mutations of type IV glomerular basement
membrane collagen may masquerade as FSGS
Papazachariou and colleagues analyzed the frequency of mutations in patients of 234 members of 24
families from Greece with familial microscopic hematuria. Heterozygous mutations in COL4A3/A4 were
found in 42 individuals from 12 families, five of which developed ESRD. Kidney biopsies revealed focal
and segmental glomerulosclerosis (FSGS) on light microscopy and thin basement membrane on
electron microscopy. These cases demonstrate the possibility of misdiagnosis of “later onset Alport
syndrome” as primary FSGS in the absence of genetic analysis, particularly when there is limited or no
tissue available for electron microscopy. This man’s family history, clinical manifestations, and biopsy
findings are most consistent with later-onset Alport syndrome due to heterozygous mutations in
COL4A3/A4 rather than familial FSGS. Therefore, option C is correct. Mutations in the genes noted in
the other distractors are associated with familial FSGS and would not be associated with thin basement
membranes on electron microscopy or familial microhematuria (options A, C, and D are incorrect).

NSAP Secondary GN Answers and Explanations-September 2018: Page 19 of 25

 • Papazachariou L, Papagregoriou G, Hadjipanagi D, Demosthenous P, Voskarides K, Koutsofti
C, Stylianou K, Ioannou P, Xydakis D, Tzanakis I, Papadaki A, Kallivretakis N, Nikolakakis N,
Perysinaki G, Gale DP, Diamantopoulos A, Goudas P, Goumenos D, Soloukides A, Boletis I,
Melexopoulou C, Georgaki E, Frysira E, Komianou F, Grekas D, Paliouras C, Alivanis P,
Vergoulas G, Pierides A, Daphnis E, Deltas C: Frequent COL4 mutations in familial
microhematuria accompanied by later-onset Alport nephropathy due to focal segmental
glomerulosclerosis. Clin Genet 92: 517-552, 2017

Question 24
Answer D: Antiviral therapy, rituximab or cyclophosphamide, plus plasmapheresis
Educational objective: Manage mixed cryoglobulinemia manifesting with rapidly progressive
glomerulonephritis and other end-organ injury
This man has severe manifestations of type II mixed cryoglobulinemia consequent to hepatitis C virus
infection that include digital necrosis and rapidly progressive glomerulonephritis requiring dialysis. The
Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Glomerulonephritis
recommends intravenous methylprednisolone, plasmapheresis, rituximab or cyclophosphamide, and
antiviral therapy for rapidly progressive life-threatening disease in patients with type II mixed
cryoglobulinemia consequent to hepatitis C virus. The value of rituximab in treating patients with mixed
cryoglobulinemia and severe manifestations was shown in a multicentered trial of 59 patients by De
Vita et al. In this study, significantly more patients treated with rituximab had treatment success at one
year compared with conventional therapy. The KDIGO Workgroup acknowledged that the evidence
supporting this approach was of low quality and that further randomized controls trials are needed.
However, available evidence indicates that an aggressive approach is warranted when there is life
threatening end-organ injury as noted in this man. Therefore, option D is the best answer and is favored
over the other options. There is accumulating data supporting the use of concomitant antiviral therapy
for the treatment of hepatitis C virus-associated cryoglobulinemia. The VASCUVALDIC Study found an
88% complete remission rate in hepatitis C virus-associated cryoglobulinemia in subjects treated with
sofosbuvir and ribavirin. Notably, 30% of the patients in this study received immunosuppression with
rituximab, corticosteroids, and plasmapheresis. More recently, Sise et al. reported achievement of
sustained virologic response in 10 of 12 patients treated with sofosbuvir plus ribavirin or sofosbuvir plus
simeprevir, strengthening support for inclusion of antiviral therapy in hepatitis C virus-associated
cryoglobulinemia. Of the seven patients with glomerulonephritis (six of whom received treatment with
rituximab, corticosteroids, and plasmapheresis), five had improvement or stabilization of kidney
function.

NSAP Secondary GN Answers and Explanations-September 2018: Page 20 of 25

 • Ramos-Casals M, Stone JH, Cid MC, Bosch X: The cryoglobulinemias. Lancet 379: 348-360,
2012
• Sise ME, Bloom AK, Wisocky J, Lin MV, Gustafson JL, Lundquist AL, Steele D, Thiim M,
Williams WW, Hashemi N, Kim AY, Thadhani R, Chung RT: Treatment of hepatitis C virus-
associated mixed cryoglobulinemia with sofosbuvir-based direct-acting antiviral agents.
Hepatology 63: 408–417, 2016
• Saadoun D, Thibault V, Si Ahmed SN, Alric L, Mallet M, Guillaud C, Izzedine H, Plaisier A,
Fontaine H, Costopoulos M, Le Garff-Tavernier M, Hezode C, Pol S, Musset L, Poynard T,
Cacoub P: Sofosbuvir plus ribavirin for hepatitis C virus-associated cryoglobulinemia vasculitis:
VASCUVALDIC study. Ann Rheum Dis 75: 1777-1782, 2016
• Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO
Clinical Practice Guideline for Glomerulonephritis. Kidney Inter Suppl 2: 200–203, 2012
• Kidney Disease: Improving Global Outcomes. KDIGO clinical practice guidelines for the
prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney
Int Suppl 2008: S1–S99
• De Vita S, Quartuccio L, Isola M, Mazzaro C, Scaini P, Lenzi M, Campanini M, Naclerio C,
Tavoni A, Pietrogrande M, Ferri C, Mascia MT, Masolini P, Zabotti A, Maset M, Roccatello D,
Zignego AL, Pioltelli P, Gabrielli A, Filippini D, Perrella O, Migliaresi S, Galli M, Bombardieri S,
Monti G: A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic
vasculitis. Arthritis Rheum 64: 843-853, 2012

Question 25 lamividin,sedofovir,entecavir Rx HBV

Answer B: Entecavir
Educational objective: Manage membranous glomerulonephritis due to hepatitis B virus
infection
This man with hepatitis B-related membranous nephropathy has cirrhosis with portal hypertension.
Nucleoside analogues are preferred over pegylated-interferon in patients with cirrhosis and portal
hypertension because interferon-based therapy is associated with an increased risk of infection and
hepatic dysfunction. Therefore, entecavir is the best management options for this man (option B is
correct, and options A and D are incorrect). Antiviral therapy is favored over immunosuppressive
therapy for patients with hepatitis B-related membranous nephropathy in the absence of rapidly
progressive glomerulonephritis. Furthermore, rituximab is contraindicated in patient with hepatitis B
virus infection. Hence, option C is incorrect.

NSAP Secondary GN Answers and Explanations-September 2018: Page 21 of 25

 • Wang WN, Wu MY, Ma FZ, Sun T, Xu ZG: Meta-analysis of the efficacy and safety of
nucleotide/nucleoside analog monotherapy for hepatitis B virus-associated glomerulonephritis.
Clin Nephrol 85: 21-29, 2016
• Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH; American Association
for the Study of Liver Diseases: AASLD guidelines for treatment of chronic hepatitis B.
Hepatology 63: 261-283, 2016

Question 26
Answer D: Cyclophosphamide plus corticosteroids
Educational objective: Manage persistent glomerulonephritis in the setting of endocarditis
The differential diagnosis of this immune complex glomerulonephritis (GN) is the endocarditis itself, an
independent autoimmune process triggered by the infection, or two independent processes (infection
and an unrelated autoimmune disease). The key to management is to differentiate GN due to ongoing
infection from an autoimmune disease that is now active, for whatever reason, with no active infection.
For the former, ongoing supportive care with antibiotics is needed; for the latter control of the
autoimmune process with immunosuppression is needed. In this case, the persistent evidence of active
GN despite adequate treatment and resolution of infection favors the use of immunosuppression.
Therefore, option D is correct. Option A, to support and wait for resolution is risky given the activity of
the process. This woman does not have evidence of significant mitral valve dysfunction, heart failure,
paravalvular extension, annular abscess, heart block, persistent infection, recurrent systemic
embolization, and/or a vegetation >10 mm (plus one other indication) that would warrant valve
replacement. Therefore, option B is incorrect. Eculizumab would be an option if the biopsy was
consistent with C3 GN, which can also be seen in the setting of infection, but the biopsy findings are
most consistent with an immune complex GN (option C is incorrect).
• Marinozzi MC, Roumenina LT, Chauvet S, Hertig A, Bertrand D, Olagne J, Frimat M, Ulinski T,
Deschenes G, Burtey S, Delahousse M, Moulin B, Legendre C, Fremeaux-Bacchi V, Le
Quintrec M: Anti-Factor B and Anti-C3b Autoantibodies in C3 Glomerulopathy and Ig-Associated
Membranoproliferative GN. J Am Soc Nephrol 28: 1603-1613, 2017

Question 27
Answer C: Conduct further hematological investigation to search for a B cell clone
Educational objective: Evaluate and manage IgA-proliferative glomerulonephritis with
monoclonal immunoglobulin deposits
The findings of monotypic IgA deposits is most consistent with IgA-proliferative glomerulonephritis with
monoclonal immunoglobulin deposits (IgA-PGNMID). Therefore, initial management should focus on a

NSAP Secondary GN Answers and Explanations-September 2018: Page 22 of 25

search for an underlying B cell clone. Vignon et al. reported a series of 14 cases of IgA-PGNMID. The
authors noted that it is often difficult to distinguish between monotypic and polytypic IgA deposits
because polytypic IgA deposits are associated with lambda light chain deposits. The presence of kappa
light chain deposits should raise suspicion for IgA-PGNMID rather than IgA nephropathy.
Comprehensive hematologic and immunologic investigations are required to diagnose B-cell clones in
these patients. Routine serum protein immunofixation and electrophoresis identified monoclonal IgA
gammopathy in only 5 of 14 patients in this series. Use of serum immunoblot and bone marrow
molecular studies, however, uncovered an underlying small B-cell clone in 9 of the cases. Therefore,
option C is correct. Optimal therapy of IgA-PGNMID remains uncertain, but treatment of an underlying
B cell clone should be considered when present. Prednisone would be a consideration for polytypic IgA
nephropathy because of the persistent proteinuria >1 g per day despite adequate blood pressure
control on angiotensin blockade. However, this patient has monotypic IgA deposits that require further
hematologic investigation. Hence, option A is incorrect. It is too early to consider rituximab therapy
pending further hematologic and immunologic evaluation. For example, further studies could potentially
reveal IgA multiple myeloma that would require a proteosome-based regimen rather than rituximab.
Thus, option B is incorrect. Screening for celiac disease with testing for anti-tissue transglutaminase
antibody is reasonable for patients with polytypic IgA nephropathy with gastrointestinal symptoms and
not monotypic IgA deposits as noted in this patient. Hence, option D is incorrect.
• Vignon M, Cohen C, Faguer S, Noel LH, Guilbeau C, Rabant M, Higgins S, Hummel A, Hertig A,
Francois H, Lequintrec M, Vilaine E, Knebelmann B; Pourrat J, Chauveau D, Goujon JM,
Javaugue V, Touchard G, El Karoui K, Bridoux F: The clinicopathologic characteristics of kidney
diseases related to monotypic IgA deposits. Kidney Int 91: 720-728, 2017

Question 28
Answer C: Anti-B cell therapy with rituximab plus bendamustine
Educational objective: Treat monoclonal immunoglobulin deposition disease
Most cases of monoclonal immunoglobulin deposition disease are associated with plasma cell
disorders. However, B cell clones can also produce light chains and cause MIDD. In this case, a B cell
clone was identified on bone marrow biopsy and flow cytometry. Therefore, treatment should be
directed against the B cell clone, and option C is correct. A proteosome-based regimen would be
appropriate in cases of MIDD secondary to a plasma cell derived clone, which was not the case in this
woman; hence, option A is incorrect. Initial treatment should focus on eradicating the B cell clone rather
than autologous hematopoietic cell transplantation. Therefore, option B is incorrect. Use of
plasmapheresis has not been studied in MIDD and would not abrogate the B cell clone (option D is
incorrect).

NSAP Secondary GN Answers and Explanations-September 2018: Page 23 of 25

 • Kourelis TV, Nasr SH, Dispenzieri A, Kumar SK, Gertz MA, Fervenza FC, Buadi FK, Lacy MQ,
Erickson SB, Cosio FG, Kapoor P, Lust JA, Hayman SR, Rajkumar V, Zeldenrust SR, Russell
SJ, Dingli D, Lin Y, Gonsalves W, Lorenz EC, Zand L, Kyle RA, Leung N: Outcomes of patients
with renal monoclonal immunoglobulin deposition disease. Am J Hematol 91: 1123-1128, 2016

Question 29
Answer A: IgG4-related disease
Educational objective: Recognize ANCA-associated vasculitis/IgG4-related overlap syndrome
The finding of lymphoplasmacytic infiltrates surrounded by areas fibrosis is most consistent with
coexistent IgG4-related disease in this man with pauci-immune necrotizing glomerulonephritis
secondary to ANCA-associated vasculitis (option A is correct). Danlos et al. reported a series of 18
patients with ANCA-associated vasculitis and IgG4 overlap syndrome. Affected individuals had AAV
plus other manifestations of IgG4-related disease such as chronic periaortitis, prevertebral fibrosis,
orbital masses, and tubulointerstitial nephritis. Granulomatosis with polyangiitis was present in 78% of
patients, with 50% having positive PR3-ANCA. Sarcoidosis can cause lacrimal gland enlargement, but
would have different histopathology (i.e., noncaseating granulomas). Kikuchi disease most commonly
presents with fever and cervical lymphadenopathy, most commonly in young woman, and may be
associated with systemic lupus erythematosus. Lacrimal gland enlargement has been reported but is
infrequent. The diagnosis is usually made on lymph node biopsy, with characteristic necrosis and a
histiocytic cellular infiltrate. The lacrimal gland pathology is more consistent with IgG4-related disease
than Kikuchi disease; therefore, option C is incorrect. Cogan's syndrome is characterized by
vestibuloauditory dysfunction and interstitial keratitis. It may also be associated with concomitant aortitis
or large- or medium- to small-sized vessel vasculitis. Lacrimal gland involvement has not been
described. Cogan’s syndrome is unlikely in the absence of distinctive vestibuloauditory dysfunction
(option D is incorrect).
• Danlos FX, Rossi GM, Blockmans D, Emmi G, Kronbichler A, Durupt S, Maynard C, Luca L,
Garrouste C, Lioger B, Mourot-Cottet R, Dhote R, Arlet JB, Hanslik T, Rouvier P, Ebbo M;
Puechal X, Nochy D, Carlotti A, Mouthon L, Guillevin L, Vaglio A, Terrier B, French Vasculitis
Study G: Anti-neutrophil cytoplasmic antibody-associated vasculitides and IgG4-related disease:
A new overlap syndrome. Autoimmun Rev 16: 1036-1043, 2017
• Pepe F, Disma S, Teodoro C, Pepe P, Magro G: Kikuchi-Fujimoto disease: a clinicopathologic
update. Pathologica 108: 120-129, 2016
• Chavis PS, Fallata A, Al-Hussein H, Clunie D, Huaman A; Lacrimal gland involvement
in Kikuchi-Fujimoto disease. Orbit 17: 113-117, 1998

NSAP Secondary GN Answers and Explanations-September 2018: Page 24 of 25

 • Durtette C, Hachulla E, Resche-Rigon M, Papo T, Zénone T, Lioger B, Deligny C, Lambert M,
Landron C, Pouchot J, Kahn JE, Lavigne C, De Wazieres B, Dhote R, Gondran G, Pertuiset E,
Quemeneur T, Hamidou M, Sève P, Le Gallou T, Grasland A, Hatron PY, Fain O, Mekinian A;
SNFMI and CRI: Cogan syndrome: Characteristics, outcome and treatment in a French
nationwide retrospective study and literature review. Autoimmun Rev 16: 1219-1223, 2017

Question 30
Answer C: Further evaluation should include testing for hepatitis C virus infection
Educational objective: Counsel a patient with fibrillary glomerulonephritis
Payan-Schober and coworkers reviewed the clinicopathological features of fibrillary glomerulonephritis
in a series of 42 patients between 1985 and 2015. Hepatitis C virus infection was found in 7 of 26
patients who underwent serologic testing, all of whom were black. Therefore, testing for hepatitis C is
indicated, and option C is correct. 12% of patients had a solid tumor (option A is incorrect). Of the 9
patients treated with rituximab, only 11% stabilized, 56% had progressive CKD, one-third developed
ESRD (option B is incorrect). Two patients in this series underwent transplant without recurrence
(option D is incorrect).
• Payan-Schober F, Jobson MA, Poulton CJ, Singh HK, Nickeleit V, Falk RJ, Jennette JC,
Nachman PH; Pendergraft III WF: Clinical Features and Outcomes of a Racially Diverse
Population with Fibrillary Glomerulonephritis. Am J Nephrol 45: 248-256, 2017

NSAP Secondary GN Answers and Explanations-September 2018: Page 25 of 25