Relapsing oligosymptomatic fever in a kidneypancreas transplant recipient
Giorgina Barbara Piccoli1,
Manuel Burdese1,
Giuseppe Picciotto2,
Tina Mele3,
Maura Rossetti1,
Fedele Lasaponara4,
Elisabetta Mezza1,
Massimo Gai1,
Maria Messina1,
Antonella Sargiotto2,
Giacomo Lanfranco1 and
Giuseppe Paolo Segoloni1
1 Chair of Nephrology, Department of Internal
Medicine, University of Torino, Torino, Italy2
Nuclear Medicine Unit3
II Department of Radiology4
Department of Urology, ASO S. Giovanni Battista,
Torino, Italy
Email: gbpiccoli{at}yahoo.it
Case
MV is a 53-year-old woman, who has suffered from type 1 diabetes since the age of 24, widespread end-organ damage: laser-treated retinopathy, nephropathy and (dialysis-dependent since 1998), polyneuropathy, with orthostatic hypotension and episodes of gastroparesis. Her clinical history: surgical removal of mammalian fibro-adenoma in 1984, right ovariectomy in 1986 (ovarian cyst) and acute cholecystitis in 1996. In 1986, diagnosis of large uterine myoma (diameter 6.5 cm).
A simultaneous pancreas kidney transplantation was performed in 2001, with portal-enteric drainage: the post-surgical course was uneventful, renal function and glycaemic control were good (at hospital discharge, serum creatinine 1.2 mg/dl). Immunosuppressive therapy consisted of steroids, mycophenolate mofetil and FK506; long-term prophylaxis for Pneumocystis carinii was started with co-trimoxazole. A cytomegalovirus (CMV) infection, occurring in the first months, was treated by ganciclovir.
Starting from the third month after transplantation, the patient experienced 12 recurrent febrile episodes (from May 2001 to August 2002), characterized by abrupt onset, mild transient leukocytosis, absence of symptoms pointing to any organ or apparatus, and by a prompt response (within 1224 h) to cycles of beta-lactamines. Serum creatinine remained stable (0.81.2 mg/dl). Physical examination was always unspecific.
Since the pattern was consistent with a common, rapidly responsive bacterial infection, several differential diagnoses were considered, starting from the urinary infections, probably the most common relapsing infections in renal graft patients (Table 1).
Cultural and serological tests were always negative (Table 1). Overall, 22 urine cultures were performed and only displayed Escherichia coli at low titre (25 00050 000 c.f.u./ml, respectively). The microscopic urinalyses, performed at the same time as urine cultures, at the onset of the febrile episodes or immediately afterwards, were unspecific (<6 white cells per microscopic field 400x, occasional hyaline casts, few red cells per field). Urodynamic tests were normal. The lack of symptoms, with negative urine culture and microscopic urinalysis, without increase in serum creatinine, and without any suggestive image at ultrasound renal scan, oriented the diagnostic pathway towards the search for an occult infectious focus in other settings (Table 1).
Questions
The diagnostic pathway of one of the most common causes of infection was incomplete; which test may be added?
What is your diagnosis?
Answers to the quiz on the preceding page
The cause of fever is acute pyelonephritis of the grafted kidney.
In order of probability, urinary infections came first as cause of acute infections, rapidly responsive to antibiotic therapy, after a renal graft: diagnosis is usually easy, in the presence of pollachiuria-dysuria, positive urine culture and white blood cells at microscopic urinalysis. Acute graft pyelonephritis is a potentially severe complication, with a reported incidence of 23%. The diagnosis is usually self-evident, with high fever, graft tenderness, often with low abdominal pain, increase in serum creatinine, bacteriuria and positive urine culture and leukocyturia often accompanied by bacteraemia [13]. While the differential diagnosis of relapsing fever in the immuno-compromised host takes into account a vast array of diseases (Table 1), atypical, smouldering presentations of acute pyelonephritis have been occasionally described in kidney graft recipients [47]. Therefore, taking into account the possibility of late shedding of white cells and of white cell casts, microscopic urinalysis was scheduled on alternate days, as the result of a cast-trapping phenomenon, due to the interstitial and peritubular oedema in the acute phases of pyelonephritis [8]. White cell casts were found in the urinary sediment 46 days after the resolution of the last febrile episode (Figure 1).

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Fig. 1. Microscopic urinalysis (400x), performed 4 and 5 days after the resolution of the febrile episode, showing the presence of white blood cells and casts (small box).
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99Tc-DMSA renal cortical scintigraphy showed a large, wedge-shaped, uptake defect at the upper polar region, suggesting acute pyelonephritis: the pattern of a large defect with indistinct margins, not affecting the kidney outline, indicated an acute involvement rather than chronic sequelae (Figure 2) [9].

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Fig. 2. 99Tc-DMSA renal cortical scintigraphy: a large, wedge-shaped, uptake defect at the upper polar region suggests an acute pyelonephritis.
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A computed tomography (CT) scan with contrast media, performed after a further relapse of a febrile episode, shortly after discontinuation of antibiotic therapy, demonstrated a hypodense, triangular area in the upper-polar region of the grafted kidney, clearly hyperdense, with late enhancement, suggestive of an acute lobar nephronia (Figure 3). In the search for predisposing factors, retrograde cystography was performed, showing moderate vesico-ureteric reflux. An endoscopic treatment with dextranomer-hyaluronic acid was performed, with a complete resolution at bladder scintigraphy.

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Fig. 3. CT scan with contrast media: a hypodense, triangular area in the upper-polar region of the grafted kidney (arrow) is suggestive of an acute lobar nephronia.
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The patient is presently free from infectious episodes, under chronic treatment with methenamine.
The case presented here, characterized by the complete negativity of urine cultures and microscopic urinalysis and by the lack of urinary tract symptoms, despite significant parenchymal involvement, may exemplify the limits of the common diagnostic pathways in these cases [4,9,10].
In detail:
- the absence of urinary symptoms was reported in few cases in the literature, and is presumably linked to the anaesthetic effect of diabetic neuropathy [4,911];
- the negativity of urinary cultures may be explained by the combined effect of high water intake, together with the chronic prophylaxis with trimethoprim sulphametoxazole; the negative microscopic urinalysis may be explained by the delayed appearance of leukocyte casts in acute pyelonephritis [8];
- the stability of renal function, once more in disagreement with the typical pictures [1,2,4,10], may be linked to the high renal mass and functional reserve of the grafted kidney, in a patient with low body size;
- the complete negativity of ultrasound scan is, on the contrary, not surprising, due to the low diagnostic power of this technique in non-complicated acute pyelonephritis, even if the lack of scars, after repeated episodes, is unusual. An anti-scarring effect of low dose corticosteroids may be postulated, but needs further confirmation and has so far never been reported in such a setting [6].
In summary, diagnosis of acute pyelonephritis may be very elusive after kidney transplantation and should be suspected in the presence of all fevers of unknown origin, even in the absence of apparent risk factors and of suggestive laboratory or standard radiological images.
The fact that after a series of sophisticated laboratory and radiological procedures (Table 1), the first diagnostic evidence derived from the positivity of microscopic urinalysis, gives room to underline the importance of this simple and inexpensive test, too often considered as trivial and not used to its full potential.
Conflict of interest statement. None declared.
References
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