Portal de Periódicos da CAPES

Paraplegia, proteinuria, and renal failure

2006; Elsevier BV; Volume: 69; Issue: 2 Linguagem: Inglês

10.1038/sj.ki.5000124

1523-1755

Samih H. Nasr, R. Schwarz, Vivette D. D’Agati, Glen S. Markowitz,

Hematological disorders and diagnostics

A 62-year-old African-American male with a history of paraplegia following surgery for removal of a spinal tumor 30 years earlier presented to the Emergency Department with worsening shortness of breath. He was found to have congestive heart failure, which responded well to diuresis, and renal failure with a creatinine concentration of 6.6 mg/dl (583 μmol/l). On further questioning, the patient reported a history of renal dysfunction and hypertension. The patient had a creatinine concentration of 1.4 mg/dl (124 μmol/l) 10 months before and of 3.0 mg/dl (265 μmol/l) 4 months before. Kidney biopsy had been recommended but was refused by the patient. Past medical history was significant for a severe decubitus ulcer of the hip complicated by osteomyelitis and requiring hospitalization, debridement, and long-term treatment with antibiotics via an indwelling Hickman catheter, which was discontinued 1 year before. The patient had intact bladder function and a history of recurrent cystitis, but no pyelonephritis. The patient's only prescription medication on admission was metoprolol tartrate 75 mg twice per day. There was no family history of renal disease. The patient also had a history of significant tobacco use (1.5 packs per day of cigarettes for 40 years). Physical examination revealed a well-developed male, with a blood pressure of 155/75 mmHg, no active decubitus ulcers, and no evidence of jugular venous distention. Examination of the lungs revealed diminished breath sounds at the bases and scattered rhonchi. The heart was regular in rate and rhythm with no murmurs, rubs, or gallops. The lower extremities exhibited muscular atrophy. No lower extremity edema was evident. Laboratory data were as follows: hematocrit, 34% (normal range, 42–52%); white blood count, 7.7 × 109/l (normal range, 4.0–10.5 × 109/l); platelet count 418 × 109/l (normal range, 150–500 × 109/l); blood urea nitrogen, 48 mg/dl (17.1 mmol/l) (normal range, 9–20 mg/dl (3.2–7.1 mmol/l)); 24-h urine protein, 2840 mg; aspartate aminotransferase, 22 U/l (normal range, 10–40 U/l); alanine aminotransferase, 14 U/l (normal range, 10–45 U/l); and serum albumin, 1.7 g/dl (17 g/l) (normal range, 3.5–5.0 g/dl (35–50 g/l)). Urinalysis revealed 4+ proteinuria and a bland sediment. Hepatitis C antibody was positive. All other serologies were negative or normal, including hepatitis B surface antigen, antinuclear antibody, antineutrophilic cytoplasmic antibody, and C3 and C4 complement levels. A chest radiograph showed small bilateral pleural effusions. An echocardiogram revealed mild left ventricular hypertrophy but no evidence of infiltrative disease. A renal sonogram showed normal-sized kidneys, with a 2.3 cm mass at the lower pole of the left kidney that was suspicious for malignancy. A renal biopsy was performed. Light microscopic examination disclosed two cores of renal cortex containing 31 glomeruli, 10 of which were globally sclerotic. Glomeruli appeared enlarged and displayed marked global expansion of the mesangial matrix by amorphous, eosinophilic, nonargyrophilic material that stained weakly positive with the periodic acid–Schiff stain and blue-gray with the trichrome stain (Figure 1a). When stained with Congo red and viewed under polarized light, apple-green birefringence diagnostic of amyloidosis was seen (Figure 1b). The amyloid material also extended segmentally to involve the glomerular capillary walls. Multiple glomeruli displayed segmental scars with adhesions to Bowman's capsule. There was diffuse, moderate to severe tubular atrophy and interstitial fibrosis involving approximately 70% of the cortex sampled and accompanied by moderate chronic interstitial inflammation. The majority of arterioles and small arteries were markedly expanded by amorphous, congophilic material consistent with amyloid (Figure 1c). Larger vessels showed moderate to severe arteriosclerosis. Immunofluorescence staining for IgG, IgM, IgA, C3, C1q, fibrinogen, albumin, and kappa and lambda light chains was negative in glomeruli. Staining for C3 and IgM was seen in arterioles, corresponding to areas of hyalinosis. Immunohistochemical staining for serum amyloid A (SAA) protein, a marker of secondary/amyloid A (AA) amyloid, was positive in the distribution of the amyloid deposits (Figure 1d). Ultrastructural evaluation revealed randomly oriented, non-branching fibrils within the mesangial matrix and glomerular basement membrane with a diameter of 12 nm, confirming the diagnosis of amyloidosis. The light and electron microscopic findings, including the apple-green birefringence when stained with Congo red and viewed under polarized light and the fibril diameter of 12 nm, were diagnostic of renal amyloidosis. The negative immunofluorescence staining for kappa and lambda light chains excluded primary amyloidosis. The positive immunohistochemical staining for SAA in the distribution of the amyloid deposits confirmed the diagnosis of secondary/AA amyloidosis. Amyloidosis is a diverse group of diseases that share in common the extracellular tissue deposition of randomly oriented fibrils that measure 8–12 nm in diameter. The amyloid fibrils are composed of low-molecular-weight proteins that form β-pleated sheets, best demonstrated by X-ray crystallography or infrared spectroscopy. The defining pathologic feature of amyloid deposits is the affinity for Congo red dye and the property of exhibiting apple-green birefringence when viewed under polarized light. In all forms of amyloid, additional components of the deposits include glycosaminoglycans (i.e. heparan sulfate proteoglycan) and the amyloid P component. Amyloidosis is subclassified according to the precursor protein. In the kidney, the two most common subtypes of amyloidosis are primary (i.e. light chain) amyloidosis, in which the amyloid fibrils are composed of immunoglobulin light chains, and secondary (AA) amyloidosis, in which the fibrils are derived from SAA, an acute-phase reactant protein. Four SAA gene loci have been identified in humans.1.Steel D.M. Whitehead A.S. The major acute phase reactants: C-reactive protein, serum amyloid P component and serum amyloid A protein.Immunol Today. 1994; 15: 81Abstract Full Text PDF PubMed Scopus (867) Google Scholar SAA1 and SAA2 products are apolipoproteins synthesized primarily by the liver and transported in the serum in association with high-density lipoprotein. SAA3 is a pseudogene, and SAA4 encodes constitutive SAA, which is also synthesized by the liver. The transcription of the SAA1 and SAA2 genes increases in response to inflammatory stimuli such as tumor necrosis factor-α, interleukin 1, and interleukin 6.2.Thorn C.F. Lu Z.Y. Whitehead A.S. Regulation of the human acute phase serum amyloid A genes by tumour necrosis factor-alpha, interleukin-6 and glucocorticoids in hepatic and epithelial cell lines.Scand J Immunol. 2004; 59: 152Crossref PubMed Scopus (78) Google Scholar AA is an 8.5 kDa protein that results from the enzymatic cleavage of the carboxyl terminus of the 12.5 kDa SAA1 or SAA2 by macrophages. The two main putative mechanisms thought to be important in AA amyloidogenesis include increased synthesis of SAA by hepatocytes in response to acute and chronic inflammation3.Gillmore J.D. Lovat L.B. Persey M.R. et al.Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein.Lancet. 2001; 24: 358Google Scholar and incomplete proteolysis with aberrant degradation of SAA to AA protein by macrophages.4.Kluve-Beckerman B. Liepnieks J.J. Wang L. Benson M.D. A cell culture system for the study of amyloid pathogenesis. Amyloid formation by peritoneal macrophages cultured with recombinant serum amyloid A.Am J Pathol. 1999; 155: 123Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar Intrinsic properties of the degradation fragments may also be important, with smaller fragments preferentially depositing in glomeruli and larger ones in vessel walls.5.Westermark G.T. Sletten K. Grubb A. Westermark P. AA-amyloidosis: tissue component-specific association of various protein AA subspecies and evidence of a fourth SAA gene product.Am J Pathol. 1990; 137: 377-383PubMed Google Scholar Secondary (AA) amyloidosis occurs in the setting of chronic immune activation. In the United States and many developed countries, the most common condition associated with secondary amyloidosis is rheumatoid arthritis, including juvenile and adult forms. Other diseases associated with secondary amyloidosis include ankylosing spondylitis, inflammatory bowel disease, psoriasis, Still's disease, familial Mediterranean fever, and chronic infections including tuberculosis, bronchiectasis, chronic osteomyelitis, heroin abuse with ‘skin popping’,6.Bakir A.A. Dunea G. Drugs of abuse and renal disease.Curr Opin Nephrol Hypertens. 1996; 5: 122-126Crossref PubMed Scopus (44) Google Scholar and chronic decubitus ulcers. As a result of improved therapy, the incidence of secondary amyloidosis has decreased over the past 3 decades and the demographics have shifted. In the antibiotic era, secondary amyloidosis is more commonly associated with autoimmune inflammatory diseases, such as rheumatoid arthritis, and less commonly associated with chronic infections.7.Gertz M.A. Kyle R.A. Secondary systemic amyloidosis. Response and survival in 64 patients.Medicine. 1991; 70: 246-256Crossref PubMed Scopus (325) Google Scholar, 8.Browning M.J. Banks R.A. Tribe C.R. et al.Ten years' experience of an amyloid clinic—a clinicopathological survey.Q J Med. 1985; 54: 213-227PubMed Google Scholar, 9.Joss N. McLaughlin K. Simpson K. Boulton-Jones J.M. Presentation, survival and prognostic markers in AA amyloidosis.Q J M. 2000; 93: 535-542Crossref Scopus (95) Google Scholar The kidney is the main target of secondary amyloidosis, with renal involvement noted in 91% of patients in a large series.7.Gertz M.A. Kyle R.A. Secondary systemic amyloidosis. Response and survival in 64 patients.Medicine. 1991; 70: 246-256Crossref PubMed Scopus (325) Google Scholar The first manifestation of secondary amyloidosis typically is nephrotic-range proteinuria, often associated with renal insufficiency. Additional symptoms depend on the organs involved. Outside of the kidney, gastrointestinal symptoms are most common and include malabsorption, diarrhea, constipation, and bleeding.7.Gertz M.A. Kyle R.A. Secondary systemic amyloidosis. Response and survival in 64 patients.Medicine. 1991; 70: 246-256Crossref PubMed Scopus (325) Google Scholar Unlike the situation in primary amyloidosis, macroglossia, neuropathy, and congestive heart failure occur infrequently.7.Gertz M.A. Kyle R.A. Secondary systemic amyloidosis. Response and survival in 64 patients.Medicine. 1991; 70: 246-256Crossref PubMed Scopus (325) Google Scholar, 8.Browning M.J. Banks R.A. Tribe C.R. et al.Ten years' experience of an amyloid clinic—a clinicopathological survey.Q J Med. 1985; 54: 213-227PubMed Google Scholar Outcomes in secondary amyloidosis are poor, with a median survival of 24 and 53 months in two series.7.Gertz M.A. Kyle R.A. Secondary systemic amyloidosis. Response and survival in 64 patients.Medicine. 1991; 70: 246-256Crossref PubMed Scopus (325) Google Scholar, 9.Joss N. McLaughlin K. Simpson K. Boulton-Jones J.M. Presentation, survival and prognostic markers in AA amyloidosis.Q J M. 2000; 93: 535-542Crossref Scopus (95) Google Scholar Clinical parameters that adversely influence outcome include cardiac involvement and the degree of renal insufficiency, hypoalbuminemia, and proteinuria.7.Gertz M.A. Kyle R.A. Secondary systemic amyloidosis. Response and survival in 64 patients.Medicine. 1991; 70: 246-256Crossref PubMed Scopus (325) Google Scholar, 9.Joss N. McLaughlin K. Simpson K. Boulton-Jones J.M. Presentation, survival and prognostic markers in AA amyloidosis.Q J M. 2000; 93: 535-542Crossref Scopus (95) Google Scholar, 10.Tanaka F. Migita K. Honda S. et al.Clinical outcome and survival of secondary (AA) amyloidosis.Clin Exp Rheumatol. 2003; 21: 343-346PubMed Google Scholar, 11.Odabas A.R. Cetinkaya R. Selcuk Y. et al.Clinical and biochemical outcome of renal amyloidosis.Int J Clin Pract. 2002; 56: 342-344PubMed Google Scholar In an older series, the most common cause of death in secondary amyloidosis was uremia, including complications of dialysis.7.Gertz M.A. Kyle R.A. Secondary systemic amyloidosis. Response and survival in 64 patients.Medicine. 1991; 70: 246-256Crossref PubMed Scopus (325) Google Scholar More recently, infection has emerged as the most common cause of death.9.Joss N. McLaughlin K. Simpson K. Boulton-Jones J.M. Presentation, survival and prognostic markers in AA amyloidosis.Q J M. 2000; 93: 535-542Crossref Scopus (95) Google Scholar Treatment of secondary amyloidosis is directed at controlling the underlying inflammatory process. Examples include colchicine administration in patients with familial Mediterranean fever, immunosuppressant therapy (cyclophosphamide, methotrexate, and azathioprine) in patients with rheumatic diseases, and antibiotics in patients with chronic infections (such as bronchiectasis, decubitus ulcers, and chronic osteomyelitis).7.Gertz M.A. Kyle R.A. Secondary systemic amyloidosis. Response and survival in 64 patients.Medicine. 1991; 70: 246-256Crossref PubMed Scopus (325) Google Scholar In a recent study of 25 patients with secondary amyloidosis due to rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis, inhibitors of tumor necrosis factor, including infliximab and etanercept, were shown to be effective.12.Fernandez-Nebro A. Tomero E. Ortiz-Santamaria V. et al.Treatment of rheumatic inflammatory disease in 25 patients with secondary amyloidosis using tumor necrosis factor alpha antagonists.Am J Med. 2005; 118: 552-556Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar Over a mean follow-up period of 70 weeks, renal function remained stable or improved in 83% of patients and a 50% decline in proteinuria was achieved in 50% of patients.12.Fernandez-Nebro A. Tomero E. Ortiz-Santamaria V. et al.Treatment of rheumatic inflammatory disease in 25 patients with secondary amyloidosis using tumor necrosis factor alpha antagonists.Am J Med. 2005; 118: 552-556Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar Low-molecular-weight anionic sulfonates that interfere with the interaction between SAA and heparan sulfate proteoglycan have been found to be effective in reducing AA amyloid progression in a murine model,13.Kisilevsky R. Lemieux L.J. Fraser P.E. et al.Arresting amyloidosis in vivo using small-molecule anionic sulphonates or sulphates: implications for Alzheimer's disease.Nat Med. 1995; 1: 143-148Crossref PubMed Scopus (338) Google Scholar and represent a potential therapeutic strategy for the human disease. Renal disease is a frequent complication of spinal cord injury, accounting for 50% of patient deaths prior to the availability of hemodialysis and 22% in the post-dialysis era.14.Tribe C.R. Silver J.R. Renal Failure in Paraplegia. Pitman, London, UK1969: 54-90Google Scholar, 15.Borges P.M. Hackler R.H. The urologic status of the Vietnam war paraplegic: a 15-year prospective followup.J Urol. 1982; 127: 710-711PubMed Google Scholar The most common patterns of renal disease seen in patients with spinal cord injury are chronic pyelonephritis and secondary amyloidosis.16.Barton C.H. Vaziri N.D. Gordon S. Tilles S. Renal pathology in end-stage renal disease associated with paraplegia.Paraplegia. 1984; 22: 31-41Crossref PubMed Scopus (25) Google Scholar, 14.Tribe C.R. Silver J.R. Renal Failure in Paraplegia. Pitman, London, UK1969: 54-90Google Scholar Secondary amyloidosis has been found at autopsy in 23–81% of patients with chronic paraplegia in three series.17.Dietrick R.B. Russi S. Tabulation and review of autopsy findings in fifty-five paraplegics.J Am Med Assoc. 1958; 166: 41-44Crossref PubMed Scopus (27) Google Scholar, 14.Tribe C.R. Silver J.R. Renal Failure in Paraplegia. Pitman, London, UK1969: 54-90Google Scholar, 16.Barton C.H. Vaziri N.D. Gordon S. Tilles S. Renal pathology in end-stage renal disease associated with paraplegia.Paraplegia. 1984; 22: 31-41Crossref PubMed Scopus (25) Google Scholar Secondary amyloidosis typically results from chronic infection in patients with long-standing spinal cord injury. Amyloidosis occurs many years after spinal cord injury, with the most common underlying conditions being chronic decubitus ulcers, often associated with chronic osteomyelitis, and chronic pyelonephritis complicating neurogenic bladder.14.Tribe C.R. Silver J.R. Renal Failure in Paraplegia. Pitman, London, UK1969: 54-90Google Scholar, 16.Barton C.H. Vaziri N.D. Gordon S. Tilles S. Renal pathology in end-stage renal disease associated with paraplegia.Paraplegia. 1984; 22: 31-41Crossref PubMed Scopus (25) Google Scholar, 17.Dietrick R.B. Russi S. Tabulation and review of autopsy findings in fifty-five paraplegics.J Am Med Assoc. 1958; 166: 41-44Crossref PubMed Scopus (27) Google Scholar, 18.Malament M. Friedman F. Amyloidosis of paraplegia.Arch Phys Med Rehabil. 1965; 46: 406-411PubMed Google Scholar A large study found 65 cases of amyloidosis among 174 autopsies performed on chronic paraplegic patients dying in the National Spinal Injuries Center in the United Kingdom.14.Tribe C.R. Silver J.R. Renal Failure in Paraplegia. Pitman, London, UK1969: 54-90Google Scholar In all 65 patients, amyloidosis was present in the kidney. Among the 65 patients, 60 (92%) had decubitus ulcers, of which 47 (78%) were associated with underlying osteomyelitis. Clinical and pathological evidence of chronic urinary tract infection also was present in all of the 65 patients. In recent years, improved management of neurogenic bladder and pressure ulcers in spinal cord injury patients has led to a decrease in the incidences of urinary tract infections, skin infections, and osteomyelitis. This in turn has led to a decreased incidence of both chronic pyelonephritis and secondary amyloidosis.19.DeVivo M.J. Krause J.S. Lammertse D.P. Recent trends in mortality and causes of death among persons with spinal cord injury.Arch Phys Med Rehabil. 1999; 80: 1411-1419Abstract Full Text PDF PubMed Scopus (653) Google Scholar The prognosis for secondary amyloidosis in spinal cord injury patients is somewhat unclear. Efforts should be directed at prevention of conditions associated with secondary amyloidosis. Patients should be carefully screened and treated for cutaneous ulceration that might lead to decubitus ulcer formation and for urinary tract infection. With more severe decubitus ulcers, surgical intervention may be indicated. When amyloidosis occurs, it is unclear to what extent antibiotics, chemotherapy, and possibly surgery will lead to decreased production of fibrils or dissolution of the existing amyloid deposits. Based upon data collected from patients with a variety of etiologies of secondary amyloidosis, reduction in serum SAA values below a critical level may lead to regression of amyloid and improved organ function.3.Gillmore J.D. Lovat L.B. Persey M.R. et al.Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein.Lancet. 2001; 24: 358Google Scholar With more advanced disease, renal replacement therapy is often necessary. Review of the literature provides little insight into the prognosis of secondary amyloidosis in patients with spinal cord injury, in that most of the reported cases come from older literature and autopsy series. In the few studies that included living patients, advanced renal failure was present at the time of diagnosis and did not resolve.14.Tribe C.R. Silver J.R. Renal Failure in Paraplegia. Pitman, London, UK1969: 54-90Google Scholar Following the renal biopsy, the patient refused further diagnostic testing, chemotherapy, or hemodialysis. There was no clinical evidence of rheumatoid arthritis, ankylosing spondylitis, or inflammatory bowel disease. There was no history of tuberculosis (and a chest radiograph was unrevealing). There was no history of drug abuse and no physical evidence of ‘skin-popping’. The patient's secondary amyloidosis was presumed to be related to the previous, long-standing decubitus ulcer and underlying chronic osteomyelitis. The patient returned 1 month later with a potassium of 7.0 mmol/l (normal range, 3.6–5.0 mmol/l) and a creatinine concentration of 20.6 mg/dl (1821 μmol/l) and underwent emergent hemodialysis.