- Email: [email protected]
Fever, nephrotic syndrome, and rapidly progressive renal failure
the renal consult
http://www.kidney-international.org & 2007 International Society of Nephrology
Fever, nephrotic syndrome, and rapidly progressive renal failure H Izzedine1, I Brocheriou2, V Martinez3, L Camous1, M-C Guillemont1 and G Deray1 1
Department of Nephrology, Pitie-Salpetriere Hospital, Paris, France; 2Department of Pathology, Pitie-Salpetriere Hospital, Paris, France and 3Laboratory of Cellular Immunology, Pitie-Salpetriere Hospital, Paris, France
CASE PRESENTATION A 52-year-old African woman, living in France since 5 years, presented with dyspnea and pyrexia. She had a 1-month history of sore throat treated with amoxicillin, migratory polyarthralgia, drenching night sweats, and an evanescent, maculo-papular, non-pruritic rash mainly on her limbs lasting less than 1 week at a time. She denied smoking, alcohol abuse, and illicit drugs use. She had no risk factors for HIV. Examination on admission revealed a temperature of 39.51C, tachycardia, a blood pressure of 120/70 mm Hg, pallor, jaundice, splenomegaly, and bilateral inflammation of knee and ankle joints with synovitis, and severe tenderness of the wrist with signs of fluid overload. There was no sign of meningeal irritation, no focal neurological deficit and normal fundus examination. There were fine crepitations involving the left lung base. Heart sounds were normal on auscultation with no murmur. She was admitted for analgesia and antibiotics pending the results of infective screens and blood tests. Peripheral smear showed no malarial parasite. Her coagulation profile was normal and there was no biochemical evidence of hemolysis. Biochemistry values are summarized in Table 1. Human Immunodeficiency Virus serology, plasma HIV viral load, and p24 determination were negative. Serologies for, hepatitis B and C, Parvovirus B19, cytomegalovirus, Epstein–Barr virus, leptospira, bartonella, rickettsia, chlamydia, mycoplasma pneumoniae, legionella, Widal test, rapid malaria test, toxoplasma, and syphilis were all negative. Brucella agglutination test and leishmania leukococentration were also negative. Hemoglobin electrophoresis ruled out sickle cell disease. Laboratory evaluation for systemic or malignant diseases, including rheumatoid factor, antibodies to double-stranded deoxyribonucleic acid, smooth muscle cell, liver/kidney Correspondence: H Izzedine, Department of Nephrology, La Pitie´-Salpeˆtrie`re Hospital, 47–80 Boulevard de l’Hoˆpital, Assistance Publique-Hopitaux de Paris, Pierre et Marie Curie University, 75013 Paris, France. E-mail: [email protected]
microsomal, mitochondrial, anti-cardiolipin, anti-Scl, antineutrophilic cytoplasmic antibody, anti-Ro, anti-La, anti-SM, anti-ribonucleoprotein, anti-Jo-1, and anti-glomerular basement membrane antibodies were all negative. Immunological parameters were noncontributory with polyclonal hypergammaglobulinemia, normal immunoglobulin (Ig) A, IgM, complement levels, and negative cryoglobulinemia. Chest X-ray was normal. Renal ultrasound showed enlarged, swollen kidneys measuring 12.6 cm in length each. Total body computed tomography revealed splenomegaly, with the rest of the scan being unremarkable. This association between a nephrotic syndrome, fever, cutaneous lesions, pharyngitis and arthralgias suggested the diagnoses of either postinfectious or membranoproliferative glomerulonephritis. A first trans-jugular kidney biopsy was then performed (Figure 1). Trans-thoracic echocardiography suspected the presence of mitral valve endocarditis. Despite empirical treatment with Cefotaxim and gentamicin, she did not improve. The maculo-papular rash on her limbs persisted alongside with high fevers. Bone marrow biopsy and aspiration revealed moderately hyper-cellular marrow with trilineage maturation, and increased number of macrophages, however, without hemophagocytosis. Repeated serologies and cultures were negative. A second trans-oesophageal echocardiography revealed that the systolic function and chamber sizes were normal; there was no valvular dysfunction, evidence of vegetations, nor pericardial effusion. Her renal function worsened (creatinine peaking at 600 mmol/l 1 week later) and hemodialysis became necessary. Suspecting a rapidly progressive glomerulonephritis, of postinfectious or vasculitic nature, a second trans-jugular kidney biopsy was performed (Figures 2 and 3). At this stage we were faced with a severely ill 52-year-old African woman presenting with pyrexia of unknown origin, migratory polyarthopathy, fleeting maculopapular rash, pancytopenia, and rapidly progressive glomerulonephritis with renal failure requiring renal support.
Kidney International (2007) 72, 651–656; doi:10.1038/sj.ki.5002298; published online 25 April 2007
KIDNEY BIOPSY FINDINGS
Received 26 January 2007; revised 16 March 2007; accepted 20 March 2007; published online 25 April 2007
The two renal biopsies were similar and consistent with collapsing glomerulopathy (CG) (Figure 1).
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Table 1 | Biochemistry values at baseline and after 2 weeks follow-up Laboratory tests 3
WBC count ( 10 /ml) Neutrophil count ( 103/ml) Hemoglobin (g/dl) Platelet count ( 103/ml) Peripheral smear Haptoglobin (g/l) Bilirubin (mmol/l) ALT (IU/l) Urea (mmol/l) Creatinine (mmol/l) Albumin (g/l) LDH (IU/l) CRP (mg/l) Ferritin (ng/ml) Triglyceride (mmol/l) Dipstick urinalysis Urine microscopy 24 h urinary protein (g)
At admission
Two weeks later
13.2 8.5
15.5 10.0
8.2 80.000
7.0 60.000
Microcytic hypochromic, anisopoikilocytosis, and polychromatic cells, without schizocytes 2.50 2.30 20 77 25 78 7.6 150 550 27 21 1269 1065 150 200 2570 4000 10 10 4+ protein without leukocyte or red blood cells RBCs less than 1000/ml WBCs less than 1000/ml (less than 1 HPF for both), no casts 5.2 then 10 without urinary Bence Jones protein
Figure 2 | The glomerular tuft is segmentally collapsed with podocyte hypertrophy associated with microcystic dilatation of tubules and mild lymphocytic interstitial infiltrate consistent with CG. Masson’s trichrome, original magnification 400.
ALT, alanine aminotransferase; CRP, C-reactive protein; LDH, lactate dehydrogenase; RBCs, red blood cells; WBC, white blood cell.
Figure 3 | Glomerular basement membrane collapse with hypertrophy of the overlying podocytes. Jones methenamine silver; original magnification 200.
Figure 1 | The glomerular tuft is segmentally collapsed with podocyte hypertrophy associated with microcystic dilatation of tubules and mild lymphocytic interstitial infiltrate consistent with CG. Masson’s trichrome, original magnification 200.
For each, two cores of renal cortex were examined histologically after routine processing and staining. At least 25 glomeruli were sampled, of which six were sclerotic. One contained a segmental sclerosis and seven were essentially normal. The remaining 11 (45%) showed tuft collapse in association with prominence of Bowman’s space. There was no necrosis, crescents, nor proliferative features within the glomeruli. Immunohistochemistry revealed a small amount of trapped mesangial IgM and complement; IgG and IgA were completely negative. Congo red staining was also negative. Acutely damaged tubules with dilatation, flattened epithelial cells, and cytoplasmic vacuolation were seen. Moderate scarring with a patchy mixed inflammatory cell infiltrate was also present, occasionally with intra-tubular 652
infiltration by polymorphs. The vessels were essentially normal. Electron microscopy was not performed. PATHOLOGICAL DIAGNOSIS
CG in the setting of febrile pancytopenia and arthritis. CLINICAL FOLLOW-UP
The patient was diagnosed with adult onset Still’s disease (AOSD) because she met the Yamaguchi et al.,1 Cush et al.,2 and Fautrel et al.3 criteria for this diagnosis (Table 2). Glycosylated ferritin was at 52% in our patient. This marker is considered a better diagnostic tool for AOSD than total serum ferritin.3 It may, however, also be observed in macrophage activation syndrome (MAS) of other origins and so cannot be distinctive.4 She was treated with intravenous immune globulin (IVIG) (total dose 2 g/kg given over 4 days) in association with methylprednisolone pulses 15 mg/kg daily for 3 days, followed by 1 mg/kg daily prednisone with partial symptomatic improvement. Fevers ceased the day after initiation of Kidney International (2007) 72, 651–656
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H Izzedine et al.: Rapidly progressive renal failure
Table 2 | AOSD diagnostic criteria Yamaguchi et al. Major 2 points Arthralgia42 weeks* Fever4391, intermittentX1 week* Typical rash* WBC410 000 (480% granulocytes)*
Minor 1 point Sore throat* Lymphadenopathy and/or splenomegaly* LFT abnormal Negative ANA and RF*
Diagnostic Five criteria (at least two major)
Cush et al.
Fautrel et al.
Quotidian fever4391* Evanescent rash* WBC412 0*+ESR440 mm/1st h Negative RF and ANA* Carpal ankylosis
Spiking fever X 391* Arthralgia* Transient erythema* Pharyngitis* PMNX80%* Glycosylated ferritinp20%
Onset age o32 years Arthritis* Prodromal sore throat* RES involvement or abnormal LFTs Serositis* Cervical or tarsal ankylosis
Maculopapular rash* LeukocytesX10 109/l*
Probable AOSD: 10 points with 12 weeks’ observation Definite AOSD; 10 points with 6 months’ observation
Four major criteria or three major+two minor
ANA, anti-nuclear antibodies; AOSD, adult onset Still’s disease; ESR, erythrocyte sedimentation rate; LFT, liver function test; PMN: polymorphonuclear cells; RES: reticuloendothelial system; Rh, rheumatoid factor; WBC, white blood cell. *Our patients.
pulse methylprednisolone. However, as the steroids were given orally, her symptoms recurred within 3 days and she developed hepatitis, which may have been triggered by a medication or by an acute infection. All blood cultures obtained throughout the course of her illness were sterile. The patient have a global T-cell lymphopenia (443/mm3) and the analysis of flow cytometry show that during follow-up, 78–90% of monocytes–macrophages were activated (expression HLA DR). At that point, it was concluded that the addition of another agent to control disease activity was indicated. The recently reported use of anticytokine or anti-CD20 agents in refractory cases has opened new horizons in the treatment of AOSD. Amid these newly added options we have chosen Anakinra due to its better side effects profile. Anakinra (Kineret; Amgen, Inc., Thousand Oaks, CA, USA) 100 mg subcutaneously twice weekly coordinated with the dialysis schedule was initiated in association with dexamethasone pulse 40 mg daily for 3 days, resulting in remission of the rheumatological condition closely paralleled by remission of proteinuria and renal function, thereby strongly suggesting a causative link between AOSD and CG. Anakinra was well tolerated and without burning at the injection sites. Marked improvement in renal parameters has been noted, 10 days after the combined therapy. This improvement was manifested by the recovery of normal diuresis and dialysis withdrawal. Meanwhile, her renal function remained stable and she was free of dialysis, with serum creatinine within the range of 160–180 mmol/l and proteinuria of 2 þ . She was prescribed prednisone 1 mg/kg daily in four split doses. The delay Kidney International (2007) 72, 651–656
between institution of treatment and remission and dialysis stopping was 2 months. DISCUSSION
We report a rare case of AOSD-related MAS and CG which dramatically improved with interleukin-R (IL-R) antagonist and corticosteroid combination. Nephrotic syndrome associated to a febrile pharyngitis raises first the possibility of a postinfectious GN. However, the presence of CG on biopsy alongside with the clear cutaneous and articular manifestations were clues to a primary joint disease such as AOSD. Only 16 cases of AOSD-related MAS have been reported in the English language literature.5 On the other hand, Albaqumi et al.6 in their recent and excellent review on CG, mentioned only two and five cases related to AOSD7,8 and MAS,9 respectively. Table 3 summarize characteristics of the three AOSD-related CG African patients’ including ours. Collapsing glomerulopathy
CG is a distinct pattern of renal injury characterized by global or segmental collapse of the glomerular tuft, visceral hypertrophy, and hyperplasia accompanied with varying degrees of tubulointerstitial injury. It is frequently and primarily seen in patients with HIV infection10 and recently has been increasingly recognized with non-HIV medical conditions10,11 (Table 4). However, CG was rarely recognized to be MAS- or AOSD related. Clinically, CG is typically characterized by more or less abrupt onset of nephrotic-range proteinuria with rapid progression to end-stage renal failure. Laurinavicius et al.10 reported nephrotic-range proteinuria at 653
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Table 3 | Clinical and laboratory data for three patients with CG and AOSD Adult onset Still disease
Characteristics Literature Patients number age/gender/ race
No. 2 32/Man/African
No. 3 52/Woman/African
Clinical findings and biological parameters Fever 39.51C Arthritis/synovitis +/+ Hepato-splenomegaly + Adenopathy + Skin rash + Hemoglobin (g/dl) 7.8 13.2 White blood cell count (103/ml) Neutrophils count (%) 74.4 Not available Platelet count (109/l) LDH (IU/l) 1,269 Ferritin (ng/ml) 4970
401C +/ + + 7.7 17.3 14.4 444 1065 38 691
39.51C +/+ + + 7.2 17.5
Renal abnormalities Serum creatinine (mmol/l) Proteinuria (g/24 h) Serum albumin (g/l) Microhematuria Kidney size
220 5.1 31 Enlarged (12.6 cm)
515 7.2 11 Not available
180 3.5 27 Normal (11 cm)
11/25 6/25 Dilatation with prominent luminal proteinaceous casts
Several Not available Microcyst tubular dilatation, flattened epithelial cells, and cytoplasmic vacuolisation Not available
11 6 Tubular dilatation, flattened epithelial cells, and cytoplasmic vacuolisation Patchy inflammatory infiltrate
Not available Negative Swollen epithelial cells with partial effacement of the foot processes. No electron-dense deposit
Normal Negative Not performed
Oral steroid
No
No No No Well 3 years later No
MMF 1 g daily 0.4 g/kg daily for 5 days No Well 15 months after No
Pulse of methyprednisolone, then oral steroid Negative 0.5 g/kg daily for 4 days Anakinra Well 2 months after Transient
Kidney pathology No. of collapsed glomeruli No. of sclerotic glomeruli Tubules
Interstitium Vessels Immunofluorescence Electron microscopy
Treatment and outcome Steroids Cytotoxic agents Iv Ig IL-1-ra Outcome Dialysis
No. 1 46/Woman/African
Our case
Moderate scarring with a patchy mixed inflammatory cell infiltrate Normal Negative No electron-dense deposits, no fibrillary or light-chain material, and no tubulo-reticular inclusion bodies within endothelial cells
70 1065 4000
IL-1-ra, interleukin-1-receptor antagonist; Iv Ig, intravenous immunoglobulin; LDH, lactate dehydrogenase.
the time of initial presentation in 89% of patients with a median renal survival of 13–16 months. Variable outcome with respect to renal survival has been observed, with regimens consisting of steroids, with or without cyclophosphamide or cyclosporin.10,11 Valeri et al.11 noted a 14% total remission rate among the CG patients, including few attaining spontaneous remission without any therapy. Targeting the AOSD with subsequent improvement of the renal parameters indicated that CG was not an epiphenomenon. Amid the multiple etiologies of CG, our patient presented two quite rare causes. 654
Macrophage activating syndrome
MAS or hemophagocytic lymphohistiocytosis is a rare and potentially fatal disease of normal but overactive histiocytes. It is of two types – primary MAS as observed in various genetic diseases affecting the immune system and secondary (or acquired) MAS that occurs after strong immunologic activation – systemic infection (virus, bacteria, and protozoa), autoimmune disorders, or underlying malignancy. The clinical entity has to be suspected when patients present with fever unresponsive to antibiotics, general fatigue, falling erythrocyte sedimentation rate, pancytopenia of unknown origin and liver dysfunction with low fibrinogen levels, Kidney International (2007) 72, 651–656
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Table 4 | Secondary causes of collapsing glomerulopathy
Adult-onset Still disease
Infections HIV Parvovirus B19 Others (HCV, CMV, leishmaniasis, filariosis, tuberculosis, etc)
Adult-onset Still disease is a systemic inflammatory condition of unknown etiology. In 1971, Bywaters16 first described this new disease entity that he named adult Still’s disease. It involved adult patients who did not meet the criteria for classic rheumatoid arthritis but displayed features similar to those described in pediatric Still’s disease. However, the earliest documentation of an adult with signs and symptoms of AOSD was published in 1896.17 Its prevalence has been estimated to be lower than one case per 100 000 persons.18 In clinical practice, AOSD is usually considered a diagnosis by exclusion particularly when it presents as fever of unknown origin. Owing to the ambiguity of its definition and the lack of serologic markers, several criteria have been proposed for AOSD in the literature.1–3,19 Kidney involvement has been rarely reported in AOSD. Mesangial glomerulonephritis, disseminated intravascular coagulation, thrombocytopenic purpura,20 interstitial nephritis,21 subacute glomerulitis,22 and renal amyloidosis leading to renal insufficiency have been reported to occur in patients with AOSD. Kumar et al.8 reported a 46-year-old Afro-Carribean woman who presented concomitant occurrence of AOSD and CG. The patient was treated with steroids, resulting in remission of the rheumatological condition closely paralleled by remission of proteinuria and renal function, thereby strongly suggesting a causative link between AOSD disease and CG. Bennett et al.7 reported severe AOSD and CG improved successfully with intravenous immune globulin and mycophenolate mofetil in a 32-year-old African man. The pathogenesis of AOSD is poorly understood and the treatment empirical. It essentially involves the use of nonsteroidal anti-inflammatory drugs, steroids, immunosuppressants, and, currently, biologic agents to control fever, arthritis, and systemic disease. Elevated levels of IL-1 have been implicated in the pathogenesis of AOSD and IL-1 blockers have emerged as possible therapeutic options. Aelion et al.23 reported the successful outcome of daily subcutaneous anakinra (100 mg), a recombinant IL-1 receptor antagonist (IL1-rA), in two patients with persistent AOSD. The first patient achieved complete clinical remission on anakinra alone within days, paralleled by normalized laboratory values, while the other patient was weaned off corticosteroids within weeks and remained in remission on anakinra and MTX.23 In another series of three AOSD patients, addition of anakinra to a corticosteroid regimen resulted in clinical improvement within days and, subsequently, tapering of the corticosteroid dosage.24 A recent study of four patients also demonstrated the efficacy of anakinra in refractory AOSD. Remission was sustained, and prednisone eventually discontinued, in three of the four patients. Convincingly, when anakinra was withdrawn in two patients, their disease relapsed with fever, arthritis, rash, and elevation of laboratory markers within days. Both patients rapidly responded to reinstitution of IL-rA.25 CG must be suspected in AOSD and/or MAS with unexplained renal insufficiency or proteinuria. In this
Drugs and toxic Pamidronate Interferon Heroin Post transplantation De novo Recurrent Others (thrombotic microangiopathy, acute vascular rejection, etc) Autoimmune disorders Systemic lupus erythematous-like disease Adult Still disease Others (mixed connective tissue disease, cerebral arteritis, etc) Inflammatory disease Weber-Christian disease Malignancies Multiple myeloma Acute monoblastic leukemia Macrophage activation syndrome Genetic disorders Mitochondrial cytopathy Action myoclonus-renal failure syndrome Homozygous sickle cell anemia CMV, cytomegalovirus; HCV, hepatitis C virus.
marked hypertriglyceridemia, and elevated ferritin, lymphadenopathy, and sometimes skin rash, lung infiltration.12 There are few reports of renal involvement in MAS. Acute renal failure is thought to be the most consistent feature12 and is considered by some authors as a strong prognostic factor.13 In one series of 57 patients with reactive MAS, 62% had evidence of renal impairment with 17% requiring dialysis.14 Moreover, in a multicentric retrospective study which included 11 patients, acute renal failure was associated with nephrotic syndrome in 90.9% and death occurred in seven cases.9 However, Ramanan et al.15 describe three children with systemic onset juvenile rheumatoid arthritis who had glomerular involvement complicating MAS with a favorable outcome. Nonetheless, biopsy-proven renal involvement has remained poorly documented. Thaunat et al.9 clarified the clinicopathological profile of patients with nephrotic syndrome occurring during MAS in 11 HIVnegative black African patients. Renal pathological findings included CG (45.5%), minimal change glomerulopathy (36.3%), and thrombotic-microangiopathy (18.2%). Treatment of MAS is not uniform. In the absence of prospective controlled trials in MAS, corticosteroids, cyclosporin A, etoposide, anti-tumor necrosis factor-a drugs, and plasmapheresis are administered with varied success. Kidney International (2007) 72, 651–656
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situation, renal biopsy is necessary to establish a definitive diagnosis. Historically, treatment consisted of nonsteroidal anti-inflammatory drugs, often in combination with low-dose corticosteroids. Immunosuppressants (mainly methotrexate, but also intramuscular gold, azathioprine, cyclosporine A, leflunomide, and cyclophosphamide) and intravenous g-globulin are efficacious and have been used as steroid-sparing drugs. The recently reported use of anticytokine and anti-CD20 agents in refractory cases has opened new horizons in the treatment of AOSD and provided important clues as to its pathophysiology. Anakinra in addition to steroids looks like a promising combination for the treatment of this condition as it was the case in our patient. REFERENCES 1. Yamaguchi M, Ohta A, Tsunematsu T et al. Preliminary criteria for classification of adult Still’s disease. J Rheumatol 1992; 19: 424–430. 2. Cush JJ, Medsger TA, Christy WC et al. Adult onset Still’s disease: clinical course and outcome. Arthritis Rheum 1987; 30: 186–194. 3. Fautrel B, Zing E, Golmard JL et al. Proposal for a new set of classification criteria for adult-onset Still disease. Medicine (Baltimore) 2002; 81: 194–200. 4. Lambotte O, Cacoub P, Costedoat-Chalumeau N et al. High ferritin and low glycosylated ferritin may also be a marker of excessive macrophage activation. J Rheumatol 2003; 30: 1027–1028. 5. Arlet JB, Le TH, Marinho A et al. Reactive haemophagocytic syndrome in adult-onset Still’s disease: a report of six patients and a review of the literature. Ann Rheum Dis 2006; 65: 1596–1601. 6. Albaqumi M, Soos TJ, Barisoni L, Nelson PJ. Collapsing glomerulopathy. J Am Soc Nephrol 2006; 17: 2854–2863. 7. Bennett AN, Peterson P, Sangle S et al. Adult onset Still’s disease and collapsing glomerulopathy: successful treatment with intravenous immunoglobulins and mycophenolate mofetil. Rheumatology (Oxford) 2004; 43: 795–799. 8. Kumar S, Sheaff M, Yaqoob M. Collapsing glomerulopathy in adult Still’s disease. Am J Kidney Dis 2004; 43: 4–10. 9. Thaunat O, Delahousse M, Fakhouri F et al. Nephrotic syndrome associated with hemophagocytic syndrome. Kidney Int 2006; 69: 1892–1898.
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Laurinavicius A, Hurwitz S, Rennke HG. Collapsing glomerulopathy in HIV and non-HIV patients: a clinicopathological and follow-up study. Kidney Int 1999; 56: 2203–2213. Valeri A, Barisoni L, Appel GB et al. Idiopathic collapsing focal segmental glomerulosclerosis: a clinicopathologic study. Kidney Int 1996; 50: 1734–1746. Reiner AP, Spivak JL. Hematophagic histiocytosis. A report of 23 new patients and a review of the literature. Medicine (Baltimore) 1988; 67: 369–388. Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child 2001; 85: 421–426. Emmenegger U, Reimers A, Frey U et al. Reactive macrophage activation syndrome: a simple screening strategy and its potential in early treatment initiation. Swiss Med Wkly 2002; 132: 230–236. Ramanan AV, Rosenblum ND, Feldman BM et al. Favorable outcome in patients with renal involvement complicating macrophage activation syndrome in systemic onset juvenile rheumatoid arthritis. J Rheumatol 2004; 31: 2068–2070. Bywaters EG. Still’s disease in the adult. Ann Rheum Dis 1971; 30: 121–133. Bannatyne GA, Wohlmann AS. Rheumatoid arthritis: its clinical history, etiology and pathology. Lancet 1896; 1: 1120–1125. Wakai K, Ohta A, Tamakoshi A et al. Estimated prevalence and incidence of adult Still’s disease: findings by a nationwide epidemiological survey in Japan. J Epidemiol 1997; 7: 221–225. Crispin JC, Martinez-Banos D, Alcocer-Varela J. Adult-onset Still disease as the cause of fever of unknown origin. Medicine (Baltimore) 2005; 84: 331–337. Perez MG, Rodwig Jr FR. Chronic relapsing thrombotic thrombocytopenic purpura in adult onset Still’s disease. South Med J 2003; 96: 46–49. Bujak JS, Aptekar RG, Decker JL, Wolff SM. Juvenile rheumatoid arthritis presenting in the adult as fever of unknown origin. Medicine (Baltimore) 1973; 52: 431–444. Rivera F, Gil CM, Gil MT et al. Vascular renal AA amyloidosis in adult Still’s disease. Nephrol Dial Transplant 1997; 12: 1714–1716. Aelion J, Odhav S. Prompt response to treatment with anakinra in adult onset Still’s disease. Ann Rheum Dis 2004; 63: S281. Haraoui B, Bourrelle D, Kaminska E. Anakinra in the treatment of adult onset Still’s disease. Ann Rheum Dis 2004; 63: S293–S294. Fitzgerald AA, Leclercq SA, Yan A et al. Rapid responses to anakinra in patients with refractory adult onset Still’s disease. Arthritis Rheum 2005; 52: 1794–1803.
Kidney International (2007) 72, 651–656
http://www.kidney-international.org & 2007 International Society of Nephrology
Fever, nephrotic syndrome, and rapidly progressive renal failure H Izzedine1, I Brocheriou2, V Martinez3, L Camous1, M-C Guillemont1 and G Deray1 1
Department of Nephrology, Pitie-Salpetriere Hospital, Paris, France; 2Department of Pathology, Pitie-Salpetriere Hospital, Paris, France and 3Laboratory of Cellular Immunology, Pitie-Salpetriere Hospital, Paris, France
CASE PRESENTATION A 52-year-old African woman, living in France since 5 years, presented with dyspnea and pyrexia. She had a 1-month history of sore throat treated with amoxicillin, migratory polyarthralgia, drenching night sweats, and an evanescent, maculo-papular, non-pruritic rash mainly on her limbs lasting less than 1 week at a time. She denied smoking, alcohol abuse, and illicit drugs use. She had no risk factors for HIV. Examination on admission revealed a temperature of 39.51C, tachycardia, a blood pressure of 120/70 mm Hg, pallor, jaundice, splenomegaly, and bilateral inflammation of knee and ankle joints with synovitis, and severe tenderness of the wrist with signs of fluid overload. There was no sign of meningeal irritation, no focal neurological deficit and normal fundus examination. There were fine crepitations involving the left lung base. Heart sounds were normal on auscultation with no murmur. She was admitted for analgesia and antibiotics pending the results of infective screens and blood tests. Peripheral smear showed no malarial parasite. Her coagulation profile was normal and there was no biochemical evidence of hemolysis. Biochemistry values are summarized in Table 1. Human Immunodeficiency Virus serology, plasma HIV viral load, and p24 determination were negative. Serologies for, hepatitis B and C, Parvovirus B19, cytomegalovirus, Epstein–Barr virus, leptospira, bartonella, rickettsia, chlamydia, mycoplasma pneumoniae, legionella, Widal test, rapid malaria test, toxoplasma, and syphilis were all negative. Brucella agglutination test and leishmania leukococentration were also negative. Hemoglobin electrophoresis ruled out sickle cell disease. Laboratory evaluation for systemic or malignant diseases, including rheumatoid factor, antibodies to double-stranded deoxyribonucleic acid, smooth muscle cell, liver/kidney Correspondence: H Izzedine, Department of Nephrology, La Pitie´-Salpeˆtrie`re Hospital, 47–80 Boulevard de l’Hoˆpital, Assistance Publique-Hopitaux de Paris, Pierre et Marie Curie University, 75013 Paris, France. E-mail: [email protected]
microsomal, mitochondrial, anti-cardiolipin, anti-Scl, antineutrophilic cytoplasmic antibody, anti-Ro, anti-La, anti-SM, anti-ribonucleoprotein, anti-Jo-1, and anti-glomerular basement membrane antibodies were all negative. Immunological parameters were noncontributory with polyclonal hypergammaglobulinemia, normal immunoglobulin (Ig) A, IgM, complement levels, and negative cryoglobulinemia. Chest X-ray was normal. Renal ultrasound showed enlarged, swollen kidneys measuring 12.6 cm in length each. Total body computed tomography revealed splenomegaly, with the rest of the scan being unremarkable. This association between a nephrotic syndrome, fever, cutaneous lesions, pharyngitis and arthralgias suggested the diagnoses of either postinfectious or membranoproliferative glomerulonephritis. A first trans-jugular kidney biopsy was then performed (Figure 1). Trans-thoracic echocardiography suspected the presence of mitral valve endocarditis. Despite empirical treatment with Cefotaxim and gentamicin, she did not improve. The maculo-papular rash on her limbs persisted alongside with high fevers. Bone marrow biopsy and aspiration revealed moderately hyper-cellular marrow with trilineage maturation, and increased number of macrophages, however, without hemophagocytosis. Repeated serologies and cultures were negative. A second trans-oesophageal echocardiography revealed that the systolic function and chamber sizes were normal; there was no valvular dysfunction, evidence of vegetations, nor pericardial effusion. Her renal function worsened (creatinine peaking at 600 mmol/l 1 week later) and hemodialysis became necessary. Suspecting a rapidly progressive glomerulonephritis, of postinfectious or vasculitic nature, a second trans-jugular kidney biopsy was performed (Figures 2 and 3). At this stage we were faced with a severely ill 52-year-old African woman presenting with pyrexia of unknown origin, migratory polyarthopathy, fleeting maculopapular rash, pancytopenia, and rapidly progressive glomerulonephritis with renal failure requiring renal support.
Kidney International (2007) 72, 651–656; doi:10.1038/sj.ki.5002298; published online 25 April 2007
KIDNEY BIOPSY FINDINGS
Received 26 January 2007; revised 16 March 2007; accepted 20 March 2007; published online 25 April 2007
The two renal biopsies were similar and consistent with collapsing glomerulopathy (CG) (Figure 1).
Kidney International (2007) 72, 651–656
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Table 1 | Biochemistry values at baseline and after 2 weeks follow-up Laboratory tests 3
WBC count ( 10 /ml) Neutrophil count ( 103/ml) Hemoglobin (g/dl) Platelet count ( 103/ml) Peripheral smear Haptoglobin (g/l) Bilirubin (mmol/l) ALT (IU/l) Urea (mmol/l) Creatinine (mmol/l) Albumin (g/l) LDH (IU/l) CRP (mg/l) Ferritin (ng/ml) Triglyceride (mmol/l) Dipstick urinalysis Urine microscopy 24 h urinary protein (g)
At admission
Two weeks later
13.2 8.5
15.5 10.0
8.2 80.000
7.0 60.000
Microcytic hypochromic, anisopoikilocytosis, and polychromatic cells, without schizocytes 2.50 2.30 20 77 25 78 7.6 150 550 27 21 1269 1065 150 200 2570 4000 10 10 4+ protein without leukocyte or red blood cells RBCs less than 1000/ml WBCs less than 1000/ml (less than 1 HPF for both), no casts 5.2 then 10 without urinary Bence Jones protein
Figure 2 | The glomerular tuft is segmentally collapsed with podocyte hypertrophy associated with microcystic dilatation of tubules and mild lymphocytic interstitial infiltrate consistent with CG. Masson’s trichrome, original magnification 400.
ALT, alanine aminotransferase; CRP, C-reactive protein; LDH, lactate dehydrogenase; RBCs, red blood cells; WBC, white blood cell.
Figure 3 | Glomerular basement membrane collapse with hypertrophy of the overlying podocytes. Jones methenamine silver; original magnification 200.
Figure 1 | The glomerular tuft is segmentally collapsed with podocyte hypertrophy associated with microcystic dilatation of tubules and mild lymphocytic interstitial infiltrate consistent with CG. Masson’s trichrome, original magnification 200.
For each, two cores of renal cortex were examined histologically after routine processing and staining. At least 25 glomeruli were sampled, of which six were sclerotic. One contained a segmental sclerosis and seven were essentially normal. The remaining 11 (45%) showed tuft collapse in association with prominence of Bowman’s space. There was no necrosis, crescents, nor proliferative features within the glomeruli. Immunohistochemistry revealed a small amount of trapped mesangial IgM and complement; IgG and IgA were completely negative. Congo red staining was also negative. Acutely damaged tubules with dilatation, flattened epithelial cells, and cytoplasmic vacuolation were seen. Moderate scarring with a patchy mixed inflammatory cell infiltrate was also present, occasionally with intra-tubular 652
infiltration by polymorphs. The vessels were essentially normal. Electron microscopy was not performed. PATHOLOGICAL DIAGNOSIS
CG in the setting of febrile pancytopenia and arthritis. CLINICAL FOLLOW-UP
The patient was diagnosed with adult onset Still’s disease (AOSD) because she met the Yamaguchi et al.,1 Cush et al.,2 and Fautrel et al.3 criteria for this diagnosis (Table 2). Glycosylated ferritin was at 52% in our patient. This marker is considered a better diagnostic tool for AOSD than total serum ferritin.3 It may, however, also be observed in macrophage activation syndrome (MAS) of other origins and so cannot be distinctive.4 She was treated with intravenous immune globulin (IVIG) (total dose 2 g/kg given over 4 days) in association with methylprednisolone pulses 15 mg/kg daily for 3 days, followed by 1 mg/kg daily prednisone with partial symptomatic improvement. Fevers ceased the day after initiation of Kidney International (2007) 72, 651–656
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Table 2 | AOSD diagnostic criteria Yamaguchi et al. Major 2 points Arthralgia42 weeks* Fever4391, intermittentX1 week* Typical rash* WBC410 000 (480% granulocytes)*
Minor 1 point Sore throat* Lymphadenopathy and/or splenomegaly* LFT abnormal Negative ANA and RF*
Diagnostic Five criteria (at least two major)
Cush et al.
Fautrel et al.
Quotidian fever4391* Evanescent rash* WBC412 0*+ESR440 mm/1st h Negative RF and ANA* Carpal ankylosis
Spiking fever X 391* Arthralgia* Transient erythema* Pharyngitis* PMNX80%* Glycosylated ferritinp20%
Onset age o32 years Arthritis* Prodromal sore throat* RES involvement or abnormal LFTs Serositis* Cervical or tarsal ankylosis
Maculopapular rash* LeukocytesX10 109/l*
Probable AOSD: 10 points with 12 weeks’ observation Definite AOSD; 10 points with 6 months’ observation
Four major criteria or three major+two minor
ANA, anti-nuclear antibodies; AOSD, adult onset Still’s disease; ESR, erythrocyte sedimentation rate; LFT, liver function test; PMN: polymorphonuclear cells; RES: reticuloendothelial system; Rh, rheumatoid factor; WBC, white blood cell. *Our patients.
pulse methylprednisolone. However, as the steroids were given orally, her symptoms recurred within 3 days and she developed hepatitis, which may have been triggered by a medication or by an acute infection. All blood cultures obtained throughout the course of her illness were sterile. The patient have a global T-cell lymphopenia (443/mm3) and the analysis of flow cytometry show that during follow-up, 78–90% of monocytes–macrophages were activated (expression HLA DR). At that point, it was concluded that the addition of another agent to control disease activity was indicated. The recently reported use of anticytokine or anti-CD20 agents in refractory cases has opened new horizons in the treatment of AOSD. Amid these newly added options we have chosen Anakinra due to its better side effects profile. Anakinra (Kineret; Amgen, Inc., Thousand Oaks, CA, USA) 100 mg subcutaneously twice weekly coordinated with the dialysis schedule was initiated in association with dexamethasone pulse 40 mg daily for 3 days, resulting in remission of the rheumatological condition closely paralleled by remission of proteinuria and renal function, thereby strongly suggesting a causative link between AOSD and CG. Anakinra was well tolerated and without burning at the injection sites. Marked improvement in renal parameters has been noted, 10 days after the combined therapy. This improvement was manifested by the recovery of normal diuresis and dialysis withdrawal. Meanwhile, her renal function remained stable and she was free of dialysis, with serum creatinine within the range of 160–180 mmol/l and proteinuria of 2 þ . She was prescribed prednisone 1 mg/kg daily in four split doses. The delay Kidney International (2007) 72, 651–656
between institution of treatment and remission and dialysis stopping was 2 months. DISCUSSION
We report a rare case of AOSD-related MAS and CG which dramatically improved with interleukin-R (IL-R) antagonist and corticosteroid combination. Nephrotic syndrome associated to a febrile pharyngitis raises first the possibility of a postinfectious GN. However, the presence of CG on biopsy alongside with the clear cutaneous and articular manifestations were clues to a primary joint disease such as AOSD. Only 16 cases of AOSD-related MAS have been reported in the English language literature.5 On the other hand, Albaqumi et al.6 in their recent and excellent review on CG, mentioned only two and five cases related to AOSD7,8 and MAS,9 respectively. Table 3 summarize characteristics of the three AOSD-related CG African patients’ including ours. Collapsing glomerulopathy
CG is a distinct pattern of renal injury characterized by global or segmental collapse of the glomerular tuft, visceral hypertrophy, and hyperplasia accompanied with varying degrees of tubulointerstitial injury. It is frequently and primarily seen in patients with HIV infection10 and recently has been increasingly recognized with non-HIV medical conditions10,11 (Table 4). However, CG was rarely recognized to be MAS- or AOSD related. Clinically, CG is typically characterized by more or less abrupt onset of nephrotic-range proteinuria with rapid progression to end-stage renal failure. Laurinavicius et al.10 reported nephrotic-range proteinuria at 653
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Table 3 | Clinical and laboratory data for three patients with CG and AOSD Adult onset Still disease
Characteristics Literature Patients number age/gender/ race
No. 2 32/Man/African
No. 3 52/Woman/African
Clinical findings and biological parameters Fever 39.51C Arthritis/synovitis +/+ Hepato-splenomegaly + Adenopathy + Skin rash + Hemoglobin (g/dl) 7.8 13.2 White blood cell count (103/ml) Neutrophils count (%) 74.4 Not available Platelet count (109/l) LDH (IU/l) 1,269 Ferritin (ng/ml) 4970
401C +/ + + 7.7 17.3 14.4 444 1065 38 691
39.51C +/+ + + 7.2 17.5
Renal abnormalities Serum creatinine (mmol/l) Proteinuria (g/24 h) Serum albumin (g/l) Microhematuria Kidney size
220 5.1 31 Enlarged (12.6 cm)
515 7.2 11 Not available
180 3.5 27 Normal (11 cm)
11/25 6/25 Dilatation with prominent luminal proteinaceous casts
Several Not available Microcyst tubular dilatation, flattened epithelial cells, and cytoplasmic vacuolisation Not available
11 6 Tubular dilatation, flattened epithelial cells, and cytoplasmic vacuolisation Patchy inflammatory infiltrate
Not available Negative Swollen epithelial cells with partial effacement of the foot processes. No electron-dense deposit
Normal Negative Not performed
Oral steroid
No
No No No Well 3 years later No
MMF 1 g daily 0.4 g/kg daily for 5 days No Well 15 months after No
Pulse of methyprednisolone, then oral steroid Negative 0.5 g/kg daily for 4 days Anakinra Well 2 months after Transient
Kidney pathology No. of collapsed glomeruli No. of sclerotic glomeruli Tubules
Interstitium Vessels Immunofluorescence Electron microscopy
Treatment and outcome Steroids Cytotoxic agents Iv Ig IL-1-ra Outcome Dialysis
No. 1 46/Woman/African
Our case
Moderate scarring with a patchy mixed inflammatory cell infiltrate Normal Negative No electron-dense deposits, no fibrillary or light-chain material, and no tubulo-reticular inclusion bodies within endothelial cells
70 1065 4000
IL-1-ra, interleukin-1-receptor antagonist; Iv Ig, intravenous immunoglobulin; LDH, lactate dehydrogenase.
the time of initial presentation in 89% of patients with a median renal survival of 13–16 months. Variable outcome with respect to renal survival has been observed, with regimens consisting of steroids, with or without cyclophosphamide or cyclosporin.10,11 Valeri et al.11 noted a 14% total remission rate among the CG patients, including few attaining spontaneous remission without any therapy. Targeting the AOSD with subsequent improvement of the renal parameters indicated that CG was not an epiphenomenon. Amid the multiple etiologies of CG, our patient presented two quite rare causes. 654
Macrophage activating syndrome
MAS or hemophagocytic lymphohistiocytosis is a rare and potentially fatal disease of normal but overactive histiocytes. It is of two types – primary MAS as observed in various genetic diseases affecting the immune system and secondary (or acquired) MAS that occurs after strong immunologic activation – systemic infection (virus, bacteria, and protozoa), autoimmune disorders, or underlying malignancy. The clinical entity has to be suspected when patients present with fever unresponsive to antibiotics, general fatigue, falling erythrocyte sedimentation rate, pancytopenia of unknown origin and liver dysfunction with low fibrinogen levels, Kidney International (2007) 72, 651–656
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Table 4 | Secondary causes of collapsing glomerulopathy
Adult-onset Still disease
Infections HIV Parvovirus B19 Others (HCV, CMV, leishmaniasis, filariosis, tuberculosis, etc)
Adult-onset Still disease is a systemic inflammatory condition of unknown etiology. In 1971, Bywaters16 first described this new disease entity that he named adult Still’s disease. It involved adult patients who did not meet the criteria for classic rheumatoid arthritis but displayed features similar to those described in pediatric Still’s disease. However, the earliest documentation of an adult with signs and symptoms of AOSD was published in 1896.17 Its prevalence has been estimated to be lower than one case per 100 000 persons.18 In clinical practice, AOSD is usually considered a diagnosis by exclusion particularly when it presents as fever of unknown origin. Owing to the ambiguity of its definition and the lack of serologic markers, several criteria have been proposed for AOSD in the literature.1–3,19 Kidney involvement has been rarely reported in AOSD. Mesangial glomerulonephritis, disseminated intravascular coagulation, thrombocytopenic purpura,20 interstitial nephritis,21 subacute glomerulitis,22 and renal amyloidosis leading to renal insufficiency have been reported to occur in patients with AOSD. Kumar et al.8 reported a 46-year-old Afro-Carribean woman who presented concomitant occurrence of AOSD and CG. The patient was treated with steroids, resulting in remission of the rheumatological condition closely paralleled by remission of proteinuria and renal function, thereby strongly suggesting a causative link between AOSD disease and CG. Bennett et al.7 reported severe AOSD and CG improved successfully with intravenous immune globulin and mycophenolate mofetil in a 32-year-old African man. The pathogenesis of AOSD is poorly understood and the treatment empirical. It essentially involves the use of nonsteroidal anti-inflammatory drugs, steroids, immunosuppressants, and, currently, biologic agents to control fever, arthritis, and systemic disease. Elevated levels of IL-1 have been implicated in the pathogenesis of AOSD and IL-1 blockers have emerged as possible therapeutic options. Aelion et al.23 reported the successful outcome of daily subcutaneous anakinra (100 mg), a recombinant IL-1 receptor antagonist (IL1-rA), in two patients with persistent AOSD. The first patient achieved complete clinical remission on anakinra alone within days, paralleled by normalized laboratory values, while the other patient was weaned off corticosteroids within weeks and remained in remission on anakinra and MTX.23 In another series of three AOSD patients, addition of anakinra to a corticosteroid regimen resulted in clinical improvement within days and, subsequently, tapering of the corticosteroid dosage.24 A recent study of four patients also demonstrated the efficacy of anakinra in refractory AOSD. Remission was sustained, and prednisone eventually discontinued, in three of the four patients. Convincingly, when anakinra was withdrawn in two patients, their disease relapsed with fever, arthritis, rash, and elevation of laboratory markers within days. Both patients rapidly responded to reinstitution of IL-rA.25 CG must be suspected in AOSD and/or MAS with unexplained renal insufficiency or proteinuria. In this
Drugs and toxic Pamidronate Interferon Heroin Post transplantation De novo Recurrent Others (thrombotic microangiopathy, acute vascular rejection, etc) Autoimmune disorders Systemic lupus erythematous-like disease Adult Still disease Others (mixed connective tissue disease, cerebral arteritis, etc) Inflammatory disease Weber-Christian disease Malignancies Multiple myeloma Acute monoblastic leukemia Macrophage activation syndrome Genetic disorders Mitochondrial cytopathy Action myoclonus-renal failure syndrome Homozygous sickle cell anemia CMV, cytomegalovirus; HCV, hepatitis C virus.
marked hypertriglyceridemia, and elevated ferritin, lymphadenopathy, and sometimes skin rash, lung infiltration.12 There are few reports of renal involvement in MAS. Acute renal failure is thought to be the most consistent feature12 and is considered by some authors as a strong prognostic factor.13 In one series of 57 patients with reactive MAS, 62% had evidence of renal impairment with 17% requiring dialysis.14 Moreover, in a multicentric retrospective study which included 11 patients, acute renal failure was associated with nephrotic syndrome in 90.9% and death occurred in seven cases.9 However, Ramanan et al.15 describe three children with systemic onset juvenile rheumatoid arthritis who had glomerular involvement complicating MAS with a favorable outcome. Nonetheless, biopsy-proven renal involvement has remained poorly documented. Thaunat et al.9 clarified the clinicopathological profile of patients with nephrotic syndrome occurring during MAS in 11 HIVnegative black African patients. Renal pathological findings included CG (45.5%), minimal change glomerulopathy (36.3%), and thrombotic-microangiopathy (18.2%). Treatment of MAS is not uniform. In the absence of prospective controlled trials in MAS, corticosteroids, cyclosporin A, etoposide, anti-tumor necrosis factor-a drugs, and plasmapheresis are administered with varied success. Kidney International (2007) 72, 651–656
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situation, renal biopsy is necessary to establish a definitive diagnosis. Historically, treatment consisted of nonsteroidal anti-inflammatory drugs, often in combination with low-dose corticosteroids. Immunosuppressants (mainly methotrexate, but also intramuscular gold, azathioprine, cyclosporine A, leflunomide, and cyclophosphamide) and intravenous g-globulin are efficacious and have been used as steroid-sparing drugs. The recently reported use of anticytokine and anti-CD20 agents in refractory cases has opened new horizons in the treatment of AOSD and provided important clues as to its pathophysiology. Anakinra in addition to steroids looks like a promising combination for the treatment of this condition as it was the case in our patient. REFERENCES 1. Yamaguchi M, Ohta A, Tsunematsu T et al. Preliminary criteria for classification of adult Still’s disease. J Rheumatol 1992; 19: 424–430. 2. Cush JJ, Medsger TA, Christy WC et al. Adult onset Still’s disease: clinical course and outcome. Arthritis Rheum 1987; 30: 186–194. 3. Fautrel B, Zing E, Golmard JL et al. Proposal for a new set of classification criteria for adult-onset Still disease. Medicine (Baltimore) 2002; 81: 194–200. 4. Lambotte O, Cacoub P, Costedoat-Chalumeau N et al. High ferritin and low glycosylated ferritin may also be a marker of excessive macrophage activation. J Rheumatol 2003; 30: 1027–1028. 5. Arlet JB, Le TH, Marinho A et al. Reactive haemophagocytic syndrome in adult-onset Still’s disease: a report of six patients and a review of the literature. Ann Rheum Dis 2006; 65: 1596–1601. 6. Albaqumi M, Soos TJ, Barisoni L, Nelson PJ. Collapsing glomerulopathy. J Am Soc Nephrol 2006; 17: 2854–2863. 7. Bennett AN, Peterson P, Sangle S et al. Adult onset Still’s disease and collapsing glomerulopathy: successful treatment with intravenous immunoglobulins and mycophenolate mofetil. Rheumatology (Oxford) 2004; 43: 795–799. 8. Kumar S, Sheaff M, Yaqoob M. Collapsing glomerulopathy in adult Still’s disease. Am J Kidney Dis 2004; 43: 4–10. 9. Thaunat O, Delahousse M, Fakhouri F et al. Nephrotic syndrome associated with hemophagocytic syndrome. Kidney Int 2006; 69: 1892–1898.
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