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IDNEY BIOPSY TEACHING CASE

Diabetic Woman With Massive Proteinuria and Acute Renal Failure

Ramesh Nair, MD, and Mowaffaq Said, MD

NDEX WORDS: Anti–glomerular basement membrane (anti-GBM) disease; diabetes; diabetic nephropathy; crescen-

ic; biopsy.

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EPHROTIC SYNDROME and renal insuf-ficiency are frequent accompaniments of

iabetic nephropathy.1,2 However, a second dis-ase superimposed on diabetic nephropathy is ofoncern, especially if the proteinuria is massiver renal failure is deemed to be acute. Primarylomerulopathies associated with diabetic ne-hropathy, although uncommon, have been re-orted previously, and any number of secondiseases can affect the diabetic kidney.3–11 Weresent an unusual and rather unexpected causef acute renal failure and massive proteinuria in aatient with a history of diabetes. The case showshe complexities involved in such instances andhe value of a renal biopsy in the management ofidney disease in selected individuals.

CASE REPORT

A 25-year-old woman with a 2-year history of type 2iabetes mellitus, hypertension, and morbid obesity waseferred to us by her primary care physician for evaluation ofn elevated serum creatinine level detected on a routineffice visit. Her baseline serum creatinine was 1.1 mg/dL (94mol/L) 3 months previously. Her diabetes and hyperten-

ion were poorly controlled. She was a chronic cigarettemoker ( pack/d). There was no history of hematuria,emoptysis, or sinusitis. Relevant physical examination wasiven. The patient was in no acute distress. Her bloodressure was 211/121 mm Hg and respiratory rate was 22reaths/min, with a pulse oximetry reading of 100% on roomir. The only significant feature on physical examination wasorbid obesity and 2� pitting edema in both lower extremi-

ies. Ocular fundus examination showed no evidence ofiabetic retinopathy. Chest radiograph showed mild pulmo-

From Nephropathology Associates, Little Rock, AR; andissouri Delta Medical Center, Sikeston, MO.Received January 12, 2005; accepted in revised form

ebruary 23, 2005.Originally published online as doi:10.1053/j.ajkd.2005.02.035

n July 5, 2005.Address reprint requests to Ramesh Nair, MD, Nephropa-

hology Associates, 10802 Executive Center Dr, Ste 111,enton Bldg, Little Rock, AR 72211. E-mail: rameshnair@

ycos.com© 2005 by the National Kidney Foundation, Inc.0272-6386/05/4602-0023$30.00/0

pdoi:10.1053/j.ajkd.2005.02.035

American Journal of K62

ary vascular congestion and normal-sized heart borders.erum creatinine level was 5.6 mg/dL (495 �mol/L), bloodrea nitrogen level was 45 mg/dL (16.1 mmol/L), hemoglo-in level was 9.2 g/dL (92 g/L), and hematocrit was 26.7%.rinalysis showed microscopic hematuria and 24-hour urinerotein excretion was 16.5 g. Antinuclear antibody, antineu-rophil cytoplasmic antibody, and anti–glomerular basementembrane (anti-GBM) antibody tests were requested, and

esults were pending at the time of renal biopsy.

enal Biopsy FindingsThirteen glomeruli were available for light microscopic

valuation. Glomeruli showed diffuse nodular sclerosis witharked mesangial matrix expansion. Capillary loops were

hickened. Eight glomeruli contained crescents that wereredominately cellular, with a few showing early fibrocellu-ar changes (Fig 1). There was moderate interstitial fibrosisnd tubular atrophy affecting the cortex. Diffuse interstitialnflammation with a mixed cellular composition also wasresent. There was moderate arterial and arteriolar sclerosis.Immunofluorescence staining for immunoglobulin G

IgG), IgM, IgA, C3, C1q, albumin, fibrinogen, and � and �ight chains was done. Glomeruli showed diffuse nodularclerosis. Three of 6 glomeruli contained crescents. On anntensity scale of 0 to 3�, there was diffuse linear GBMtaining for IgG (3�), albumin (1�), � light chain (3�), and

light chain (3�). (Note the 2� difference in intensity oftaining for IgG and albumin [Fig 2].) Mild, variable, andegmental ultrafinely granular GBM staining for C3 (trace to�) also was present. Bright and diffuse fibrinogen stainingas present in all glomerular crescents. All other stains wereegative in glomeruli and tubules.Three glomeruli with nodular sclerosis, 1 with a cellular

rescent, were available for ultrastructural evaluation, whichhowed glomeruli with uniformly thickened capillary loops.lectron-dense and fibrillary deposits were absent.

iagnosisDiagnoses were (1) crescentic glomerulonephritis, type I

anti-GBM antibody disease) and (2) chronic diabetic ne-hropathy.

reatment and Follow-UpThe patient was started on pulse methylprednisolone

herapy at 500 mg/d intravenously. Additional blood investi-ation results were available after initiation of methylpred-isolone treatment. Serum anti-GBM antibodies were posi-ive at titers of 7.9 IU/L (normal, �3 IU/L). Anti-

yeloperoxidase, anti-proteinase 3, and antinuclearntibodies were not detected. The patient was started on

lasmapheresis at 3 times weekly.

idney Diseases, Vol 46, No 2 (August), 2005: pp 362-366

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PROTEINURIA AND RENAL FAILURE IN A DIABETIC 363

DISCUSSION

The major differential diagnoses of primaryidney diseases associated with various clinicalyndromes in a patient with diabetes are listed inable 1. Although nephrotic syndrome, micro-copic hematuria, and renal insufficiency are allommon features of chronic diabetic nephropa-hy, the combined presence of massive protein-ria and unexplained renal failure with hematu-ia justified a renal biopsy in our patient. Theiagnostic challenges in this patient are dis-ussed.

First, this patient had massive proteinuria. Theost common cause of nephrotic syndrome in

dults is diabetic nephropathy.1 Nephrotic-range

Fig 1. Light microscopic findings. (A) Low-power vilomeruli with nodular sclerosis and cellular crescentiew of a glomerulus with nodular sclerosis and aperiodic acid–Schiff stain; original magnification �200

Fig 2. Immunofluorescence findings. (A) Glomerulu�

3 ). (B) Glomerulus shows less intense staining for albumin (

original magnification �200).

roteinuria in a patient with diabetes usually isndicative of progressive diabetic nephropathy. Pro-einuria in patients with diabetes is caused bylomerular hyperfiltration as a consequence of in-reased glomerular capillary hydrostatic pressure,oss of GBM-negative charges, and increased poreize.25 Although nephrotic syndrome is common inatients with diabetes, the severe degree of protein-ria in our patient made a second disease, such asembranous nephropathy, minimal change dis-

ase, or amyloidosis, likely. However, the diagno-is of anti-GBM disease was completely unex-ected.

Second, microscopic hematuria also is com-on in patients with diabetic nephropathy and

ws renal cortex with moderate interstitial fibrosis andr stain; original magnification �100). (B) High-powerr crescent compressing underlying capillary loops

ws bright linear basement membrane staining for IgG�

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an be found in up to 30% of patients withiabetes, with 13% containing red blood cellasts in urine.15 Causes of hematuria in a patientith diabetes can be attributed to microaneurysm

ormation and ectatic capillary loops, which areharacteristic of diabetic nephropathy.26 So whenoes microscopic hematuria raise enough con-ern to warrant a biopsy? Hommel et al27 empha-ized the importance of a renal biopsy in patientsith diabetes with permanent or recurrent micro-

copic hematuria in the absence of evidence forrinary tract disorders. Heine et al28 concludedhat the presence of more than 4 acanthocytesdysmorphic erythrocytes) per 100 erythrocytesn urinary sediment favored a primary glomeru-opathy other than diabetic nephropathy. In short,patient with diabetes with recurrent or perma-

ent microscopic hematuria having more than 4canthocytes/100 erythrocytes, in the absence ofrinary tract abnormalities, may benefit fromdditional clinical investigations and, if neces-ary, a renal biopsy to rule out a primary glomer-lonephritis.The histopathologic diagnosis of crescentic

Table 1. Differential Diagnoses for a Second KidneyDisease in Patients With Diabetes

iabetes with nephrotic syndromeDiabetic nephropathy1,2

Membranous glomerulopathy12

Minimal change disease13,14

Deposition diseasesAmyloidosis5

Monoclonal immunoglobulin deposition disease*iabetes with hematuria/nephritic syndromeDiabetic nephropathy15

Immune complex glomerulonephritisIgA nephropathy7,9,16

Postinfectious glomerulonephritis7,8

Membranoproliferative glomerulonephritis5

Lupus11

Crescentic glomerulonephritis (current case)iabetes with acute renal failureRecently discovered chronic diabetic nephropathy17

Acute tubular injury18,19

Acute interstitial nephritis11,20,21

Light chain cast nephropathy22

Crescentic glomerulonephritis (current case)iabetes with rapidly progressive glomerulonephritisCrescentic glomerulonephritis23,24

Diabetic nephropathy17

*Personal experience (R.N.); 1 case at Nephropathologyssociates.

lomerulonephritis in a patient with diabetic ne- d

hropathy also can pose some problems. Glomer-lar crescents can be a nonspecific finding inatients with diabetic nephropathy.29 Crescentormation is considered secondary to the rupturef capillary loops affected by microaneurysms,ith consequent leakage of blood leading to

eactive parietal epithelial cell reaction. In thesenstances, crescents usually are focal and involveccasional glomeruli only. However, they can beworrisome feature in certain instances, and a

erological investigation may be necessary toule out crescentic glomerulonephritis. In theurrent biopsy, the diffuse nature of the cellularrescents made the diagnosis straightforward.he awareness that focal cellular crescent forma-

ion occurs in patients with diabetic nephropathyan prevent unnecessary investigations and harm-ul therapeutic interventions.

Another issue in a patient with diabetes andrescentic glomerulonephritis is the presence ofinear glomerular capillary loop staining. Brightinear GBM staining is a usual accompanimentf diabetic nephropathy.30 However, it invariablys accompanied by equally bright linear stainingor albumin. The mere presence of bright linearBM staining for IgG in a patient with diabetesoes not indicate anti-GBM disease. The inten-ity of staining should be compared with that oflbumin, which would be considerably less orbsent in the presence of actual anti-GBM anti-odies.31 The current biopsy specimen showedignificantly less staining intensity with albuminn contrast to IgG. This was confirmed later byerological evidence for anti-GBM antibodies.gain, it is important to compare the staining

ntensity of IgG and albumin and initiate serologi-al tests leading to appropriate therapeutic inter-entions.Anti-GBM disease is a rare association with

iabetes. Only 8 cases have been reported in thenglish-language literature.3,31–35 The presencef diffuse cellular crescents and linear GBMtaining for IgG in the absence or markedlyower intensity of staining for albumin is charac-eristic of this entity. Lesser degrees of linear ornely granular staining for complement 3 alsoommonly are present in glomerular capillaryoops.36 Ideally, this diagnosis should be con-rmed serologically. Conversely, serological evi-ence of anti-GBM antibodies in a patient with

iabetes with acute renal failure does not always

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PROTEINURIA AND RENAL FAILURE IN A DIABETIC 365

ndicate anti-GBM disease. DeAangelo et al37

eported a patient with diabetes with serologicalvidence of anti-GBM antibodies and acute renalailure, for whom the renal biopsy showed acutenterstitial nephritis with no evidence of crescen-ic glomerulonephritis. False-positive serum anti-BM antibody titers, although rare, can occur.38

iopsy confirmation can avoid potentially harm-ul treatment.

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