| BackgroundMultiple myeloma (MM) is a neoplastic disorder composed of the immature and mature plasma cells origins from B cells. It is a systemic disseminated disease and accounts for10%of all hematologic malignancies.MM has a complex array of clinical manifestations including bone lesions, anemia, renal damage, compromised immune function and hypercalcemia. Renal impairment is a common and serious complication of MM and represents one of the major causes of morbidity and mortality in this condition. It occurs in25%-50%of newly diagnosed patients with MM, and the incidence of renal impairment shows an obvious upward trend in recent years. Renal damage is caused by the large number of monoclonal plasma cells produce immunoglobulin and light chain. Its clinical manifestations include proteinuria, renal tubular dysfunction, nephrotic syndrome, acute renal failure and chronic renal failure.MM produced several diverse effects on kidneys, such as in the renal proximal tubule affects its reabsorption, in the renal diatal tubule forms myeloma cast and in renal glomerular leads to light chain deposition disease. The majority mechanism of MM-associated renal damage is a large number of monoclonal light chains (Bence Jones protein) excrete from the kidney, in addition with hypercalcemia, hypericemia, high viscosity syndrome, dehydration, infections, drug nephrotoxicity and contrast agent. Urine monoclonal light chains can cause a variety of pathological changes in the kidneys, including "myeloma kidney" or cast nephropathy, amyloidosis, light chain deposition diease and acquired adult Fanconi syndrome.Renal distal tubule injury (cast nephropathy) is the most important factor of renal damage, accounting for about60%.When the concentration of urine monoclonal light chains in glomerular ultrafiltrate exceeds the reabsorptive capacity of proximal tubular epithelium, urine monoclonal light chains may coprecipitate with Tamm-Horsfall protein (THP) in distal tubules to produce casts. A lot of light chains casts block the tubules, tubular obstruction increase intraluminal pressure, reduces glomerular filtration rate and reduces interstitial blood flow, thus eventually cause glomerular damage. However, some studies found that the formation of casts affected the occurrence and development of cast nephropathy, but the direct toxicity of urine monoclonal light chains on renal tubular epithelial cells also played an important role. So, we thought that MM renal damage is caused by proximal tubule injury and distal tubule formation of casts. When the urine monoclonal light chains has not exceed the reabsorption capacity of proximal tubule, the proximal tubule damage is the mainly reason in the early stage.The renal damage in patients with amyloidosis and light chain deposition disease are due to large amounts of monoclonal immunoglobulin and their fragments secreted by myeloma cells abnormal deposited in the kidney. Their pathology often shows glomerular lesions, such as the glomerular basement membrane proliferation, the mesangium proliferation and tuberous sclerosis. Their majory clinical manifestation is nephrotic syndrome. The type of urine monoclonal light chains is not the same in amyloidosis and light chain deposition disease, the more common X, type light chain occurred in amyloidosis, whereas in light chain deposition disease type κ light chain accounted for about70%. Acquired adult Fanconi syndrome is due to urine monoclonal light chains induce an exceedingly unusual disorder characterized by failure in the reabsorptive capacity of the proximal tubules. The clinical manifestations are glycosuria, high carbonate urine, aminoaciduria, hypercalciuria, tubular proteinuria, renal proximal tubule acid poisoning.The majority of renal damage in MM patients is difficult to reverse. Renal improvement was evident within the first three months of treatment. MM patients with renal damage should make the renal function returned to normal as soon as possible, especially those with less proteinuria, a lower degree of renal failure and reversible hypercalcemia in patients after early intervention, more than50%of patients’ renal damage improved. Therefore, we can identify the MM early renal damage and give positive intervention can effectively reverse renal damage and prolong the survival of patients.At present, only renal biopsy can give an exact definition of the extent and type of renal damage, even if it cannot be routinely used because of its potential related risks. Therefore, effective and reliable laboratory parametes to identify the MM early renal damage is necessary.Blade’s study had shown that the median survival of the patients with normal renal renal function was34.5months, whereas that of the patients with glomerular damage was8.6months. Therefore, the glomerular damage was the one of high-risk factors that affection the prognosis of MM patients. But the clinical significance and prognosis of MM patients with renal tubular damage has not been elucidated. The performances of tubular damage are the concentration of low molecular weight urinary proteins (such as urinary RBP and urinary NAG) increased. Previous studies had demonstrated that the effectiveness of low molecular weight urinary proteins diagnosis of the MM early renal damage, but their reliability and specifity are unclear.Objective and significanceThis study designed to evaluate the clinical significance of low molecular weight urinary proteins diagnosis of the MM early renal damage though a retrospective analysis obout the clinical data of newly diagnosed278patients with MM. It purposed to explore effective and reliable laboratory indicators for identify MM early renal damage and further to analyze the prognosis of patients with MM early renal damage. To raise the awareness of MM early renal damage, particularly in patients with indolent early-stage MM, in order to more accurately define when to start therapy, thereby reducing the incidence of end-stage renal disease and prolonging survival.Methods1Patients selection and groupingIn this study, we reviewed the records of consecutive patients (278) in whom MM was initially diagnosed in our center from January2004, to May2012. All enrolled patients had no heart, liver, kidney and urinary tract infections and other diseases, and recently unused nephrotoxic drugs. These patients were divided into three groups:glomerular damage groups (Scr≥2mg/dl, n=143), tubular damage group (RBP≥0.5mg/L, NAG≥17.8U/g·cr, n=114) and normal group (n=21).2The contents of the studyClinical and laboratory data were compared among three groups. The correlations of urinary RBP or urinary NAG with urea nitrogen (BUN), Scr, srum cystatin-C (Cys-C), clearance of creatinine (Ccr),24h proteinuria and24h urine light chains were further analyzed. The correlations of the scores of renal tubulointerstitial lesions with low molecular weight urinary proteins in61patients were also analyzed. The area under curve (ROC curve) was used to evaluate and compare the discrimination of urinary RBP and urinary NAG Analysis of overall survival and median survival time of the follow-up of219patients with MM, the survival time between the three groups were compared.3Statistical analysisStatistical analysis was performed using SPSS for Windows, version13.0(SPSS; Chicago, IL, USA). Measurement data comparisons between three groups were performed using one-way ANOVA or Kruskal-Wallis H test. The x2test were used to assess the statistical significance of Count data comparisons. Nonparametric correlation (Spearman test) was used to quantify the strength of the linear relationship. The area under curve was used to evaluate and compare the discrimination of low molecular weight urinary proteins (RBP and NAG). Patient survival analysis was performed using the method of life table, Kaplan and Meier and multivariate COX analysisi. Statistical significance was assumed at P<0.05.Result1Patients characteristicThe three groups in gender, age, serum Alb and24h urinary light chain showed no significant difference (P>0.05), but in the typing and staging showed significant difference (P<0.05). Hb in glomerular damage group was significantly lower than normal group, tubular damage group (P<0.05).24-hour urine protein in tubular damage group and glomerular damage group was significantly higher than normal group (P<0.001). Urinary RBP and urinary NAG among the three groups were significantly different (P<0.05), glomerular damage group had higher urinary RBP than tubular damage group. However, glomerular damage group had lower urinary NAG than tubular damage group. The two groups had higher urinary RBP and urinary NAG than normal group.2The correlations of urinary RBP or urinary NAG with BUN, Scr, Cys-C, Ccr, 24h proteinuria and24h urine light chainsUrinary RBP related positively to the level of Scr, BUN, Cys-C,24h proteinuria (r=0.74; r=0.61; r=0.61; r=0.31), and related negatively to the level of Ccr (r=-0.66). Urinary NAG related positively to the level of24h proteinuria, Ccr (r=0.36; r=0.17) and related negatively to the level of Cys-C (r=-0.23).3The correlations of urinary RBP or urinary NAG with renal tubulointerstitial lesionsThe extent of renal tubulointerstitial lesions (4levels) of low molecular weight proteins were compared by Kruskal-wallis H test. The four groups of concentrations of RBP were not all the same (H=23.58, P<0.01).However, there were no significant difference between the four groups of NAG (P>0.05).Spearman correlation analysis showed the renal tubulointerstitial lesions significantly correlated with the content of urinary RBP (r=0.60, P<0.01) and weakly with NAG (r=-0.26, P=0.05). The area under ROC curve of RBP was0.84(P<0.01), whereas NAG was0.36(P=0.17).4Survival analysisA total of219MM patients were followed up,3-year overall survival was42%and the median surivial time was29.9months.The3-year overall survival of the20patients in normal group was88%, that of the105patients in tubular damage group was39%,94patients in glomerular damage group was38%.The median survival of patients in normal group was55.8months, whereas that of patients in tubular damage group was29.4months (P<0.05), patients in glomerular damage group was26.1months (P<0.05). In105patients with tubular damage group, the median survival of22patients who recovered from urinary RBP and NAG was50.2months vs27.9months for25patients those with irreversible urinary RBP and NAG (P<0.05). No significant differences in survival were found in patients with normal group vs those with reversible urinary RBP and NAG Multivariate COX analysis revealed that serum Alb (B=0.498, RR=1.645, P=0.030) and Scr (B=0.560, RR=1.751, P=0.014) are independence risk factors for MM.ConclusionIn conclusion:(a) demonstrate the effectiveness of low molecular weight urinary proteins (urinary RBP and NAG) diagnosis of the MM early renal damage;(b) further confirm the reliability of low molecular weight urinary proteins diagnosis of the MM early renal damage;(c) urinary RBP is significantly correlate with renal tubular damage, compared with urinary NAG, urinary RBP can better assess the extent of renal damage, and has higher specificity;(d) may be the degree of renal damage were more severe and the prognosis of patients with MM were more worse;(e) early renal damage recovery after treatment the prognosis of patients with MM likely better than not restored, and the prognosis is no difference with the without renal damage. |
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