NephSAP Volume 18, Number 1, March 2019

Primary Glomerular Diseases

Answers and Explanations

Question 1
Answer A: Cystoscopy and computed tomographic urogram if the cystoscopy is normal
Educational objective: Evaluate microscopic hematuria
This patient has low grade, persistent microscopic hematuria. A urine sediment examination reveals
moderate dysmorphism of erythrocytes, which might suggest a glomerular source. However, risk
factors for bladder cancer are present (age, smoking). Nearly 100% of erythrocytes excreted in
normal urine are dysmorphic. The addition of normo-morphic red cells (e.g., from a bladder source)
will result in an admixture of dysmorphic and normo-morphic red blood cells as observed here. The
most appropriate step is to exclude a bladder or upper urinary tract lesion with cystoscopy and CT
urography (especially if the cystoscopy is negative). While the percentage of dysmorphic
erythrocytes in a urine sediment can be useful in evaluating the probability of a glomerular source,
care must be taken to exclude urinary tract pathology in patients with very low grade microscopic
hematuria and borderline urine erythrocyte dysmorphism, especially in patients at increased risk for
neoplasia. A 24-hour urine for albumin would add little to the evaluation since the patient’s
albuminuria has already been quantified with three measurements of the urine albumin/creatinine
ratio (option B is incorrect). The most important next step in this patient’s evaluation is to exclude a
urologic malignancy. Therefore, the urologic workup should be performed before embarking on
serologic studies in this man without compelling evidence of lupus or underlying monoclonal
paraproteinemia (options C and D are incorrect).
• Koo KC, Lee KS, Choi AR, Rha KH, Hong SJ, Chung BH: Diagnostic impact of dysmorphic
red blood cells on evaluating microscopic hematuria: the urologist's perspective. Int Urol
Nephrol 48(7):1021-7, 2016
• Hamadah AM, Gharaibeh K, Mara KC, Thompson KA, Lieske JC, Said S, Nasr SH, Leung
N: Urinalysis for the diagnosis of glomerulonephritis: role of dysmorphic red blood cells.
Nephrol Dial Transplant 2017
• Birch DF, Fairley KF, Whitworth JA, Forbes I, Fairley JK, Cheshire GR, Ryan GB: Urinary
erythrocyte morphology in the diagnosis of glomerular hematuria. Clin Nephrol 20(2):78-84,
1983

Question 2
Answer B: Glomerular hypertrophy
Educational objective: Recognize the morphologic features of low nephron endowment

NephSAP Primary Glomerular Diseases Answers, V 18, N1, March 2019: Page 1 of 17
The combination of low glomerular density and marked glomerular enlargement is a feature that
strongly suggests the presence of low birth nephron endowment in kidney biopsies performed in
children with minimal change disease or focal segmental glomerulosclerosis. Hence, option B is
correct. The other options do not provide any useful information on nephron endowment at birth
(options A, C, and D are incorrect).
• Koike K, Ikezumi Y, Tsuboi N, Kanzaki G, Haruhara K, Okabayashi Y, Sasaki T, Ogura M,
Saitoh A, Yokoo T: Glomerular Density and Volume in Renal Biopsy Specimens of Children
with Proteinuria Relative to Preterm Birth and Gestational Age. Clin J Am Soc Nephrol
12(4):585-590, 2017

Question 3
Answer D: Start empiric therapy with oral corticosteroids
Educational objective: Manage steroid-responsive minimal change disease with infrequent
relapses
This patient has a clinical course highly indicative of steroid–responsive nephrotic syndrome due to
underlying minimal change disease, with infrequent relapses. The patient should be retreated with
corticosteroids (option D is correct). There is no indication of steroid resistance that might justify a
search for a genetic mutation; thus, option A is incorrect. In the absence of evidence of steroid
resistance, there is no indication to employ calcineurin inhibitor therapy (option B is incorrect) or to
perform a repeat kidney biopsy (option C is incorrect).
• Vivarelli M, Massella L, Ruggiero B, Emma F: Minimal Change Disease. Clin J Am Soc
Nephrol 12(2):332-345, 2017
• KDIGO Clinical Practice Guidelines for Glomerulonephritis. Kidney Int Suppl 2:163-171;177-
180, 2012

Question 4 sclerotic positve IgM,C3 ,C1q

Answer A: Perform genetic testing for a podocytopathy
Educational objective: Evaluate steroid-resistant focal and segmental glomerulosclerosis
This patient a steroid-resistant form of focal and segmental glomerulosclerosis (FSGS) (not
otherwise specified [NOS] variant). The IgM and C3 deposition implies an unfavorable prognosis. A
search for a genetic mutation is the next most appropriate step in this patient’s evaluation because it
may help to guide future treatment and help predict the risk of recurrence of the disease following
kidney transplantation. Therefore, option A is correct. The lack of African-American ancestry makes
APOL1 risk alleles less likely, albeit not impossible. Determination of APOL1 risk status is unlikely to
alter management at this point; hence, option B is less attractive. Lymphoma would be a very rare
cause of an FSGS lesion at this age (option C is incorrect). There is no proven value for B7-1
(CD80) staining of renal biopsies in FSGS lesions (option D is incorrect).

NephSAP Primary Glomerular Diseases Answers, V 18, N1, March 2019: Page 2 of 17
 • De Vriese AS, Sethi S, Nath KA, Glassock RJ, Fervenza FC: Differentiating Primary,
Genetic, and Secondary FSGS in Adults: A Clinicopathologic Approach. J Am Soc Nephrol
29(3):759-774, 2018
• Hommos MS, De Vriese AS, Alexander MP, Sethi S, Vaughan L, Zand L, Bharucha K,
Lepori N, Rule AD, Fervenza FC: The Incidence of Primary vs Secondary Focal Segmental
Glomerulosclerosis: A Clinicopathologic Study. Mayo Clin Proc 92(12):1772-1781, 2017
• Zand L, Glassock RJ, De Vriese AS, Sethi S, Fervenza FC: What are we missing in the
clinical trials of focal segmental glomerulosclerosis? Nephrol Dial Transplant 32(Suppl 1):
i14-i21, 2017
• 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(12):795-804, 2017
• Novelli R, Gagliardini E, Ruggiero B, Benigni A, Remuzzi G: Any value of podocyte B7-1 as
a biomarker in human MCD and FSGS? Am J Physiol Renal Physiol 310(5): F335-41, 2016

Question 5
Answer C: Anti-thrombospondin 7A staining of the renal biopsy specimen
Educational objective: Evaluate membranous nephropathy
Although it is uncommon, primary membranous nephropathy due to anti-thrombospondin type-1
domain-containing 7A (THSD7A) auto-antibodies characteristically shows IgG4 dominant IgG
deposition and negative serum anti-phospholipase A2 receptor (PLA2R) auto-antibodies plus
negative PLA2R antigen staining in glomeruli. Hence, option C is correct. These patients may have
a high risk of underlying cancer (60%). A search for C3/C4 depression would not likely be helpful in
the absence of clinical evidence of systemic lupus erythematosus (option A is incorrect). The
absence of mesangial deposits tends to exclude lupus nephritis; hence, there is no need to
measure anti-nuclear antibody or anti-double stranded DNA antibody in light of the biopsy findings
(option B is incorrect). Monoclonal Ig deposition disease is highly unlikely based on the morphologic
features of the biopsy (option D is incorrect).
• Hoxha E, Beck LH Jr, Wiech T, Tomas NM, Probst C, Mindorf S, Meyer-Schwesinger C,
Zahner G, Stahl PR, Schöpper R, Panzer U, Harendza S, Helmchen U, Salant DJ, Stahl RA:
An Indirect Immunofluorescence Method Facilitates Detection of -Specific Antibodies in
Membranous Nephropathy. J Am Soc Nephrol 28(2):520-531, 2017
• De Vriese AS, Glassock RJ, Nath KA, Sethi S, Fervenza FC: A Proposal for a Serology-
Based Approach to Membranous Nephropathy. J Am Soc Nephrol 28(2):421-430, 2017

ba pee comprehensive
Question 6
Answer E: Observe with renin-angiotensin inhibition therapy only

NephSAP Primary Glomerular Diseases Answers, V 18, N1, March 2019: Page 3 of 17
Educational objective: Manage membranous nephropathy
This patient has all the characteristics of primary membranous nephropathy due to the presence of
anti-phospholipase A2 receptor (PLA2R) antibody, but with a low-titer of anbti-PLA2R antibody at
presentation. The relatively low titer of anti-PLA2R antibody indicates a reasonable probability of a
spontaneous remission (>50%) in the next few months. Hence, a conservative approach to
treatment is indicated in the absence of severe nephrotic syndrome or progressive loss of renal
function. Thus, option E is correct and option B, C and D are incorrect. Age appropriate cancer
screening is always indicated, but this patient’s age and absence of any other compelling clinical
information that would warrant an evaluation for an underlying malignancy is lacking (option A is
incorrect).
• De Vriese AS, Glassock RJ, Nath KA, Sethi S, Fervenza FC: A Proposal for a Serology-
Based Approach to Membranous Nephropathy. J Am Soc Nephrol 28(2):421-430, 2017

Question 7
Answer B: Combinations of rituximab with low-dose cyclophosphamide can achieve very
high remission rates
Educational objective: Cite evidence regarding the use of rituximab for the treatment of
membranous glomerulopathy
Recent observational data has suggested marked efficacy of combinations of rituximab and low-
dose cyclophosphamide. Therefore, option B is correct. Rituximab monotherapy is a valuable agent
in the treatment of primary membranous nephropathy, even for patients who have failed to respond
to other treatment regimens (option A is incorrect). Cravedi and co-workers compared the outcomes
of a B cell-driven rituximab treatment with the standard four-dose 375 mg/m2 regimen of rituximab.
Patients allocated to the B cell-driven protocol only received a second dose of rituximab only if they
had >5 B cells per mm3 in the peripheral blood after the first 375 mg/m2 dose. Both groups achieved
a similar reduction in proteinuria. Thus, option C is incorrect. Concurrent corticosteroid therapy is
not required for rituximab to be effective; hence, option D is incorrect.
• Ruggenenti P, Fervenza FC, Remuzzi G: Treatment of membranous nephropathy: time for a
paradigm shift. Nat Rev Nephrol 13(9):563-579, 2017
• Roccatello D, Sciascia S, Di Simone D, Solfietti L, Naretto C, Fenoglio R, Baldovino S,
Menegatti E: New insights into immune mechanisms underlying response to rituximab in
patients with membranous nephropathy: A prospective study and a review of the literature.
Autoimmun Rev 15(6):529-38, 2016
• Cortazar FB, Leaf DE, Owens CT, Laliberte K, Pendergraft WF 3rd, Niles JL: Combination
therapy with rituximab, low-dose cyclophosphamide, and prednisone for idiopathic
membranous nephropathy: a case series. BMC Nephrol 18(1):44, 2017

NephSAP Primary Glomerular Diseases Answers, V 18, N1, March 2019: Page 4 of 17
 • Cravedi P, Ruggenenti P, Sghirlanzoni MC, Remuzzi G: Titrating rituximab to circulating
B cells to optimize lymphocytolytic therapy in idiopathic membranous nephropathy. Clin
J Am Soc Nephrol 2, 932–937, 2007

C2 cresent
Question 8
Answer D: Treatment with high-dose steroids, cyclophosphamide, and plasmapheresis
Educational objective: Choose the best treatment strategy for rapidly progressive crescentic
IgA nephropathy
This patient has crescentic IgA Nephropathy with rapidly progressive renal disease. While no RCTs
have been performed, observational data suggests efficacy for an aggressive combined
immunosuppressive approach, including therapeutic apheresis. Therefore, option D is correct, and
the other listed options are incorrect.
• Xie X, Lv J, Shi S, Zhu L, Liu L, Chen M, Wang Y, Cui Z, Wang X, Liu L, Yu X, Zhou F, Zhao
MH, Zhang H: Plasma exchange as an adjunctive therapy for crescentic IgA nephropathy.
Am J Nephrol 44(2):141-9, 2016

Question 9
Answer E: Increased serum C3 and normal C4 levels
Educational objective: Correctly identify factors that do and do not predict a worse
prognosis of IgA nephropathy
In patients with IgA Nephropathy, extensive C4d deposition in the mesangium, persistent
microscopic hematuria, low birth weight, and a low glomerular density on renal biopsy are all
associated with a poor prognosis. Increased C4 and reduced C3, not increased serum C3 and
normal C4 levels as indicated in option E, in patients with IgA nephropathy also may be associated
with a poor prognosis. Therefore, option E is the correct answer to the question because the other
options indicate factors that portend a less favorable prognosis (options A, B, C, and D are
incorrect).
• Rath A, Tewari R, Mendonca S, Badwal S, Nijhawan VS: Oxford classification of IgA
nephropathy and C4d deposition; correlation and its implication. J Nephropharmacol 5(2):75-
79, 2015
• Sevillano AM, Gutiérrez E, Yuste C, Cavero T, Mérida E, Rodríguez P, García A, Morales E,
Fernández C, Martínez MA, Moreno JA, Praga M: Remission of Hematuria Improves Renal
Survival in IgA Nephropathy. J Am Soc Nephrol 28(10):3089-3099, 2017
• Coppo R, Fervenza FC: Persistent Microscopic Hematuria as a Risk Factor for Progression
of IgA Nephropathy: New Floodlight on a Nearly Forgotten Biomarker. J Am Soc Nephrol
28(10):2831-2834, 2017

NephSAP Primary Glomerular Diseases Answers, V 18, N1, March 2019: Page 5 of 17
 • Ruggajo P, Svarstad E, Leh S, Marti HP, Reisæther AV, Vikse BE: Low Birth Weight and
Risk of Progression to End Stage Renal Disease in IgA Nephropathy--A Retrospective
Registry-Based Cohort Study. PLoS One 11(4): e0153819, 2016
• Chen ZJ, Li H, Cai JF, Zhang X, Li C, Zou PM, Li MX, Chen LM, Li XM, Li XW, Wen YB: The
Neglected Significance of Glomerular Density as a 5-year Progression Indicator for IgA
Nephropathy. Chin Med Sci J 32(3):145-151, 2017
• Pan M, Zhang J, Li Z, Jin L, Zheng Y, Zhou Z, Zhen S, Lu G: Increased C4 and decreased
C3 levels are associated with a poor prognosis in patients with immunoglobulin A
nephropathy: a retrospective study. BMC Nephrol 18(1):231, 2017

Question 10
Answer B: A posttransplant regimen consisting of tacrolimus, MMF, and early corticosteroid
withdrawal
Educational objective: Recognize that early withdrawal of corticosteroids increases the risk
of recurrent IgA nephropathy following kidney transplantation
The early withdrawal of steroids post-transplantation is predictive of an increased risk of recurrence
of IgA nephropathy in a renal allograft. Therefore, option B is the correct answer, and option A is
incorrect. The presence of crescents in the native kidney biopsy also predicts the risk of recurrent
IgA nephropathy following kidney transplantation. Hence, option C is incorrect. Serum IgA levels are
of no utility to predict recurrence (option D is incorrect).
• Avasare RS, Rosenstiel PE, Zaky Z, Tsapepas DS, Appel GB, Markowitz GS, Bomback AS,
Canetta PA: Predicting Post-Transplant Recurrence of IgA Nephropathy: The Importance of
Crescents. Am J Nephrol 45(2):99-106, 2017
• Leeaphorn N, Garg N, Khankin EV, Cardarelli F, Pavlakis M: Recurrence of IgA nephropathy
after kidney transplantation in steroid continuation versus early steroid-withdrawal regimens:
a retrospective analysis of the UNOS/OPTN database. Transpl Int 31(2):175-186, 2018

Question 11
Answer C: Serum free light chains and immunofixation
Educational objective: Evaluate C3 glomerulonephritis in an older adult
This older adult patient has a lesion of C3 glomerulonephritis. In this age–group, an underlying
monoclonal immunoglobulin-related disease (C3 glomerulonephritis with masked monoclonal
deposits) that results in activation of the alternative complement pathway must be suspected and
measurement of serum free light chains with serum immunofixation is the best approach to screen
for this entity. Hence, option C is correct. Genetic analysis, soluble C5b-C9 serum levels, and C3
nephritic factor testing will not likely be useful for diagnosis (options A, B and D are incorrect).
Lupus nephritis is not suspected. Therefore, serologic testing for anti-nuclear antibody or anti-
double stranded DNA antibody is unlikely to be helpful (option E is incorrect).

NephSAP Primary Glomerular Diseases Answers, V 18, N1, March 2019: Page 6 of 17
 • Doshi M, Lahoti A, Danesh FR, Batuman V, Sanders PW; American Society of Nephrology
Onco-Nephrology Forum: Paraprotein-related kidney disease: kidney injury from
paraproteins-what determines the site of injury? Clin J Am Soc Nephrol 11(12):2288-2294,
2016
• Lloyd IE, Gallan A, Huston HK, Raphael KL, Miller DV, Revelo MP, Khalighi MA: C3
glomerulopathy in adults: a distinct patient subset showing frequent association with
monoclonal gammopathy and poor renal outcome. Clin Kidney J 9(6):794-799, 2016
Question 12
Answer D: Stain biopsy specimen for DNAJB9 deposition
Educational objective: Recognize DNAJB9 as a specific immunohistochemical marker for
fibrillary glomerulonephritis
This patient has several clinical characteristics compatible with a diagnosis of fibrillary
glomerulonephritis, but electron microscopy is unavailable. Staining for DNAJB9 deposits is highly
sensitive and specific for this diagnosis. None of the other tests will have this high degree of
precision. Hence, option D is correct, and options A, B, C and E are incorrect. Anti-PLA2R staining
is not indicated in a non-membranous nephropathy glomerular lesion. C4d deposition is highly
variable in fibrillary GN. Fibrillary GN lesions can be Congo red negative or positive.
• Nasr SH, Vrana JA, Dasari S, Bridoux F, Fidler ME, Kaaki S, Quellard N, Rinsant A, Goujon
JM, Sethi S, Fervenza FC, Cornell LD, Said SM, McPhail ED, Herrera Hernandez LP,
Grande JP, Hogan MC, Lieske JC, Leung N, Kurtin PJ, Alexander MP: DNAJB9 is a specific
immunohistochemical marker for fibrillary glomerulonephritis. Kidney Int Rep 3(1):56-64,
2017
• Dasari S, Alexander MP, Vrana JA, Theis JD, Mills JR, Negron V, Sethi S, Dispenzieri A,
Highsmith WE Jr, Nasr SH, Kurtin PJ: DnaJ Heat Shock Protein Family B Member 9 Is a
Novel Biomarker for Fibrillary GN. J Am Soc Nephrol 29(1):51-56, 2018
• Andeen NK, Yang HY, Dai DF, MacCoss MJ, Smith KD: DnaJ Homolog Subfamily B
Member 9 Is a Putative Autoantigen in Fibrillary GN. J Am Soc Nephrol 29(1):231-239, 2018

Question 13
Answer A: Presence of two APOL1 high-risk alleles
Educational objective: Recognize the presence of two high risk APOL1 alleles increases the
risk of collapsing focal and segmental glomerulosclerosis (FSGS) more than other variants
of FSGS
The possession of two high risk APOL1 alleles increases the risk of collapsing focal and segmental
glomerulosclerosis (FSGS). None of the other options reliably predict this kind of risk. Hyper-
expression of CD80 (B7-1) in podocytes has been described in several proteinuric conditions
including focal and segmental glomerulosclerosis, diabetic glomerulosclerosis, membranous
nephropathy, and minimal change glomerulopathy. Its presence does not distinguish between the

NephSAP Primary Glomerular Diseases Answers, V 18, N1, March 2019: Page 7 of 17
 IgM la NOS haya,

variants of FSGS. Hence, option B is incorrect. Nonspecific binding of IgM in the mesangium is
commonly seen in glomeruli of all variants of FSGS (option C is incorrect). Zhang and coworkers
found that patients with glomerular IgM and C3 deposition had worse renal outcomes. Collapsing
focal segmental glomerulosclerosis carries an increased risk of thrombotic microangiopathy,
whereas the risk of thrombotic microangiopathy is lower in other FSGS variants; therefore, option D
is incorrect.
• Raja R, Nada R, Yadav AK, Kumar A, Goyal A, Kumar V, Rathi M, Kohli HS, Gupta KL,
Sakhuja V, Jha V: A prospective study of collapsing focal segmental glomerulosclerosis.
Ren Fail 38(6):894-8, 2016
• Kopp JB, Winkler CA, Zhao X, Radeva MK, Gassman JJ, D'Agati VD, Nast CC, Wei C,
Reiser J, Guay-Woodford LM, Pollak MR, Hildebrandt F, Moxey-Mims M, Gipson DS,
Trachtman H, Friedman AL, Kaskel FJ; FSGS-CT Study Consortium: Clinical Features and
Histology of Apolipoprotein L1-Associated Nephropathy in the FSGS Clinical Trial. J Am
Soc Nephrol 26(6):1443-8, 2015
• Zhang YM, Gu QH, Huang J, Qu Z, Wang X, Meng LQ, Wang F, Liu G, Cui Z, Zhao MH:
Clinical Significance of IgM and C3 Glomerular Deposition in Primary Focal Segmental
Glomerulosclerosis. Clin J Am Soc Nephrol 11(9):1582-9, 2016
• Buob D, Decambron M, Gnemmi V, Frimat M, Hoffmann M, Azar R, Gheerbrant JD,
Guincestre T, Noël C, Copin MC, Glowacki F: Collapsing glomerulopathy is common in the
setting of thrombotic microangiopathy of the native kidney. Kidney Int 90(6):1321-1331,
2016

Question 14
Answer B: 6.6 per 100 patient years
Educational objective: Define the approximate risk of progression to kidney failure in a
patient with focal and segmental glomerulosclerosis
These values come directly from a landmark study of outcomes of focal and segmental
glomerulosclerosis (FSGS) lesions in the large cohort of 466 patients with presumed primary FSGS.
Option B is correct, and options A, C, D and E are incorrect.
• Troost JP, Trachtman H, Nachman PH, Kretzler M, Spino C, Komers R, Tuller S, Perumal K,
Massengill SF, Kamil ES, Oh G, Selewski DT, Gipson P, Gipson DS: An Outcomes-Based
Definition of Proteinuria Remission in Focal Segmental Glomerulosclerosis. Clin J Am Soc
Nephrol 13(3):414-421, 2018

Question 15
Answer E: His age

NephSAP Primary Glomerular Diseases Answers, V 18, N1, March 2019: Page 8 of 17
Educational objective: Recognize that disease onset at a young age is the most important
factor in determining whether a patient may have an underlying genetic cause of steroid-
unresponsive FSGS
The most important determinant of a likely genetic cause of steroid-unresponsive FSGS is the age
of the patient. The other options are weak or unhelpful determinants of this risk. Therefore, option E
is correct, and options A through D are incorrect.
• Preston R, Stuart HM, Lennon R: Genetic testing in steroid-resistant nephrotic syndrome:
why, who, when and how? Pediatr Nephrol 34(2):195-210, 2019
• De Vriese AS, Sethi S, Nath KA, Glassock RJ, Fervenza FC: Differentiating primary, genetic,
and secondary FSGS in adults: A clinicopathologic approach. J Am Soc Nephrol 29(3):759-
774, 2018

Question 16
Answer B: Information on his birth weight will be of value in determining his prognosis
Educational objective: Discern that low birth weight and low nephron endowment is an
important risk factor for progression of focal and segmental glomerulosclerosis
It has been known for some time that low birth weight (and nephron under-endowment) is a risk
factor for progressive focal and segmental glomerulosclerosis (FSGS) (option B is correct).
Possession of two high risk alleles of APOL1 increases the risk of collapsing FSGS but does not
influence the likelihood of a response to treatment (option A is incorrect). Laurin et al. found that the
overall renal survival was similar in patients with collapsing FSGS compared with patients with
FSGS, not otherwise specified, after controlling for exposure to immunosuppressive therapy (option
C is incorrect). FSGS carries a high risk thrombotic microangiopathy (option D is incorrect).
• Hodgin JB, Rasoulpour M, Markowitz GS, D'Agati VD: Very low birth weight is a risk factor
for secondary focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 4(1):71-6, 2009
• Buob D, Decambron M, Gnemmi V, Frimat M, Hoffmann M, Azar R, Gheerbrant JD,
Guincestre T, Noël C, Copin MC, Glowacki F: Collapsing glomerulopathy is common in the
setting of thrombotic microangiopathy of the native kidney. Kidney Int 90(6):1321-1331, 2016
• Parsa A, Kao WH, Xie D, Astor BC, Li M, Hsu CY, Feldman HI, Parekh RS, Kusek
JW, Greene TH, Fink JC, Anderson AH, Choi MJ, Wright JT Jr, Lash JP, Freedman BI, Ojo
A, Winkler CA, Raj DS, Kopp JB, He J, Jensvold NG, Tao K, Lipkowitz MS, Appel LJ; AASK
Study Investigators; CRIC Study Investigators: APOL1 risk variants, race, and progression of
chronic kidney disease. N Engl J Med 369(23):2183-96, 2013
• Heymann J, Winkler CA, Hoek M, Susztak K, Kopp JB: Therapeutics for APOL1
nephropathies: putting out the fire in the podocyte. Nephrol Dial Transplant 32(Suppl 1): i65-
i70, 2017

NephSAP Primary Glomerular Diseases Answers, V 18, N1, March 2019: Page 9 of 17
• Laurin LP, Gasim AM, Derebail VK, McGregor JG, Kidd JM, Hogan SL, Poulton CJ, Detwiler
RK, Jennette JC, Falk RJ, Nachman PH: Renal Survival in Patients with Collapsing
Compared with Not Otherwise Specified FSGS. Clin J Am Soc Nephrol 11:1752-1759, 2016

NephSAP Primary Glomerular Diseases Answers, V 18, N1, March 2019: Page 10 of 17
Question 17
Answer A: Serum anti−PLA2R antibody negative and PLA2R1 antigen positive in glomeruli
Educational objective: Know that the absence of anti-PLA2R antibody in the serum and
positive histologic PLA2R antigen staining in membranous nephropathy with normal kidney
function is a reliable indicator of remission at 6 months
Absence of anti-PLA2R antibody in the serum with a positive PLA2R antigen stain in a renal biopsy
of a patient with membranous nephropathy (and normal renal function) is a reliable indicator of the
likelihood of a remission at some time in the next 6 months. Therefore, option A is correct, and the
other listed options are incorrect.
• De Vriese AS, Glassock RJ, Nath KA, Sethi S, Fervenza FC: A Proposal for a Serology-
Based Approach to Membranous Nephropathy. J Am Soc Nephrol 28(2):421-430, 2017
• Timmermans SA, Abdul Hamid MA, Cohen Tervaert JW, Damoiseaux JG, van Paassen P;
Limburg Renal Registry: Anti-PLA2R antibodies as a prognostic factor in PLA2R-related
membranous nephropathy. Am J Nephrol 42(1):70-7, 2015

Question 18
Answer C: Rituximab therapy would likely offer better prospects for long-term control of her
disease
Educational objective: Know that rituximab is emerging as a preferred agent for long-term
control of relapses in minimal change disease
Rituximab is emerging as a preferred agent for long-term control of relapses in minimal change
disease. Therefore, option C is correct. While both mycophenolate mofetil and tacrolimus are
effective in inducing remissions in frequently relapsing steroid-dependent minimal change disease,
relapses are very common when treatment is discontinued. Nephrotoxicity is a concern with long-
term tacrolimus therapy. Hence, option A and B are incorrect. The risk of ESRD remains low in
steroid-sensitive MCD (option D is incorrect).
• Dehoux L, Hogan J, Dossier C, Fila M, Niel O, Maisin A, Macher MA, Kwon T, Baudouin V,
Deschênes G: Mycophenolate mofetil in steroid-dependent idiopathic nephrotic syndrome.
Pediatr Nephrol 31(11):2095-101, 2016
• Sandoval D, Poveda R, Draibe J, Pérez-Oller L, Díaz M, Ballarín J, Saurina A, Marco H,
Bonet J, Barros X, Fulladosa X, Torras J, Cruzado JM: Efficacy of mycophenolate treatment
in adults with steroid-dependent/frequently relapsing idiopathic nephrotic syndrome. Clin
Kidney J 10(5):632-638, 2017
• Papakrivopoulou E, Shendi AM, Salama AD, Khosravi M, Connolly JO, Trompeter R:
Effective treatment with rituximab for the maintenance of remission in frequently relapsing
minimal change disease. Nephrology (Carlton) 21(10):893-900, 2016

NephSAP Primary Glomerular Diseases Answers, V 18, N1, March 2019: Page 11 of 17
Question 19
Answer C: Magnitude of proteinuria tamayaz
Educational objective: Recognize clinical features that discriminate between diabetic
nephropathy and non-diabetic glomerular lesions
Non-diabetic glomerular lesions are commonly found in kidney biopsies of patients with type 2
diabetes mellitus and “atypical” presentations of nephrotic syndrome or chronic kidney disease. The
magnitude of proteinuria is not helpful in distinguishing those with or without superimposed non-
diabetic glomerular lesions. Therefore, option C is correct. A prolonged duration of diabetes mellitus
and the presence of proliferative retinopathy bespeak toward a diagnosis of diabetic kidney disease
more than the magnitude of proteinuria (options A and B are incorrect). The presence of glomerular
hematuria indicates the possibility of a superimposed proliferative glomerular lesion, although low
grade dysmorphic hematuria may be present in diabetic nephropathy, particularly in the presence of
mesangiolysis and capillary aneurysm formation. Dysmorphic hematuria more reliably distinguishes
non-diabetic glomerular lesions from diabetic kidney disease than the level of proteinuria. Hence,
option D is incorrect.
• Dong Z, Wang Y, Qiu Q, Zhang X, Zhang L, Wu J, Wei R, Zhu H, Cai G, Sun X, Chen X:
Clinical predictors differentiating non-diabetic renal diseases from diabetic nephropathy in a
large population of type 2 diabetes patients. Diabetes Res Clin Pract 121:112-118, 2016
• Lee YH, Kim KP, Kim YG, Moon JY, Jung SW, Park E, Kim JS, Jeong KH, Lee TW, Ihm CG,
Jo YI, Choi HY, Park HC, Lee SY, Yang DH, Yi JH, Han SW, Lee SH: Clinicopathological
features of diabetic and nondiabetic renal diseases in type 2 diabetic patients with nephrotic-
range proteinuria. Medicine 96: e8047, 2017

Question 20
Answer D: Normal with no abnormality seen
Educational objective: Know that most healthy live donors with “idiopathic (primary)
microscopic hematuria” who undergo a kidney biopsy have no pathologic abnormalities
In otherwise healthy live donors with “idiopathic (primary) microscopic hematuria” who undergo a
kidney biopsy, the most common finding is normal kidney (62%). Therefore, option D is correct. C3
glomerulopathy would be very rarely seen (option A is incorrect). IgA nephropathy is seen in 9%
(option B is incorrect) and thin basement membrane nephropathy is seen in 28% of biopsies in
healthy live donors with idiopathic (primary) microscopic hematuria (option C is incorrect).
• Hassan EA, Ali TZ, Abdulbaki A, Ibrahim IA, Almanae HM, Aleid HA: Histopathologic
Findings of Potential Kidney Donors With Asymptomatic Microscopic Hematuria: Impact on
Donation. Transplant Proc 49(8):1729-1732, 2017

NephSAP Primary Glomerular Diseases Answers, V 18, N1, March 2019: Page 12 of 17
Question 21
Answer A: Lower mesangial proliferation grade
Educational objective: Identify kidney biopsy findings indicating a high risk of relapse in
minimal change disease
A number of features in a kidney biopsy suggest a high risk of relapse following successful
treatment of minimal change disease with corticosteroids. These include lower mesangial
proliferation grade (option A is correct) and evidence of glomerular enlargement (option B is
incorrect). Acute tubular necrosis and the extent of global glomerulosclerosis have no apparent
influence on this risk (options C and D are incorrect).
• Lee H, Yoo KD, Oh YK, Kim DK, Oh KH, Joo KW, Kim YS, Ahn C, Han JS, Lim CS:
Predictors of Relapse in Adult-Onset Nephrotic Minimal Change Disease. Medicine
(Baltimore) 95(12): e3179, 2016
• Lee SW, Yu MY, Baek SH, Ahn SY, Kim S, Na KY, Chae DW, Chin HJ: Glomerular
Hypertrophy Is a Risk Factor for Relapse in Minimal Change Disease Patients. Nephron
132(1):43-50, 2016

Question 22
Answer D: IgM and C3 deposition kawata sclerosis
Educational objective: Identify IgM plus C3 deposition in focal and segmental
glomerulosclerosis as a marker of treatment unresponsiveness and adverse prognosis
The findings by immunofluorescence examination of a kidney biopsy in focal and segmental
glomerulosclerosis can have potential prognostic implications. Combined deposition of IgM and C3
seems to indicate a poor response to treatment and an unfavorable long-term prognosis. Therefore,
option D is correct, and the other listed options are incorrect.
• Pačić A, Šenjug P, Bacalja J, Tišljar M, Horvatić I, Bulimbašić S, Knotek M, Galešić
K, Galešić Ljubanović D: IgM as a novel predictor of disease progression in secondary focal
segmental glomerulosclerosis. Croat Med J 58(4):281-291, 2017
• Connor TM, Aiello V, Griffith M, Cairns T, Roufosse CA, Cook HT, Pusey CD: The natural
history of immunoglobulin M nephropathy in adults. Nephrol Dial Transplant 32(5):823-829,
2017
• Zhang YM, Gu QH, Huang J, Qu Z, Wang X, Meng LQ, Wang F, Liu G, Cui Z, Zhao MH:
Clinical Significance of IgM and C3 Glomerular Deposition in Primary Focal Segmental
Glomerulosclerosis. Clin J Am Soc Nephrol 11(9):1582-9, 2016

NephSAP Primary Glomerular Diseases Answers, V 18, N1, March 2019: Page 13 of 17
Question 23
Answer C: Repeated immunofluorescence study of a pronase digested paraffin block
section
Educational objective: Diagnose “membranous-like” glomerulopathy with masked IgG
kappa deposition
This case represents the “classic” presentation for a “membranous-like” glomerulopathy with
masked IgG kappa deposition. It typically appears in young women with some auto-immune
manifestations, but without overt systemic lupus erythematosus. It is best diagnosed by
immunofluorescence studies of pronase digestion of paraffin embedded tissue. The staining is
typically monotypic IgG kappa. About half of the patients in the retrospective analysis by Larson et
al. had a spontaneous remission, whereas about 10% progressed to ESRD. There was no
correlation between the treatment and outcome in this report. Treatments included renin-
angiotensin blockade alone or in combination with immunosuppression, corticosteroids, calcineurin
inhibitors, mycophenolate mofetil, azathioprine, rituximab, and hydroxychloroquine.
• Larsen CP, Boils CL, Cossey LN, Sharma SG, Walker PD: Clinicopathologic features of
membranous-like glomerulopathy with masked IgG kappa deposits. Kidney Int Rep
1(4):299-305, 2016

Question 24
Answer B: Initiate treatment with rituximab
Educational objective: Diagnose and manage primary membranous nephropathy
Since the patient wishes to maintain normal ovarian function, a course of rituximab is favored over
cyclophosphamide. Hence, option B is correct and option A is incorrect. In the face of a greatly
elevated serum anti-PLA2R antibody level and no features to suggest a secondary lesion, this
patient almost certainly has primary membranous nephropathy and a kidney biopsy is not needed to
confirm the diagnosis. Corticosteroids alone will not likely be helpful (option D is incorrect).
• De Vriese AS, Glassock RJ, Nath KA, Sethi S, Fervenza FC: A proposal for a serology-
based approach to membranous nephropathy. J Am Soc Nephrol 28(2):421-430, 2017
• Cattran DC, Brenchley PE: Membranous nephropathy: integrating basic science into
improved clinical management. Kidney Int 91(3):566-574, 2017

Question 25
Answer A: Increased C4d mesangial deposition
Educational objective: Know that increased C4d mesangial deposition in IgA nephropathy
signifies a worse prognosis
Several features in the pathologic examination of IgA Nephropathy are useful in estimating
prognosis, beyond those features incorporated into the OXFORD-MEST-C scoring system:
Increased C4d mesangial deposition (option A is correct), reduced glomerular density (option B is

NephSAP Primary Glomerular Diseases Answers, V 18, N1, March 2019: Page 14 of 17
incorrect), and extensive peripheral capillary deposition of IgA (option C is incorrect) all signify a
worse prognosis. The extent of IgG co-deposition has little consistent effect on prognosis (option D
is incorrect).
• Segarra A, Romero K, Agraz I, Ramos N, Madrid A, Carnicer C, Jatem E, Vilalta R, Lara
LE, Ostos E, Valtierra N, Jaramillo J, Arredondo KV, Ariceta G, Martinez C: Mesangial C4d
Deposits in Early IgA Nephropathy. Clin J Am Soc Nephrol 13(2):258-264, 2018
• Chen ZJ, Li H, Cai JF, Zhang X, Li C, Zou PM, Li MX, Chen LM, Li XM, Li XW, Wen YB:
The neglected significance of glomerular density as a 5-year progression indicator for IgA
nephropathy. Chin Med Sci J 32(3):145-151, 2017
• Alvarado AS, Andeen NK, Brodsky S, Hinton A, Nadasdy T, Alpers CE, Blosser C, Najafian
B, Rovin BH: Location of glomerular immune deposits, not co-deposition of immunoglobulin
G, influences definitive renal outcomes in immunoglobulin A nephropathy. Nephrol Dial
Transplant 33: 1168-1175, 2018
• Shin DH, Lim BJ, Han IM, Han SG, Kwon YE, Park KS, Lee MJ, Oh HJ, Park JT, Han
SH, Kang SW, Yoo TH: Glomerular IgG deposition predicts renal outcome in patients with
IgA nephropathy. Mod Pathol 29(7):743-52, 2016

Question 26
Answer C: Serum free light chain assay
Educational objective: Diagnose C3 glomerulopathy with masked monoclonal deposits
This case is strongly suggestive of an underlying monoclonal immunoglobulin disease causing
interference with factor H and C3 convertase, leading to the development of C3 glomerulonephritis.
A serum free light chain assay is an important first choice test. Therefore, option C is correct, and
the other listed options are incorrect.
• Doshi M, Lahoti A, Danesh FR, Batuman V, Sanders PW; American Society of Nephrology
Onco-Nephrology Forum: Paraprotein-related kidney disease: kidney injury from
paraproteins-what determines the site of injury? Clin J Am Soc Nephrol 11(12):2288-2294,
2016
• Lloyd IE, Gallan A, Huston HK, Raphael KL, Miller DV, Revelo MP, Khalighi MA: C3
glomerulopathy in adults: a distinct patient subset showing frequent association with
monoclonal gammopathy and poor renal outcome. Clin Kidney J 9(6):794-799, 2016

NephSAP Primary Glomerular Diseases Answers, V 18, N1, March 2019: Page 15 of 17
Question 27
Answer C: Staining of renal biopsy specimen for DNAJB9
Educational objective: Diagnose fibrillary glomerulonephritis with a “pseudo-linear”
immunofluorescence pattern for IgG on kidney biopsy
This case illustrates that some patients with fibrillary glomerulonephritis may display a “pseudo-
linear” immunofluorescence pattern for IgG, resembling anti-GBM disease, but 100% will have
DNAJB9 positivity. Thus, option C is correct, and the other listed options are incorrect.
• El-Husseini A, Aycinena JC, George B, Jennings S, Cornea V, Sawaya BP: Fibrillary
glomerulonephritis masquerading as rapidly progressive glomerulonephritis with pseudo-
linear glomerular basement membrane staining. Clin Nephrol 84(4):231-5, 2015
• Thomas JA, Vasin D, Lin M, Anderson AE, Alpers CE: A case of mistaken identity: fibrillary
glomerulonephritis masquerading as crescentic anti-glomerular basement membrane
disease. Clin Nephrol 85(2):114-20, 2016

Question 28
Answer B: Serum albumin <2.5 g/dl at the time of diagnosis prior to transplant
Educational objective: Identify a serum albumin of <2.5 g/dl as a factor that predicts the risk
of recurrent focal and segmental glomerulosclerosis following kidney transplant
Among the options given, only a low serum albumin level will help to discriminate the risk of a
recurrence of FSGS in a renal allograft. Therefore, option B is correct, and the other listed options
are incorrect. Patients with recurrent FSGS had a mean 24-hour urinary protein excretion of 11.7 g
compared to 4.6 g in those without recurrence (option A is incorrect). Patients with a recurrence had
a significantly higher eGFR at diagnosis (104 versus 53 ml/min per 1.73 m2). Hence, option C is
incorrect. A family history of nephrotic syndrome would increase the likelihood of a genetic form of
FSGS and reduce the probability of a recurrence following renal transplantation (option D is
incorrect).
• Maas RJ, Deegens JK, van den Brand JA, Cornelissen EA, Wetzels JF: A retrospective
study of focal segmental glomerulosclerosis: clinical criteria can identify patients at high risk
for recurrent disease after first renal transplantation. BMC Nephrol 14:47, 2013

Question 29
Answer C: Rituximab 375 mg/m2 weekly for 4 doses
Educational objective: Manage frequently relapsing, steroid-dependent nephrotic syndrome
due to minimal change disease
Current evidence from randomized clinical trials strongly suggests that rituximab is the best choice
for a patient with these characteristics. Hence, option C is correct, and the other listed options are
incorrect.

NephSAP Primary Glomerular Diseases Answers, V 18, N1, March 2019: Page 16 of 17
 • Papakrivopoulou E, Shendi AM, Salama AD, Khosravi M, Connolly JO, Trompeter R:
Effective treatment with rituximab for the maintenance of remission in frequently relapsing
minimal change disease. Nephrology (Carlton) 21(10):893-900, 2016
• King C, Logan S, Smith SW, Hewins P: The efficacy of rituximab in adult frequently
relapsing minimal change disease. Clin Kidney J 10(1):16-19, 2017
• Boumediene A, Vachin P, Sendeyo K, Oniszczuk J, Zhang SY, Henique C, Pawlak
A, Audard V, Ollero M, Guigonis V, Sahali D: NEPHRUTIX: A randomized, double-blind,
placebo vs Rituximab-controlled trial assessing T-cell subset changes in Minimal Change
Nephrotic Syndrome. J Autoimmun 88:91-102, 2018
• Miyabe Y, Takei T, Iwabuchi Y, Moriyama T, Nitta K: Amelioration of the adverse effects of
prednisolone by rituximab treatment in adults with steroid-dependent minimal-change
nephrotic syndrome. Clin Exp Nephrol 20(1):103-10, 2016

Question 30
Answer A: IgA nephropathy
Educational objective: Know the most frequent causes of asymptomatic microscopic
hematuria
Lee et al. conducted a retrospective analysis of 350 patients with asymptomatic microscopic
hematuria with baseline normal kidney function who underwent biopsy at a single center in Korean
between 2002 and 2011. The average ago of the cohort was 40.26 years, and 77.7% were female.
IgA nephropathy was the most common diagnosis, with a frequency of 46.9%, followed by idiopathic
mesangial proliferative glomerulonephritis (43.1%). Ten patients in this cohort, all of whom had IgA
nephropathy, subsequently developed proteinuria. Three patients in this series had progressive
CKD with an estimated GFR falling to <60 ml/min per 1.73 m2, but no patients progressed to end-
stage kidney disease over seven years of observation. Therefore, option A is correct, and the
options B through E are incorrect. Clark and coworkers completed systemic review of 1092 subjects
reported in seven studies. In this review, only 66% of subjects underwent biopsies, likely resulting in
underrepresentation of glomerular causes of hematuria. IgA nephropathy was the most common
cause of asymptomatic hematuria in patients with combined proteinuria and hematuria. Thin
basement membrane nephropathy was the most common cause of asymptomatic hematuria without
proteinuria in this review.
• Clark M, Aronoff S, Del Vecchio M: Etiologies of asymptomatic microscopic hematuria in
children - systematic review of 1092 subjects. Diagnosis 2: 211-216, 2015
• Lee HM, Hyun JI, Min JW, Lee K, Kim YK, Choi EJ, Song HC: The Natural Course of
Biopsy-Proven Isolated Microscopic Hematuria: A Single Center Experience of 350 Patients.
J Korean Med Sci 31: 909-914, 2016

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