Cervical cancer of the uterus complicated by renal AA amyloidosis.

Cervical cancer of the uterus rarely develops systemic secondary amyloidosis. We present the case of a 66-year-old female patient who manifested systemic amyloid A (AA) amyloidosis in the kidney, digestive tract, and cervix of the uterus, secondary to cervical cancer. She exhibited nephrotic syndrome, intractable diarrhea, and mild fever 3 months after she underwent an extended hysterectomy with postoperative cisplatin-based chemotherapy and whole pelvic irradiation. Further examinations revealed AA amyloidosis of the kidney and colon and cytomegalovirus infection in the colon. AA amyloid deposition was positive in the resected tissues of uterine cancer. The patient was diagnosed with systemic AA amyloidosis consecutive to cervical cancer. Despite a decrease in urinary protein after antiviral therapy, it increased 14 months later with neither apparent symptoms nor an increase in tumor marker. A second renal biopsy revealed AA amyloidosis of the kidney. Subsequent investigations revealed the recurrence of cervical cancer in the lung, liver, and lymph nodes. This case report indicated that AA amyloidosis would complicate cervical cancer and recur even after resection of neoplasm owing to other stimulation. Moreover, urine protein could be a marker for cancer relapse in known cases of cancer-derived AA amyloidosis.

Sickle cell disease: a case report of renal amyloidosis.

BACKGROUND: The development of proteinuria and reduced glomerular filtration rate is associated with higher mortality among patients with sickle cell disease (SCD). AA amyloidosis, also associated with increased mortality, in SCD is rare. We present a case of a woman with homozygous sickle cell disease with nephrotic syndrome and antibodies to double stranded DNA without clinical features of systemic lupus erythematosus. Kidney biopsy reveals AA amyloidosis and is the first report of concomitant AA amyloidosis with antibodies to double stranded DNA in SCD. CASE PRESENTATION: A 40-year-old Central African woman with homozygous sickle cell disease and history of vaso-occlusive pain crises undergoes kidney biopsy for nephrotic-range proteinuria. Kidney biopsy reveals AA type amyloidosis, which is a rare manifestation of SCD in the kidney. Her anemia worsens with an ACE inhibitor, initiated to reduce proteinuria and limit GFR decline, so it was discontinued. Hydroxyurea, shown to decrease the frequency of vaso-occlusive crises and lower proteinuria, was subsequently initiated but then discontinued due to worsening anemia. Unfortunately, her glomerular filtration rate worsens. CONCLUSIONS: AA amyloidosis and antibodies to double stranded DNA can occur in sickle cell disease. ACE inhibition and hydroxyurea decrease proteinuria so they may limit progression of chronic kidney disease. Hydroxyurea also decreases frequency of vaso-occlusive pain crises so it might be helpful in limiting progression of renal AA amyloidosis. However, further studies are needed to determine optimal treatment strategies for AA amyloidosis in sickle cell disease.

Renal Amyloidosis Associated With Kartagener Syndrome in a Dog.

A 4-year-old cocker spaniel, male, of 12kg body weight was presented because of the onset of polyuria or polydipsia. From the first months of its life, the dog had exhibited constant serous to mucopurulent nasal discharge, productive cough, sneezing, reverse sneezing, otitis, and recurrent episodes of fever. The respiratory signs had been treated several times with antibiotics, without ever achieving a complete resolution. Clinical examination revealed normal rectal temperature (38.3°C), increased respiratory rate (40breaths/min), a copious mucous nasal discharge and right deviation of the heart apex beat (ictus cordis). Increased respiratory sounds with moist rales and crackles were found on chest auscultation. An increase in serum creatinine, urea and phosphorus, hypoalbuminemia and proteinuria were found. Lateral and ventrodorsal radiographs of the thorax and of the abdomen showed the transposition of the heart, with the cardiac apex pointing toward the right (dextrocardia), bronchointerstitial lung pattern, areas of consolidation, lesions consistent with bronchiectasis caves and a mirror-image of abdominal organs, confirming the diagnosis of complete situs inversus (CSI). Respiratory signs, combined with CSI, suggested the diagnosis of Kartagener syndrome (KS). Abdominal ultrasound showed an increase in the echogenicity of the renal parenchyma, a loss of definition of the corticomedullary line, slight bilateral pyelectasis, and decreased cortical perfusion. The dog died 2 months later because of a further worsening of the clinical condition. Necroscopy demonstrated the existence of CSI, rhinosinusitis, bronchitis, and bronchiectasis, so confirming the diagnosis of KS, and renal amyloidosis. This is the first case reported in veterinary medicine of the presence of renal amyloidosis together with KS in a dog.

A patient with AL amyloidosis with negative free light chain results.

The detection and quantification of amyloidogenic monoclonal light chains are necessary for the diagnosis and evaluation of response to treatment in AL amyloidosis. However, the amyloid clone is often small and difficult to detect. We report the case of a 68-year-old man who was referred to our Center in April 2013 after syncope and the identification of left ventricular hypertrophy at echocardiography, suspected for amyloidosis. A commercial agarose gel electrophoresis immunofixation (IFE) did not reveal monoclonal components in serum and urine. The κ serum free light chain (FLC) concentration was 21.5 mg/L, λ 33 mg/L (κ/λ ratio 0.65), NT-proBNP 9074 ng/L (u.r.l. <332 ng/L) and an echocardiogram confirmed characteristic features of amyloidosis. The abdominal fat aspiration was positive and the amyloid typing by immune-electron microscopy revealed λ light chains deposits. A high-resolution (hr) IFE of serum and urine showed a faint monoclonal λ component in the urine. A bone marrow biopsy showed 8% plasma cells (BMPC) and a kappa/lambda light-chain restriction with λ light chain on immunofluorescence. The diagnosis of AL (λ) amyloidosis with cardiac involvement was made. In May 2013, patient was started on cyclophosphamide, bortezomib and dexamethasone. After six cycles, serum and urine hr-IFE were negative, the bone marrow biopsy showed 3% BMPC without light chain restriction by immunofluorescence, and a decrease of NT-proBNP was observed (5802 ng/L).Thus, treatment was discontinued. In this patient the amyloid clone could be detected only by in house hr-IFE of urine and bone marrow examination. The detection of the small dangerous amyloidogenic clone should be pursued with a combination of high-sensitivity techniques, including assessment of BMPC clonality. Studies of novel tools, such as mass spectrometry on serum and next-generation flow cytometry analysis of the bone marrow, for detecting plasma cell clones in AL amyloidosis and other monoclonal light chain-related disorders are warranted.

Serum galectin-3 levels were associated with proteinuria in patients with Familial Mediterranean Fever.

BACKGROUND: The most common and pernicious complication of Familial Mediterranean fever (FMF) is renal amyloidosis, usually affecting the kidneys, leading to end-stage renal failure. FMF-related renal amyloidosis needed to be diagnosed early. Optimal colchicine dose is effective in preventing and reversing renal amyloidosis. Galectin-3, profibrotic mediator, has regulatory functions in inflammation, fibrosis and tumorigenesis. Galectin-3 is a strong prognostic marker for heart failure. Galectin-3 plays role in diabetic nephropathy and chronic kidney disease. The aim of the study is to investigate whether galectin-3 is related to proteinuria and amyloidosis in FMF. METHODS: Seventy-five FMF patients who have no exclusion criteria and healthy controls (n = 36) were included. Serum galectin-3 was measured and morning spot urine was collected for determination of the protein/creatinine ratio (PCR). RESULTS: Serum Galectin-3 levels were significantly higher in FMF patients than the control group [969.66 (3825) pg/mL vs. 238 (921) pg/mL, respectively; P<0.001]. We classified into two groups: Group1 (n = 48) had FMF patients with proteniuria, Group2 (n = 27) had FMF patients without proteinuria. Group1 had higher levels of galectin-3 than Group2 [1106(3812) pg/mL vs. 867.3(1433) pg/mL, P < 0.001]. Galectin-3 levels were correlated with PCR in whole group and FMF group (r = 0.785, P < 0.001 and r = 0.803, P < 0.001). In ROC curve, best cutoff value = 581.50 pg/mL was used to detect proteinuria (sensitivity = 91.7 %, specificity = 71.4 %, AUC = 0.879) and optimal cutoff value = 1458.00 pg/mL was an indicator of nephrotic-range proteinuric (sensitivity = 100 %, specificity = 92.1 %, AUC = 0.983). CONCLUSION: Galectin-3 is associated with proteinuria and renal amyloidosis in FMF. Galectin-3 may play role in pathogenesis of amyloidosis.

Pathogenesis of renal failure in multiple myeloma: any role of contrast media?

The spectrum of kidney disease-associated monoclonal immunoglobulin and plasma cell malignancies is remarkably broad and encompasses nearly all nephropathologic entities. Multiple myeloma with kidney impairment at presentation is a medical emergency since the recovery of kidney function is associated with survival benefits. In most cases, kidney impairment may be the first clinical manifestation of malignant plasma cell dyscrasias like multiple myeloma and light chain amyloidosis. Multiple myeloma per se cannot be considered a main risk factor for developing acute kidney injury following intravascular administration of iodinated contrast media. The risk is increased by comorbidities such as chronic kidney disease, diabetes, hypercalcemia, dehydration, and use of nephrotoxic drugs. Before the administration of contrast media, the current recommended laboratory tests for assessing kidney function are serum creatinine measurement and the estimation of glomerular filtration rate by using the CKD-EPI equation. The assessment of Bence Jones proteinuria is unnecessary for evaluating the risk of kidney failure in patients with multiple myeloma, since this test cannot be considered a surrogate biomarker of kidney function.

Urinary excretion of nephrin in rheumatoid arthritis patients with proteinuria.

OBJECTIVES: To investigate urine excretion of nephrin in patients with proteinuric nephropathies associated with rheumatoid arthritis (RA). METHODS: We enrolled in the study 42 patients with seropositive RA and proteinuria, the control group (20 persons) was formed from healthy blood donors, the comparison group (23 persons) was formed from RA patients without proteinuria. Kidney biopsy was performed in 26 patients (glomerulonephritis was diagnosed in 14 patients, АА-amyloidosis in 7 patients and tubulointerstitial nephritis in 5 patients). RESULTS: Urine nephrin concentration in patients with RA and proteinuria was 6.2 (3.0; 8.8) ng/ml and significantly differed in its levels both in controls - 3.6 (2.4; 5.3) ng/ml (p=0.03) and RA patients without proteinuria - 3.2 (2.1; 5.1) ng/ ml (p=0.015) group. In RA patients with proteinuria, we found a positive correlation between urine nephrin and protein concentrations (r=0.4; p=0.04). Urine nephrin levels in patients of the glomerulonephritis - 7.3 (5.9; 9.2) and amyloidosis groups - 6.9 (3.9; 9.8) ng/ml were higher than in the controls (p=0.001; p=0.04) and in the group of patients without proteinuria (p=0.005; p=0.03). In the patients with tubulointerstitial nephritis urine nephrin concentration did not differ significantly with the values in both the control and the RA patients without proteinuria groups. CONCLUSIONS: According to our data, proteinuria in the overall cohort of patients with seropositive RA is associated with increased levels of urine nephrin excretion, the highest levels of nephrin excretion were registered in patients with glomerulonephritis and amyloidosis.

ELISA analysis of urinary nephrin and podocalyxin standardized by aquaporin-2 in adult patients with nephrotic syndrome.

OBJECTIVE: To investigate urinary nephrin and podocalyxin standardized by aquaporin (AQP)-2 using the enzyme-linked immunosorbent assay (ELISA) method in adult nephrotic syndrome (NS) patients. METHODS: In 107 adult NS patients (27 proliferative nephritis, 77 non-proliferative, and 3 amyloidosis) undergoing renal biopsy, urinary nephrin, podocalyxin and AQP2 were measured by ELISA. Urinary nephrin and podocalyxin were standardized by AQP2 (neph/AQP and PCX/AQP) and values were compared with 11 healthy controls. RESULTS: Urinary neph/AQP correlated positively to PCX/AQP (r = 0.51, p < 0.001). Urinary neph/AQP and PCX/AQP were lower in controls than NS patients. Both proliferative and non-proliferative NS patients excreted high urinary neph/AQP and PCX/AQP without a significant difference between them (p > 0.05). Patients with focal segmental glomerular sclerosis (FSGS) excreted higher urinary neph/AQP (p = 0.09) and PCX/AQP (p < 0.05) compared to the other patients. Urinary neph/AQP and PCX/AQP were increased in the immunoglobulin M nephropathy patients. Amyloidosis patients excreted lower neph/AQP and PCX/AQP. The sensitivity was 0.87 and specificity 0.37 when the neph/AQP borderline value of 0.16 was adopted [area under the curve (AUC) = 0.61]. The sensitivity was 0.74 and specificity 0.61 when the PCX/AQP borderline value was 3.06 (AUC = 0.69). CONCLUSIONS: Urinary neph/AQP and PCX/AQP are increased in NS patients, with FSGS patients showing the highest levels. To distinguish FSGS from other NS forms, the measurement of urinary PCX/AQP may be a practical method, and superior to neph/AQP.

Do neutrophil gelatinase-associated lipocalin and interleukin-18 predict renal dysfunction in patients with familial Mediterranean fever and amyloidosis?

BACKGROUND: The aim of this study was to evaluate whether neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL-18) predict renal disfunction in patients with familial Mediterranean fever (FMF). METHODS: This prospective study consisted of 102 patients with FMF in attack-free period, and 40 matched healthy controls. Of the patients, nine were diagnosed as amyloidosis. The patients were divided into two groups according to eGFR as below 120 mL per minute and above 120 mL per minute. Also, patients were divided into three groups according to the degree of urinary albumin excretion as normoalbuminuric, microalbuminuric, and macroalbuminuric. The serum levels of IL-18 (sIL-18) and NGAL (sNGAL), and urinary levels of IL-18 (uIL-18) and NGAL (uNGAL) were measured by using ELISA kits. RESULTS: The levels of sIL-18, sNGAL, uIL-18, and uNGAL were detected significantly higher in FMF patients, particularly in patients with amyloidosis, when compared to controls. sNGAL, uIL-18, and uNGAL were significantly higher in patients with eGFR < 120 mL per minute than in patients with eGFR ≥ 120 mL per minute. sNGAL, uIL-18, and uNGAL were correlated significantly with urinary albumin excretion, additionally, were inverse correlated with eGFR. The most remarkable findings of this study are of the higher values of sIL-18, sNGAL, uIL-18, and uNGAL in both normoalbuminuric FMF patients and patients with eGFR ≥ 120 mL per minute. CONCLUSIONS: The results of this study suggest that sIL-18, uIL-18, sNGAL, and uNGAL are reliable markers of early renal disfunction in FMF patients, and may let us take measures from the early stage of renal involvement.

Urinary cytopathology in primary bladder amyloidosis.

BACKGROUND: Amyloidosis results from the accumulation of unique extracellular proteins which are not able to be degraded via the usual mechanism of lysosomal proteolysis. Isolated collections of amyloid within the bladder are extremely uncommon, and a cytopathologic description in voided urine has not been described to date. METHODS: A retrospective review was performed at a tertiary-care hospital, and 3 patients with isolated bladder amyloidosis and corresponding voided urine specimens were identified. The following clinical data were collected for each case: age, gender, treatment and follow-up information. RESULTS: The patient age range was 76-84 years, with 2 males and 1 female. Amyloidosis was never clinically suspected. In 1 patient, a urinary amyloid manifested, which was thought to represent extraneous debris at the time of original diagnosis. Two patients never manifested signs of systemic amyloidosis or multiple myeloma, and the third was found to have a monoclonal gammopathy. CONCLUSIONS: Our results show the difficulty of diagnosing urinary amyloid in the absence of clinical suspicion. Further, the presence of urinary amyloid is unlikely in patients with bladder amyloidosis as the cohesive nature of the protein makes spontaneous shedding uncommon. Testing for systemic amyloidosis is warranted and if the disease is localized, a favorable outcome can be expected.

Waxy casts in the urinary sediment of patients with different types of glomerular diseases: results of a prospective study.

BACKGROUND: Casts are well known components of the urinary sediment. For most casts, the clinical associations are known and demonstrated, while for waxy casts they are totally unknown. METHODS: Prospective study for the search and count of waxy casts in the urinary sediment of patients with different types of glomerular diseases. RESULTS: Waxy casts were found in 39 out of 287 patients (13.6%), mostly in low number (1 to 9 out of 100 casts evaluated/sample). They were frequent in postinfectious glomerulonephritis and renal amyloidosis (5/9 patients, 44.5%, p=0.02 for each condition), while they were rare in membranous nephropathy (4/67 patients, 6.0%, 0.04) and absent in focal segmental glomerulosclerosis (0/23 patients, p=0.05). Waxy casts were associated significantly with higher serum creatinine levels (p<0.0001), with the presence of >1 leukocyte/HPF, granular casts and leukocytic casts (p=0.001 to 0.008) and with higher numbers of erythrocytes, leukocytes, renal tubular epithelial cells, granular casts, epithelial casts, and leukocytic casts (p<0.0001 to=0.03). CONCLUSIONS: Waxy casts are uncommon and few in patients with glomerular diseases and are associated with impaired renal function and with several other structures of the urinary sediment.

"Idiopathic Bence-Jones proteinuria": a new characterization of an old entity.

Idiopathic Bence-Jones proteinuria (BJP) is a rare plasma cell dyscrasia, of which the clinical and biological characteristics are yet unclear. Historical data suggested that they are at higher risk of progression to multiple myeloma or other related neoplasms, while recent findings are contradictory. To address these open questions, we evaluated a series of both BJP and monoclonal gammopathy of undetermined significance (MGUS) with production of an intact immunoglobulin plus Bence-Jones proteinuria (MGUS+BJP) with long-term follow-up, regarding their clinical characteristics and progression to multiple myeloma, amyloidosis or other related B cell lymphoproliferative disorders. Two hundred and twenty-nine persons fulfilling the 2004 criteria of MGUS were included in the final analyses: 31 had BJP and 198 had MGUS+BJP. At the time of diagnosis, significantly more persons in the BJP group had renal impairment, anaemia and polyneuropathy. A more detailed analysis revealed discrepancies between the serum and urine light chain type in nine cases, reflecting clonal heterogeneity. The number of disease progressions was higher in MGUS+BJP (n = 30) when compared to BJP (n = 1), with a rate of 1.6 and 0.4 progressions per 100 person-years, respectively. In conclusion, BJP has distinct clinical characteristics and a lower risk of progression when compared to MGUS+BJP. Our data suggest that MGUS+BJP being closer to malignant transformation may be due to the higher portion of genetically heterogeneous, pre-malignant plasma cell subclones.

Immunofixation electrophoresis was highly specific for the diagnosis of renal light-chain amyloidosis.

BACKGROUND: Renal light-chain amyloidosis (AL) is one of the common causes of massive proteinuria and nephrotic syndrome, especially in elderly patients. This study aimed to evaluate the sensitivity and specificity of serum and urine using immunofixation electrophoresis (IFE) in the diagnosis of renal AL amyloidosis in patients older than 40 years. METHODS: Patients receiving native renal biopsy in the hospital who meet the following criteria were recruited in this retrospective study: (1) proteinuria excretion ≥3.5 g/24 hr; (2) age ≥ 40 years when receiving renal biopsy and (3) biopsy-proven glomerulopathy. Serum and urine monoclonal free immunoglobulin light chains were detected using IFE. RESULTS: A total of 625 patients were recruited. Of them, 32 patients (5.12%) were diagnosed as renal AL amyloidosis. The specificities of serum, urine and serum combined urine IFE in the total 625 patients (ie, monoclonal free immunoglobulin light chain in serum or urine) for diagnosis of renal AL amyloidosis were 98.6%, 98.0% and 97.6%, respectively. For patients older than 60 years, the specificities of serum, urine and serum combined urine IFE for diagnosis of renal AL amyloidosis were 98.5%, 98.0% and 97.6%, respectively and the sensitivity of serum, urine and serum combined urine IFE for diagnosis of renal AL amyloidosis were 68.6%, 81.3% and 81.3%, respectively. CONCLUSION: Serum or urine IFE was highly specific for renal AL amyloidosis for patients older than 40 years with nephrotic-range proteinuria. In older patients (>60 years), both the sensitivity and specificity of IFE for renal AL amyloidosis were high. Combination of serum and urine IFE could improve the sensitivity with comparable specificity.

Urinary albumin excretion patterns of patients with cast nephropathy and other monoclonal gammopathy-related kidney diseases.

BACKGROUND AND OBJECTIVES: Multiple myeloma is responsible for a wide variety of renal pathologies. Urinary protein and monoclonal spike cannot be used to diagnose cast nephropathy (CN). Because albuminuria is a hallmark of glomerular disease, this study evaluated the percentage of urinary albumin excretion (%UAE) as a tool to differentiate CN from Ig light chain amyloidosis (AL), light chain deposition disease (LCDD), and acute tubular necrosis (ATN). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients were selected from the Renal Biopsy Database and the Dysproteinemia Database. Participants were excluded if laboratory data were missing within 1 week of the renal biopsy. The %UAE was obtained from urine protein electrophoresis. RESULTS: From 1992 to 2011, 260 patients were biopsied (177 with AL, 28 with LCDD, 43 with CN, and 12 with ATN). The %UAE for CN patients was significantly lower (7%) than for ATN (25%), LCDD (55%), and AL (70%) patients (P<0.001). Significant differences were also found in serum creatinine, serum albumin, free light chain ratio, total urine protein, and urine monoclonal spike; only the %UAE remained independently associated with CN in a logistic regression model (P<0.001). The area under the curve for the receiver operator characteristic curve for %UAE was 0.99. At <25%, the %UAE had a sensitivity of 0.98, specificity of 0.94, positive predictive value of 0.75, and negative predictive value of 0.99. CONCLUSIONS: This study showed that %UAE was significantly less in CN than the other three renal lesions and %UAE may thus be helpful in diagnosis of CN.

Renal histology in patients with elevated serum creatinine and concurrent normal urinalysis.

INTRODUCTION: Diagnosis of kidney disease is currently and primarily based on the measurement of serum creatinine, blood urea nitrogen, and urine output, and most kidney diseases with elevated serum creatinine accompany abnormal findings of urinalysis with microscopy, such as proteinuria or hematuria. The purpose of the current study was to determine the histologic diagnosis of patients with elevated serum creatinine and a concurrent normal urinalysis without underlying disease. METHODS: The medical records of patients who had undergone kidney biopsies between January 1, 2003 and March 1, 2008 in three medical centers were retrospectively reviewed. The patients with an elevated serum creatinine level and a normal urinalysis were enrolled. The exclusion criteria were as follows: diabetes mellitus; hypertension; chronic liver disease; malignancies; autoimmune diseases; dependence on medications; hypokalemic nephropathy; age < 18 years. Age, duration of follow-up, post-biopsy management, and the change in levels of BUN and serum creatinine from pre-biopsy to the last visit were analyzed. RESULTS: All 15 patients were included. The most frequent single diagnosis was acute interstitial interstitial nephritis, followed by hypertensive nephrosclerosis. Chronic interstitial nephritis, mesangial proliferative glomerulonephritis, acute tubular necrosis, secondary amyoloidosis, focal segmental glomerulosclerosis, and minor glomerular change were listed. The young group (< 40 years of age) included more patients with acute interstitial nephritis, and the old group (≥ 40 years of age) included more patients with hypertensive nephrosclerosis. CONCLUSION: Based on a correct histological diagnosis, all of the patients, except one, were properly managed and had preserved kidney function until the last visit.

The relation between urinary angiotensinogen and proteinuria in renal AA amyloidosis patients.

OBJECTIVE: The aim of this study was to evaluate the relationship of local intrarenal renin angiotensin system (RAS) with proteinuria in patients with renal AA amyloidosis. METHODS: Thirty-two patients with renal AA amyloidosis (19 male, mean age: 45 ± 13 years) and sixteen healthy controls (5 male, mean age: 32 ± 5 years) were included in this study. Spot urine samples were obtained to measure urinary angiotensinogen (AGT) using human AGT-ELISA, urinary creatinine and protein levels. Logarithmic transformations of urinary AGT-creatinine ratio log(UAGT/Ucre) and urinary protein-to-creatinine ratio (UPCR) were done to obtain the normal distributions of these parameters. RESULTS: Log(UAGT/UCre) was significantly higher in patients compared with the controls (1.88 ± 0.92 µg/g vs. 1.25 ± 0.70 µg/g; p = 0.023). Importantly a significantly positive correlation was found between log(UAGT/Ucre) and logUPCR in patients (r = 0.595, p = 0.006). CONCLUSIONS: Urinary AGT levels are higher in renal AA amyloidosis patients than in controls. Also, there is a significant positive correlation between urinary AGT and proteinuria in renal AA amyloidosis.

Renal amyloidosis in dogs: a retrospective study of 91 cases with comparison of the disease between Shar-Pei and non-Shar-Pei dogs.

BACKGROUND: Renal amyloidosis (RA) is a progressive and fatal renal disease. HYPOTHESIS: Clinical and pathologic manifestations of RA differ between Chinese Shar-Pei (CSPs) and non-Shar-Pei (NSPs) dogs. ANIMALS: 91 client-owned dogs. METHODS: Retrospective review of medical records of dogs with a histological diagnosis of RA. Clinical and clinicopathologic data, hospitalization, complications, and outcome were compared between CSPs and NSPs. RESULTS: Comorbid diseases were present in 64% of all dogs. CSPs were significantly younger compared to NSPs (median, 4.8 years; range: 3.6-17 versus median: 9.0 years; range: 2.4-11.1; P < .0001). The frequency of hypoalbuminemia, the most common biochemical abnormality, was higher in NSPs compared to CSPs (100% versus 64.7%, respectively; P < .001). Median serum creatinine concentration at presentation was 5.5 mg/dL, and was 3-fold higher in CSPs compared to NSPs (P = .005). Increased urine protein : creatinine ratio was present in 96% of all dogs. Nephrotic syndrome was present in 10% of NSPs but not in CSPs. Glomerular amyloid deposition, present in both CSPs (78.6%) and NSPs (95.6%) was most commonly diffuse, global, and severe. Renal medullar amyloidosis was more common in CSPs (100%) compared to NSPs (49.0%, P = .002), as was extrarenal amyloid deposition. The median survival time of all dogs was 5 days (range: 0-443 days). Serum creatinine concentration was significantly and negatively associated with survival (P = .025). CONCLUSIONS AND CLINICAL RELEVANCE: The clinical and pathologic manifestations of amyloidosis differ between CSPs and NSPs. The survival time observed herein was unexpectedly low, and argues for early surveillance and management of the underlying predisposing conditions.

Acute kidney injury during leukocyte engraftment after autologous stem cell transplantation in patients with light-chain amyloidosis.

Engraftment syndrome (ES) is a complication of hematopoietic stem cell transplantation characterized by fever, rash, and non-cardiogenic pulmonary edema. Acute kidney injury (AKI) has been recognized but is considered a minor criterion in one and excluded another definition of ES. We have noted a high incidence of AKI in patients with immunoglobulin light-chain amyloidosis (AL) undergoing autologous stem cell transplant (ASCT) around the time of leukocyte engraftment. This study was conducted to further investigate the relationship between AKI and ES. Data were collected from 377 AL patients who underwent ASCT from 7/1997 to 10/2009. Patients who experienced an elevation of serum creatinine >0.5 mg/dL within 4 days of leukocyte engraftment and anyone who presented with signs associated with ES regardless of renal manifestations were included. Forty-one patients met criteria. Twelve were excluded for positive cultures (10), acute interstitial nephritis (1), and acute cellular rejection (1). In addition to AKI (93.1%), patients also exhibit fever (82.7%), hypotension (51.7%), rash (48.2%), edema (93.1%), diarrhea (69.0%), conjunctival hemorrhage (31.0%), pulmonary edema (31.0%), pulmonary hemorrhage (13.8%), and transient encephalopathy (17.2%). Patient with pulmonary involvement were more likely to require dialysis but was not statistically significant. AKI was very common during leukocyte engraftment in AL patients. While infectious etiology accounted for some of the AKI, most appeared to be associated with ES. After infection is ruled out, ES should be considered in the differential diagnosis when evaluating AKI in this population.

Effect of lysine modification on the stability and cellular binding of human amyloidogenic light chains.

AL amyloidosis is characterized by the pathologic deposition as fibrils of monoclonal light chains (i.e., Bence Jones proteins [BJPs]) in particular organs and tissues. This phenomenon has been attributed to the presence in amyloidogenic proteins of particular amino acids that cause these molecules to become unstable, as well as post-translational modifications and, in regard to the latter, we have investigated the effect of biotinylation of lysyl residues on cell binding. We utilized an experimental system designed to test if BJPs obtained from patients with AL amyloidosis or, as a control, multiple myeloma (MM), bound human fibroblasts and renal epithelial cells. As documented by fluorescence microscopy and ELISA, the amyloidogenic BJPs, as compared with MM components, bound preferentially and this reactivity increased significantly after chemical modification of their lysyl residues with sulfo-NHS-biotin. Further, based on tryptophan fluorescence and circular dichroism data, it was apparent that their conformation was altered, which we hypothesize exposed a binding site not accessible on the native protein. The results of our studies indicate that post-translational structural modifications of pathologic light chains can enhance their capacity for cellular interaction and thus may contribute to the pathogenesis of AL amyloidosis and multiple myeloma.