<% 'if (Session("Type") <> 1 and Session("Type") <> 5 and Session("Type") <> 28) then Response.Redirect "../Msg.asp?Messaggio1=Restricted access area!!!&Messaggio2=Return to HomePage" 'if Session("UserCount") = "" then Response.Redirect "../Msg.asp?Messaggio1=Error while initialising the quiz!!!&Messaggio2=Return to HomePage" a_capo = chr(13) + chr(10) NumQuestions = 7 RightAnswer1 = "d" RightAnswer2 = "g" RightAnswer3 = "c" RightAnswer4 = "e" RightAnswer5 = "c" RightAnswer6 = "e" RightAnswer7 = "e" currentID = Request("currentID") if currentID = "" then currentID = 1 Answer1 = Request("Question1") if Request("Answer1") <> "" then Answer1 = Request("Answer1") Answer2 = Request("Question2") if Request("Answer2") <> "" then Answer2 = Request("Answer2") Answer3 = Request("Question3") if Request("Answer3") <> "" then Answer3 = Request("Answer3") Answer4 = Request("Question4") if Request("Answer4") <> "" then Answer4 = Request("Answer4") Answer5 = Request("Question5") if Request("Answer5") <> "" then Answer5 = Request("Answer5") Answer6 = Request("Question6") if Request("Answer6") <> "" then Answer6 = Request("Answer6") Answer7 = Request("Question7") if Request("Answer7") <> "" then Answer7 = Request("Answer7") if currentID = 11 or currentID = 22 or currentID = 33 or currentID = 44 or currentID = 55 or currentID = 66 then Label = "Continue" elseif currentID = 77 then Label = "Continue" else Label = "Evaluate" end if %> C. Hugo - Case study

A 45-year-old patient with leg pain followed by acute renal failure



by C. Hugo
Department of Clinical Medicine IV, Division of Nephrology and Hypertensiology, Friedrich-Alexander University Erlangen-Nuremberg Erlangen, Germany


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AB, an 84 year-old woman, body mass index 22 kg/mq, was submitted in September 1999 to hemicholectomy because of carcinoma of sigma; at that period renal function was normal (serum Creatinine -SCr- 0.6 mg/dl, GFR according to the MDRD formula 82 ml/min).
A 45-year-old Caucasian man was admitted to a peripheral hospital due to increasing pain in his right leg which had started five days before. The symptoms of the leg included pretibial edema, pallor, paresthesia, and paralysis. No peripheral pulses could be detected in his right foot.
Five days previously the patient had felt perfectly well. He was not taking any medicine, nor did he report any hospital admissions or surgery prior to the current event. He was diagnosed as having borderline hypertension with values of about 150/90 mmHg, but no treatment was proposed as yet. He was a heavy smoker, consuming 90 cigarettes daily and 200 packs per year.

Body weight was 70kg, body mass index was 26.4 kg/m2, blood pressure 150/80, heart rate 80/min, temperature 37.0 C, breathing normal.
Leukocytosis of 15.700/mm3, Hb 17.0 g/dl, platelets 364000/mm3, CRP slightly increased to 2.3 mg/dl. Serum creatinine was 1.1 mg/dl, Hst-N and diuresis normal.
Cardiac, abdominal, neurological and pulmonary status was normal.


  1. Nankivell BJ et al.; The Natural History of Chronic Allograft Nephropathy, NEJM Vol. 349:2326-33, 2003.
  2. Briganti EM et al.; Risk of renal allograft loss from recurrent glomerulonephritis, NEJM Vol. 347, No. 2:103-9, 2002.
  3. Nickeleit V et al.; Polyoma nephropathy: morphology, pathophysiology and clinical management, Curr Opin Nephrol Hypertens 12:599-605, 2003.
  4. De Bruyn Guy et al., BK virus-associated nephropathy in kidney transplant recipients, Rev Med Virol 14:193-205, 2004.
  5. Reploeg MD et al.; BK Virus: A Clinical Review, CID 33:191-202, 2001.
  6. Mannon RB; Polyomavirus Nephropathy: What have we learned? Transplantation Vol. 77, No. 9:1313-1316, 2004.
  7. Fishman JA, BK Nephropathy: What is the Role of Antiviral Therapy? Am J Transplant 3:99-100, 2003.
  8. Buehrig CK et al., Influence of surveillance renal allograft biopsy on diagnosis and prognosis of polyomavirus-associated nephropathy, Kid Int Vol. 64:665-673, 2003.
  9. Rui-Mei LI et al.; Molecular Identification of SV 40 Infection in Human Subjects and Possible Association with Kidney Disease, J Am Soc Nephrol 13:2320-2330, 2002
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Question 1) - What is the diagnosis in this patient?
(Only ONE answer is correct)

> a) arterial thrombosis
> b) arterial embolus
> c) venous thrombosis
> d) both venous and arterial thrombosis
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Doppler sonography demonstrated both venous and arterial thrombosis. An angiography was performed (Figure 1).

Figure 1:

The results of the above, together with the clinical symptoms, led to a diagnosis of thromboangitis obliterans. Thrombectomy of the A. poplitea combined with lumbar sympathectomy, as well as local thrombolytic therapy of the A. tibialis anterior and posterior, were performed. The symptoms improved and the patient was scheduled to be discharged from hospital.
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In a routine check-up two weeks after admission, creatinine was found to have increased to 1.8 mg/dl and a few days later to 2.4 mg/dl. Urine stix was 1+ for leukocytes and blood, 3+ for protein. Urine sediment showed some non glomerular erythrocytes, 8-10 leukocytes, no cylinders, many epithelial cells, some bacteria per field of vision. Glomerular, non-selective proteinuria of 6.6 g/24h was detected. emolytic-uraemic syndrome (HUS) could be hypothesized on the basis of the association of thrombocytopenia and anaemia, in spite of the absence of schistocytes. Haemolytic anaemia superimposed on anaemia secondary to renal failure could be suspected on the basis of elevated LDH and reduced haptoglobin. The patient’s age and the incomplete haematologic parameters made this hypothesis not convincing.

What is the most likely cause of renal impairment in this case? <%if currentID = 22 then%> <%end if%>

Question 2) - Would you have done a CT scan to look for pyelonephritic lesions?

> a) Contrast media
> b) Renal vein thrombosis
> c) RPGN
> d) Cholesterol emboli
> e) Antiphospholipid antibody syndrome
> f) Glomerulopathy
> g) Hard to say
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Due to a possible link between combined arterial/venous thrombosis and renal failure, the following diagnoses were considered:
  • Vasculitis
  • Antiphospholipid syndrome (primary-secondary)
  • Glomerulopathy (primary-secondary) with nephrotic syndrome
  • Left and right renal vein thromboses due to coagulopathy, malignancy, obstruction
  • Compartment syndrome with Rhabdomyolysis
  • Septicemia
  • Thrombangiitis obliterans (with renal participation?) and/or contrast media mediated ATN
  • Renal and peripheral atheroemboli or cholesterol emboli

Renal ultrasonography showed large kidneys with a thick parenchyma, a slightly hyperechogenic cortex, hypoechogenic medulla, and no signs of obstruction. The following serum parameters were negative/normal:
  • cryoglobulins ,
  • Anti-streptolysin.
  • Complement C3, C4.
  • Anti GBM-Ak by indirect immunfluorescence
  • c-ANCA, p-ANCA, ANA, ds-DNA-Ak
  • Cardiolipin-Ak
  • Protein S, C, APC-resistance.

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Nevertheless, serum creatinine further increased to 2.8 mg/dl and a renal biopsy was performed:
Figure 2 (Courtesy of Prof. U. Helmchen, University of Hamburg, Germany):

Figure 2:

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Question 3) - What do you see on these pictures of figure 2?

> a) Normal glomerulus
> b) Mesangial proliferative glomerulonephritis
> c) Crescentic glomerulonephritis
> d) Focal segmental glomerulosclerosis
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Renal biopsy (Prof. U. Helmchen, University of Hamburg, Germany):

Severe scarring and acute necrotising crescentic glomerulonephritis. Detection of linear GBM staining for human IgG indicates specific tissue-deposition of anti-GBM antibodies and, therefore, antiglomerular basement membrane disease.

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Question 4) - What results do not fit very well in this case?

> a) Urine sediment and renal biopsy
> b) Serum antibody titers and renal biopsy
> c) Proteinuria and renal biopsy
> d) Thrombotic events and renal biopsy
> e) all of these
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Antiglomerular basement membrane disease is caused by autoimmunity to a specific component of the GBM that has been identified as the carboxy-terminal, noncollagenous (NC1) domain of a type IV collagen chain ?3(IV)NC1 (1). In connection with lung hemorrhage, this rapidly progressive renal disease is called Goodpasture’s disease. Usually, the manifestation of RPGN by antiglomerular basement membrane disease is indicated by an nephritic sediment, which is not seen here. However, in rare cases, active glomerular diseases may occur without a nephritic sediment.
Depending on the specific detection method and the type of ELISA for detection of antiglomerular basement antibodies, these methods have limitations regarding specificity and sensitivity (2, 3). In particular, subacute time courses of antiglomerular basement membrane disease may have negative serum antibody titers but positive linear staining along the GBM.
RPGN is usually not associated with nephrotic syndrome and large scale proteinuria but, dependent on the degree of glomerular damage, proteinuria may be severe. Anti-GBM nephritis is not particularly associated with thrombotic events, but a nephrotic-range proteinuria may predispose to thrombotic events. In this context, it is possible, but unlikely, that anti-GBM disease may have caused severe glomerular damage with nephrotic-range proteinuria already at the time point of thrombotic events, when creatinine was still completely normal.

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Question 5) - What do you think of this case?

> a) The pathologist must be wrong
> b) Linear staining of the GBM is probably unspecific
> c) This patient has two different renal diseases
> d) This patient has an atypical FSGS
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Question 6) - What else could you do to get a better picture?

> a) Ask the pathologist again about his diagnosis
> b) Get an EM of the renal biopsy
> c) Ask the patient about specific, previous symptoms
> d) Get former lab results
> e) All of these
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The nephropathologist confirmed his diagnosis of crescentic anti-GBM disease. Crescentic glomerulonephritis was very homogenous – most crescents appeared to be at a similar stage (in contrast to vasculitic lesions).The pathologist also confirmed specific, linear and not pseudolinear IgG-staining of the GBM; IgA or IgM were not detected. Granular (by immunofluorescence) staining may appear pseudolinear in membranous glomerulopathy. Unspecific linear anti-GBM staining may appear in renal diseases such as diabetes, lupus erythematosus, light chain disease, or fibrillary glomerulopathies (4). The lesion was clearly distinct from FSGS, typical hyperproliferative crescentic lesions could be identified. <% newID = 7 else newID = 66 %>

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The coexistence of two distinct glomerular diseases was hypothesized and the following additional information supports a preexisting membranous nephropathy:

1.) Table 1: Age dependency of nephrotic syndrome

Membranous nephropathy is the most common cause of nephrotic syndrome at the age of this patient.

2.) Indicators of a preexisting nephrotic syndrome:
- The thrombogenic complications happened at a time when renal function was normal. Unfortunately, no urine analysis was done at that time or at any time before. Nevertheless, a smouldering time course of anti-GBM disease should not cause nephrotic-range proteinuria when creatinine is still normal.
- At the time of the venous and arterial thrombosis, the patient already had all the symptoms of a nephrotic syndrome, including a 3+ urine stix, low serum albumin and protein, and pretibial edema.
- The patient reported that he had suffered from pretibial edema for many years now, mainly in the evening, but does not have substantial varicosis. Sometimes in the past, he had noticed foamy urine.

3.) Electron microscopic evaluation of the biopsy revealed the presence of subepithelial electron-dense deposits especially in glomeruli with little damage indicating membranous nephropathy.
A typical EM picture of this patient is seen in Figure 3 and the subepithelial deposits are indicated by arrows.

Figure 3:

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Question 7) - What potential secondary causes can trigger anti-GBM disease?

> a) Systemic vasculitis
> b) Membranous nephropathy
> c) Renal transplantation in a patient with alport syndrome
> d) Obstructive nephropathy or lithotripsia of renal stones
> e) all of the above
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Several case reports have indicated that anti-GBM antibodies are occasionally identified in patients with coincident renal disease as indicated in question 7. It has been suggested that these renal diseases might lead to the unmasking of certain antigens of the GBM that could trigger the production of anti-GBM antibodies.
In literature, about twenty case reports have documented the superimposition of a crescentic glomerular lesion in membranous nephropathy (5, 6). About half of these cases showed crescentic glomerulonephritis, clear-cut linear staining of the GBM (and anti-GBM antibodies in serum) and subepithelial granular deposits (by EM) typical for underlying membranous nephropathy. About 40% of patients progressed from membranous nephropathy to crescentic anti-GBM nephritis, in 40% both diseases were diagnosed at the same time, but nephrotic syndrome was preexisting, while in 20% of cases anti-GBM disease came first and membranous nephropathy developed later on. In all cases, disease progression towards end-stage renal disease was rapid and prognosis was generally bad.
In this case, due to the diagnosis of crescentic glomerulonephritis, immunosuppressive therapy with cyclophosphamide and steroids was started, when creatinine was already at 3.4 mg/dl.
Two weeks later, the patient asked for a second opinion at the outpatient clinic of our Department. Meanwhile, the serum creatinine was 4.7 mg/dl. At that time, proteinuria was still in the nephrotic range, urine sediment was still not nephritic, and the ELISA for anti-GBM antibodies was negative. Extensive reevaluation of the history and laboratory data suggested the pre-existence of membranous nephropathy and nephrotic syndrome in this patient, which was confirmed by the nephropathologist evaluating the renal biopsy by EM.
Screening for malignant diseases as secondary causes of renal disease (membranous nephropathy) was completed and negative. Being concerned about false negative antibody titers, plasmapheresis was added to the therapeutic regimen and the immunosuppressive treatment was continued for 6 months. Dialysis therapy could be prevented. Serum creatinine and proteinuria was stabilized to 1.8-2.0 mg/dl and approx. 1g/24h, respectively, thanks to combined ACE-inhibiting and AII receptor antagonistic drugs.

We are indebted to Professor Dr. U. Helmchen (Nephropathology, University of Hamburg, Germany) for providing the renal histologies of the patient. <% newID = 8 else newID = 77 %>

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