Renal Pathology

Minimal Change Disease Secondary to Hodgkin's Disease

Stephen M. Bonsib
Louisiana State University Health Science Center
Shreveport


Case History
The patient is a 19-year old white female. She was first seen by her family physician because of acute onset of peripheral edema with swelling of feet and lower extremities. Two days before the patient received vaccinations (hepatitis B and meningococcal) in preparation for college. She was treated with a prednisone Dosepak pack with transient resolution of the edema. The edema recurred 1 week later and was still present at a follow up visit 1 month later. 3+ proteinuria was detected and she was referred to a nephrologist.

The initial nephrology evaluation occurred 2 months after the first onset of edema. By that time she had gained 8 kg. Physical examination was essentially unremarkable aside from significant edema. She was afebrile, with blood pressure of 110/60 mm Hg, and weight of 72.4 kg.

Family history:
No family history of renal disease.

Past medical history:
Recurrent upper respiratory infections characterized by tonsillitis

Laboratory findings:
Creatitine: 0.5 mg/dl
Urinalysis:
4+ proteinuria
No rbcs or cellular casts
24-hr urine protein: 6.5 gm
Serum albumin: 2.4 gm/dl
Cholesterol: 380 mg/dl / Triglycerides: 216 mg/dl
C3/C4: normal
ANA: negative


Slide 1 - H&E
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Slide 2 - PAS
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Figure 1 - The cortex appears normal; note absence of tubulo-interstitial disease.
Figure 2 - There are focal clusters of interstitial foam cells.
Figure 3 - There is no evidence of tubulo-interstitial changes. PAS stain.

Figure 4 - This glomerulus shows minimal mesangial matrix increase. PAS stain
Figure 5 - This is a normal glomerulus. PAS stain
Figure 6 - This is a normal glomerulus. Jones methenamine silver stain

Figure 7 - Direct immunofluorescence shows prominent mesangial deposition of IgA.
Figure 8 - This electron micrograph shows loss of podocyte foot processes. The mesangial matrix is not expanded and no electron dense deposits are present.
Figure 9 - This electron micrograph shows loss of podocyte foot processes. The mesangial matrix is not expanded and no electron dense deposits are present.


Clinical Course:
Nephrotic syndrome was diagnosed. She patient was treated with prednisone 60mg/day and given bactrim for Pneumocystis prophylaxis. A renal biopsy was performed.

Differential Diagnosis:
Nephrotic syndrome with normal renal function and no hematuria

Primary or idiopathic forms of glomerulonephritis
  • Minimal change disease

  • Focal segmental glomerulosclerosis

  • Membranous glomerulonephritis

  • Less likely, other primary gns

Secondary forms of glomerulonephritis
  • Glomerulonephritis secondary to vaccination

  • Mutation of podocyte foot process or slit diaphragm protein
    • nephrin, podocin, etc

  • A post pharyngitic gn, such as an IgA neophropathy (but no hematruia)

  • Connective tissue disease associated gn (but no clinical or serologic evidence of CTD)

Renal Biopsy Findings:
LM: The sections and special stains contain 35 glomeruli per section. No completely sclerotic glomeruli are present. There is no glomerular hypercellularity or segmental lesion, and all glomeruli have open capillary loops with normal basement membranes. There is no tubular atrophy or interstitial fibrosis, and no interstitial inflammation or edema is noted. There are focal clusters of interstitial foam cells. All arterioles and arteries are normal.

IF: The tissue contains 10 glomeruli. There is a 1+ segmental mesangial reaction for IgA, C3, kappa, and lambda. There is no reaction for IgG, IgM, C1q, or fibrin.

EM: Ultrastructural examination of 2 glomeruli shows diffuse effacement of podocyte foot processes. The capillary loop basement membranes are uniform and of normal thickness. There is no capillary loop sclerosis, hypercellularity, or electron dense deposit. The mesangial matrix is not expanded and no electron dense deposits are noted.

Morphologic Diagnosis (Not Final Diagnosis):
Minimal change disease with 'incidental' IgA deposits

Clincial Course:
May, 2006 - Prednisone Dosepak
  • Resolution of edema

  • Edema recurred 1 week later
June, 2006 - Steroid taper
  • Edema persists
July 14, 2006 - Nephrology consult
  • Nephrotic syndrome

  • Wt 72.4 kg /6.5 gm

  • Prednisone – 60 gm/day

  • Renal biopsy performed
July 27, 2006
  • Cervical lymphadenopathy noted

  • CT scan – mediastinal lymphadenopathy identified - regarded as reactive

  • Edema resolved / wt 68.3 kg

  • Still on prednisone 60 gm/day - steroid taper initiated
August 22, 2006
  • Repeat CT - suspicious for Hodgkin's disease

  • Lymph node biopsy performed

  • Prednisone taper at 30 gm/day

  • Weight increased to 70.1kg
August 29, 2006
  • Hodgkin's disease, nodular sclerosing type diagnosed

  • Chemotherapy initiated - doxorubicin, bleomycin, vinblastine, DTIC / q2 weeks
October 13, 2006
  • Prednisone 20 gm/day

  • No edema / proteinuria resolved

  • Chol 184 mg / TG 268 mg

  • Creatinine 0.7mg/dl
January, 2007
  • In remission

  • Salb = 4.6 gm/dl / total protein = 7.1 gm/dl

  • No proteinuria


Final Diagnoses:
Minimal change disease secondary to Hodgkin's disease
Possibly clincially precipitated by vaccination

"Incidental" IgA deposition
Possibly post pharyngitic-associated
Table 1 - Glomerulonephritis Associated with IgA Deposition

Minimal change disease and incidental IgA
IgA-dominant postinfectious glomerulonephritis
Mixed glomerulonephritis: IgA nephropathy and another glomerular disease
Liver disease and IgA nephropathy
Table 2 - Secondary Causes of Minimal Change Disease

Drugs, especially NSAID
Neoplasms, especially lymphoproliferative disorders
Intrinsic mutations of podocyte and slit diaphragm proteins: nephrin, podocin, -actinnin 4
Superimposed on another renal disease: IgA-N, SLE, HIV
Autoimmune and hypersensitivity disorders
Table 3 - Vaccinations and Nephrotic Syndrome

1st Author - yr Vaccine Ren biopsy Onset - Labs Treatment Outcome
Kikuchi 2002 Pneumococcal MCD/AIN <1mo Crt 1.3/10.4gm corticosteroids Resol 32 days
Keilstein 2000 Influenza MCD 4d -13.2 gm/65cc none Resol 6 wks
Islek 2000 Hep B MCD 8d - 2 gm prednisone Resol 18 days
Ozdemir 1998 Hep B MCD 17d - NRP corticosteroids Resol 20 days
Macario 1995 Hep B MCD 'after' 2nd dose - 8 gm corticosteroids Resol 14 days
Carmeli 1993 Hep B No bx 6 wks - 2+P / 1+ H none Resol 'few days'
Table 4 - Renal Complications of Neoplasia
(Modified from Ronco PM Kidney Int 56: 355, 1977)

1. Direct effects/mechanical effects
  • Parenchymal Infiltration

  • Obstructive uropathy

  • Vascular compromise
2. Indirect effects/metabolic effects
  • Monoclonal protein-associated renal diseases

  • Nephrocalcinosis

  • Electrolyte disturbances

  • Coagulopathy
3. Treatment-induced
  • Radiation/chemotherapy-associated thrombotic microangiopathy

  • Tumor lysis syndrome

  • Drug-induced tubulo-interstitial nephritis, acute and chronic

Nephrotic Syndrome: Hodgkin's Disease and Non Hodgkin's Lymphomas
0.4% incidence MCD, 0.1% incidence amyloid in series of 1700 patients
(see refs Plager, et.al. and Kramer, et al.)


Table 5 - Glomerular Diseases in Hematopoietic Malignancies
(Data from Dabbs, et. Al. Am J Med 80:63-70, 1986)

Glomerular lesion Hodgkin's disease NH Lymphoma CLL
Minimal change disease 40 * 5 2
Amyloidosis 39 ** 3
Focal segmental glom scl 2 1
Membranous gn 4 8 4
Membranoproliferative gn 2 8 7
Other proliferative gn 5 3
Crescentic/AGBM 6 *** 3
Unclassified gn 2 7
* Presenting symptom or occurs early, resolves with effective treatment of HD
**AA amyloid most cases recognized prior to 1960s, very rare since
*** All 6 AGBM disease

Table 6 - Minimal Change Disease in Patients with Hodgkin's Disease

1st Author Year # Pts Type HD Pre HD Post HD Co-exist NS Remit with HD
Audard 2006 21 NS 71% 8 * 9 4 100% **
Eagen 1977 26 3 11 12 100%
Stephan 1997 5/483 2NS/3MC 2 3 4/4
** 3/5 cases that relapsed MCD, also relapsed HD in 7, 9, and 102 months
* Only 60% of patients whose MCD preceded Hodgkin's disease remitted with steroids, most relapsed

Bibliography:
Minimal Change Disease with IgA Deposits:
  1. Association of IgA nephropathy with steroid-responsive nephrotic syndrome. A report of the Southwest Pediatric Nephrology Study Group. Am J Kidney Dis 5:157-164, 1985.

  2. Lai KN, Lai FM, Chan KW, et al. An overlapping syndrome of IgA nephropathy and lipoid nephrosis. Am J Clin Pathol 86:716-723, 1986.

  3. Cheng IK, Chan KW, Chan MK. Mesangial IgA nephropathy with steroid-responsive nephrotic syndrome: disappearance of mesangial IgA deposits following steroid-induced remission. Am J Kidney Dis 14:361-364, 1989.

  4. Waldherr R, Rambausek M, Duncker WD, et al. Frequency of mesangial IgA deposits in a non-selected autopsy series. Nephrol Dial Transplant 4:943-946, 1989.

  5. Bhandari S. The patient with acute renal failure and non-dilated urinary tract. Nephrol Dial Transplant 13:1888, 1998.
Vaccination-associated Nephrotic Syndrome:
  1. Őzdemir S, Bakkaloğlu A, Oran O: Nephrotic syndrome associated with recombinant hepatitis B vaccination: a causal relationship or just a mere association? Nephrol Dial Transplant 13:1888-1889, 1998.

  2. Islek I, Cengiz K, Cakir M, et al. Nephrotic syndrome following hepatitis B vaccination. Pediatr Nephrol 14:89-90, 2000.

  3. Carmeli Y, Oren R. Hepatitis B vaccine side-effect. Lancet 341:250-251, 1993.

  4. Macário F, Freitas L, Correia J, et al. Nephrotic syndrome after recombinant hepatitis B vaccine. Clin Nephrol43:349, 1995.

  5. Kikuchi Y, Imakiire T, Hyodo T, et al. Minimal change nephrotic syndrome, lymphadenopathy and hyperimmunoglobulinemia after immunization with a pneumococcal vaccine. Clin Nephrol 58:68-72, 2002.

  6. Kielstein JT, Termühlen L, Sohn J, et al. Minimal change nephrotic syndrome in a 65-year-old patient following influenza vaccination. Clin Nephrol 54:246-248, 2000.
Malignancy-associated glomerulonrphritis:
  1. Striker LM, Striker GE. Glomerular lesions in malignancies. Contrib Nephrol 48:111-124, 1985.

  2. Alpers CE, Cotran RS. Neoplasia and glomerular injury. Kidney Int 30:465-473, 1986.

  3. Ronco PM. Paraneoplastic glomerulopathies: new insights into an old entity. Kidney Int 56:355-377, 1999.
Nephrotic syndrome Assciated with Hodgkin's Disease
  1. Plager J, Stutzman L. Acute nephrotic syndrome as a manifestation of Hodgkin's disease. Am J Med 50:56-66, 1971.

  2. Kramer P, Sizoo W, Twiss EE. Nephrotic syndrome in Hodgkin's disease. Report of five cases and review of the literature. Neth J Med 24:114-119, 1981.

  3. Powderly WG, Cantwell BM, Fennelly JJ, et al. Renal glomerulopathies associated with Hodgkin's disease. Cancer 56:874-875, 1985.

  4. Dabbs DJ, Striker LM, Mignon F, et al. Glomerular lesions in lymphomas and leukemias. Am J Med 80:63-70, 1986.

  5. Peces R, Sánchez L, Gorostidi M, et al. Minimal change nephrotic syndrome associated with Hodgkin's lymphoma. Nephrol Dial Transplant 6:155-158, 1991.

  6. Audard V, Larousserie F, Grimbert P, et al. Minimal change nephrotic syndrome and classical Hodgkin's lymphoma: report of 21 cases and review of the literature. Kidney Int 69:2251-2260, 2006.