C3 y Enf Por Depositos Densos. AJKD

8/12/2019 C3 y Enf Por Depositos Densos. AJKD

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Kidney Biopsy Teaching Case

Alternative Pathway Dysfunction in Kidney Disease: A CaseReport and Review of Dense Deposit Disease

and C3 Glomerulopathy

Amret Hawfield, MD,1 Samy S. Iskandar, MBBCh, PhD,1 and Richard J.H. Smith, MD2

Dysfunction of the alternative pathway of complement activation provides a pathophysiologic link between

the C3 glomerulopathies dense deposit disease and glomerulonephritis with C3 deposition and the clinically

and histologically distinct atypical hemolytic uremic syndrome. Previously, dense deposit disease was known

as membranoproliferative glomerulonephritis type II, but paucity or complete lack of immunoglobulin deposition

on immunofluorescence staining and advances in our understanding of alternative pathway dysregulation have

separated it from immune complexmediated membranoproliferative glomerulonephritis types I and III. We

discuss a case of dense deposit disease and review the current pathologic classification, clinical course,

treatment options, and related conditions.

Am J Kidney Dis.61(5):828-831.2013 by the National Kidney Foundation, Inc.

INDEX WORDS: Dense deposit disease; C3 glomerulopathy; atypical hemolytic uremic syndrome (HUS);

alternative pathway; complement.

INTRODUCTION

Dense deposit disease and glomerulonephritis withC3 deposition are rare diseases affecting a small propor-tion of patients with glomerulonephritis. Dense depositdisease is thought to affect 2-3 of every million persons.1

We discuss a young man with a diagnosis of densedeposit disease, including the initial evaluation, kidneypathology, and initial treatment. Details of the kidney

biopsy illustrate the new classification of dense depositdisease as an immunoglobulin-negative complement-positive C3 glomerulopathy rather than membranoprolif-erative glomerulonephritis (MPGN) type II. Character-ization of complement and complete genetic analysis arereported. An approach to choosing initial treatment,including nonspecific therapy, plasmapheresis, ritux-imab, and the emerging use of eculizumab, is reviewed.

CASE REPORT

ClinicalHistoryandInitialLaboratoryData

An 18-year-old man with a history of recurrent streptococcal

throat infections until the age of 10 years presented to his primary

care physician with a viral illness and coincidentally was found to

have new-onset severe hypertension, with blood pressure of 180/

100 mm Hg. An echocardiogram showed preserved left ventricular

systolic function, mild tricuspid regurgitation, and mild mitral

regurgitation. A chest radiograph showed no signs of rib notching

or other abnormality. The finding of proteinuria prompted a refer-

ral to a nephrologist; his initial evaluation findings included

urinalysis significant for 100 mg/dL of protein, moderate blood,

and 5-10 red blood cells/high-power field. Serum creatinine level

was 0.7 mg/dL (estimated glomerular filtration rate was 60

mL/min/1.73 m2 by the 4-variable Modification of Diet in Renal

Disease [MDRD]Study equation), albumin level was 3.6 g/dL, and

electrolyte levels were normal. A 24-hour urine collection was

remarkable for protein excretion of 4.7 g/d. Results of serologic

workup, including antinuclear antibody, serum protein electropho-

resis, urine protein electrophoresis, hepatitis serologic tests, hu-

man immunodeficiency virus (HIV), and serum free light chainratio, were all normal or negative. Complement protein C4 level

was normal at 230 (reference range, 160-470) mg/L, whereas C3

level was mildly depressed at 560 mg/L (reference range, 900-

1,800 mg/L).

Ultrasonography showed a right kidney of 13.2 cm in length and

a left kidney of 12.7 cm. Incidental note was made of dual renal

arteries on the right. There was no evidence of obstruction, mass,

stone, or scarring. Duplex testing was negative for renal artery

stenosis, and a kidney biopsy was performed.

KidneyBiopsy

The biopsy specimen included 18 glomeruli for examination

with hematoxylin and eosin, periodic acidSchiff, periodic acid

methenamine silver, and trichrome stains. There was mesangial

hyperplasia with focal segmental accentuation of the tufts lobular

architecture, nodule formation, and adhesions to Bowman capsule.

Trichrome-stained sections showed more intense staining of the

capillary walls compared to the light green of controls, with similar

fine nodular staining in the mesangium. Silver-impregnated sec-

tions showed segmental splitting along the glomerular basement

membranes. There was minimal focal tubularatrophy, and extraglo-

merular blood vessels appeared normal (Fig 1A).

Immunofluorescence microscopy showed sparse granules of immu-

noglobulin A (IgA) and bright intense staining of C3 along the

glomerular capillary wall and in the mesangium (4). On close

scrutiny, capillary wall staining could be appreciated to segmentally

consist of 2 thin parallel lines along the glomerular basement mem-

brane. Sparse mesangial granules of and immunoglobulin light

From the 1Wake Forest School of Medicine, Winston-Salem,NC; and 2University of Iowa Carver College of Medicine, IowaCity, IA.

Received May 5, 2012. Accepted in revised form November 16,2012. Originally published online February 6, 2013.

Address correspondence to Amret Hawfield, MD, Nephrology,Wake Forest Baptist Health, Medical Center Blvd, Winston-Salem,NC 27157. E-mail:[email protected]

2013 by the National Kidney Foundation, Inc.0272-6386/$36.00http://dx.doi.org/10.1053/j.ajkd.2012.11.045

Am J Kidney Dis. 2013;61(5):828-831828
mailto:[email protected]:[email protected]://dx.doi.org/10.1053/j.ajkd.2012.11.045http://dx.doi.org/10.1053/j.ajkd.2012.11.045http://dx.doi.org/10.1053/j.ajkd.2012.11.045mailto:[email protected]


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chains were noted and interpreted as nonspecific. Sections stained for

IgG, IgM, and C1q were entirely nonreactive, and the section stained

for albumin provided a satisfactory negative control, with reactivity

over only tubular protein reabsorption droplets (Fig 1B).

Electron microscopic examination showed the presence of dense

material segmentally replacing the glomerular basement mem-

brane with intact lamina densa mostly external to the deposits.

Similarly dense round deposits were noted in the mesangium. Anoccasional subepithelial deposit also was present. There was par-

tial effacement of foot processes and microvillus transformation of

podocytes, consistent with the presence of proteinuria (Fig 1C).

Diagnosis

Assessment of alternative pathway activity and genetic testing

of complement genes revealed the presence of C3 nephritic factor

(C3Nef;Table 1). Based on the characteristic pathology and the

presence of C3Nef, dense deposit disease was diagnosed.

Clinical Follow-up

The patient initially was treated with lisinopril at a maximally

tolerated dose of 10 mg daily, with the addition of atenolol for

blood pressure control. Given an elevated urine protein-creatinineratio of 3.08 g/g and the presence of C3Nef, the patient underwent

6 sessions of plasmapheresis over a 2-week period followed by 2

doses of rituximab (1 g on days 1 and 16 after plasmapheresis was

complete). Immediately after plasma exchange, urine protein-

creatinine ratio decreased to 1.54 g/g, with a further decrease after

the first dose of rituximab to 1.049 g/g. Twenty-fourhour urine

protein quantification was 1.848 g/d.

Three months after the second dose of rituximab, C3 level

remained low at 400 mg/L, serum creatinine level was 0.6 mg/dL

(estimated glomerular filtration rate 60 mL/min/1.73 m2), serum

albumin level was 3.9 g/dL, and 24-hour urine protein excretion

was 0.83 g/d. At the time of writing, 5 months after rituximab

treatment, a low C3 level (330 mg/L) persisted and 24-hour urine

protein excretion was 1.05 g/d. Blood pressure remained con-

trolled on the lisinopril and atenolol regimen.

DISCUSSION

As the understanding of complement-mediated kid-ney disease has advanced, a new classification schemahas been proposed categorizing dense deposit diseaseand glomerulonephritis with C3 deposition as C3glomerulopathies, with the important distinction thatimmunofluorescence microscopy results lack immuno-globulin deposition and show only C3 deposition.3,4

Dense deposit disease typically is characterized by the

classic sausage-shaped amorphous dense deposits in

the lamina densa of the glomerular basement mem-brane and similarly dense nodular mesangial deposits.As noted, there is no significant immunoglobulindeposition detectable by immunofluorescence. In glo-merulonephritis with C3 deposition, mesangial andsubendothelial deposits are reminiscent of MPGNtype I or subendothelial and subepithelial depositssimilar to MPGN type III.4-10 Overlapping features of

both dense deposit disease and glomerulonephritiswith C3 deposition were present in the case wedescribe, but due to the intact lamina densa bothinternal and external to the deposits, we favored a

Figure 1. Kidney biopsy. (A) Glomerulus shows capillary wallthickening with segmental more intense staining due to overlapof the fuchsinophilic dense deposits and light green color of thenormal glomerular basement membrane (Gomori trichrome stain;original magnification,40). (B) Glomerulus stained for C3 showscapillary walland mesangial staining (fluorescein isothiocyanatelabeled rabbit anti-human C3 antibody; original magnification,40).(C) Electron micrograph shows dense deposits segmentallyreplacing glomerular basement membrane (original magnifica-tion, 2,900).

Am J Kidney Dis. 2013;61(5):828-831 829

Dense Deposit Disease


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