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Urinary proteins and renal dysfunction in patients with multiple myeloma
Biomed Pharmacother 2002 ; 56 : 139-43 © 2002 Éditions scientifiques et médicales Elsevier SAS. All rights reserved S0753332202001713/FLA
Dossier: Myeloma
Urinary proteins and renal dysfunction in patients with multiple myeloma A. Corso*, P. Zappasodi, M. Lazzarino Division of Hematology, University of Pavia, IRCCS Policlinico San Matteo, Pavia, Italy (Received 1 March 2002; accepted 4 March 2002)
Summary – Besides bone pain, pathologic fractures, anaemia, and recurrent infectious diseases, renal failure is one of the most serious complications in multiple myeloma patients. Its incidence is generally underestimated because of the low reliability of the parameters routinely used for the evaluation of renal dysfunction. Other laboratory tests in the literature are reported to be more suitable to better define the extension of the renal impairment, namely urinary proteins or creatinine clearance. We here report on the clinical implication of urinary parameters in defining the renal function in myeloma patients. © 2002 Éditions scientifiques et médicales Elsevier SAS multiple myeloma / renal function / urinary proteins
One of the major complication in multiple myeloma (MM) is represented by renal failure. It is reported as affecting up to 20% of patients at onset and up to 50% of patients during the course of the disease. This incidence is, however, underestimated because of the scarce sensitivity of the parameters routinely used to evaluate renal function, which are inadequate to identify initial renal damage. The prognosis of MM patients depends on the degree of the damage, on the presence of precipitating factors, and on the effectiveness of a prompt antineoplastic therapy which may improve or even revert the renal impairment. The possibility to recover a normal renal function is higher when the damage is minimal. So, the adoption of reliable parameters to better evaluate the extension of renal involvement is mandatory, particularly in patients with low-burden disease. PATHOGENESIS OF RENAL DAMAGE The etiology of renal failure is multifactorial and not completely understood although the excessive pro*Correspondence and reprints. E-mail address: [email protected] (A. Corso).
duction of light chains fills a central role in determining the damage. Light chains are normally produced in excess by plasma cells to guarantee an efficient immunoglobulin synthesis, and this physiologically results in release of free light chains. Once in the circulation under monomeric and dimeric form they are filtered by the glomerulus and reach the proximal tubule where they are internalised and hydrolysed by lysosomal enzymes. The excess of monoclonal light chains provokes a saturation of this endocytotic system and through a proximal tubular overload leads to damage of the tubular cells. The increased load of light chains and the reduced reabsorption causes their appearance in the distal tubule and in the urine. At the distal tubule light chains bind to the Tamm Horsfall protein (THP), a membraneanchored glycoprotein synthesized exclusively by the cells of the thick ascending limb of the loop of Henle [15]. Thus, cast formation is determined by the precipitation of the light chains in the presence of THP. The intratubular obstruction destroys the nephron population, eventually leading to an overt renal dysfunction [25, 27]. The process of proximal and distal tubular injury is reported as a dose- and time- depen-
140
A. Corso et al.
dent mechanism although it does not seem suitable for all cases. In fact, many patients can excrete large amounts of light chains without manifesting renal dysfunction. Solomon et al. have shown that intraperitoneal injection in mice of light chains purified from myeloma patients elicits the development of cast nephropathy. The incidence of renal damage, however, was significantly lower in those animals receiving light chains from patients without renal failure. These findings support the importance of the physicochemical properties of the individual light chains. Some light chains, i.e., are resistant to proteolysis by tripsin and pepsin [13]; others show themselves able to self-aggregate into large multimers under physiological conditions [21]. A low isoelectric point, an acid urinary pH and a high-degree glycosylation of THP seem to enhance the cast formation [5, 15, 25]. The pathologic process of cast formation eventually leads to interstitial fibrosis, which is considered to be determinant for the occurrence of chronic renal failure. The tubular injury, in fact, induced by casts/nephrotoxic light chains causes a tubular epithelial desquamation and a basement membrane rupture with a consequent interstitial infiltrate of macrophages and T-lymphocytes. These cells activate fibroblasts through the release of several substances (cytokines, growth factors, etc.), triggering a progressive interstitial fibrosis. This provokes a chronic renal failure through two possible mechanisms: a peritubular capillary obliteration, or an impaired reabsorption of sodium chloride, which results in a decrease of glomerular filtration rate (GFR) [17]. Besides the cast formation and the fibrosis, other factors can contribute to determining the clinical renal failure. These precipitate the fragile balance of the impaired nephrons. One of the major factors is the extracellular fluid volume depletion which accelerates tubule obstruction, decreasing tubule flow rate and lengthening the period of interaction of the proteins. The increase of calcium concentration is another precipitating factor which facilitates cast formation by promoting self-aggregation of THP [15], and reducing the GFR through vasoconstriction. Several drugs may also trigger renal failure: diuretics can cause a fall of the GFR, raising the plasma concentration of light chains; nonsteroidal antiinflammatory agents, used frequently for bone pain, can give a reduced renal flow rate as well.
ROUTINE DIAGNOSTIC PATHWAY The incidence of renal involvement in multiple myeloma, reported in the literature, varies considerably. Possible reasons are the heterogeneity of the studied populations (selected patients with advanced renal damage in the nephrology centers, and all-stage newly diagnosed myeloma patients in the hematology departments) or the low sensitivity of the parameters usually adopted for the definition of the damage [18]. Serum creatinine and urea levels are unsatisfactory markers because they are not directly correlated with GFR. In fact, serum creatinine remains in normal ranges until the GFR is reduced as much as 50% [29]. Moreover, creatinine, largely produced by muscle mass, depends on age, sex and body weight [10], and so its serum concentration is not only related to the renal function. As a matter of fact, if based on these parameters the incidence of renal dysfunction is underestimated. It rises when creatinine clearance is adopted, since it correlates better with the GFR [6]. All these parameters, however, do not enable the exact definition of the site of the damage (tubular, glomerular, mixed tubular/ glomerular) or its severity. Consequently, they are not adequate in early identification of a renal impairment since they do not correlate with the degree of tubular atrophy [8, 10-12, 19], or the number of casts [14, 22]. The better instrument for the definition of renal damage is renal biopsy, which has an important diagnostic and prognostic role. It represents the only way to exactly evaluate the degree of tubular atrophy and the extension of the tubulointerstitial fibrosis [20, 22, 24]. Histologic patterns of renal damage in MM patients have been outlined mostly by nephrologists on patients with overt renal insufficiency. To our knowledge there is no evidence of pathologic studies on patients with subclinical renal failure. This is due to the fact that renal biopsy is an invasive procedure with a low but not negligible incidence of related complications. ALTERNATIVE MARKERS OF RENAL DYSFUNCTION The need for a more accurate definition of the renal damage in MM patients has driven several authors to search for new markers of renal function as alter
Renal dysfunction in multiple myeloma
natives to the more common laboratory parameters (serum creatinine and urea levels and creatinine clearance). In particular, attention has been focused on urinary proteins since they have proved to be good indices of tubular or glomerular function [23]. Proteins of low molecular weight such as α-1 microglobulin (α-1M), β-2 microglobulin (β-2M), α-1 acid glycoprotein (AGP), β-2 glycoprotein (β-2G), retinol binding protein (RBP), lysozyme (LZ), and N acetyl B D glucosaminidase (NAG) share the property of being filtered by the glomerulus and reabsorbed and catabolized by proximal tubular cells. Therefore, when these cells lose their capacity to reabsorb them completely from the tubular lumen they are excreted in large quantities. Scarpioni et al. found some low molecular weight proteins (RBP, LZ, α-1M, β-2G) increased in myeloma patients with an apparent normal renal function [28]. They hypothesized a competitive mechanism between light chains and other low molecular weight proteins, and consequently they considered the pathological amount of low molecular-weight proteins only an overflow. Coward et al. did not support this hypothesis [9]. They found, in fact, that an increase of RBP and LZ in the urine was correlated with a reduced nephron mass and an impaired GFR, while NAG was only correlated with a tubular injury. Cooper et al. observed as well that urinary excretion of NAG, AGP, and α-1M directly correlating with free urinary light chain excretion while RBP was found altered in patients with overt renal failure, irrespective of light chain excretion [7]. A possible temporal sequence in the excretion of the low-weight urinary proteins was hypothesized by Yu et al. [32]. They suggested that initial tubular damage could give a selective tubular proteinuria of the relatively large low molecularweight proteins such as AGP, while the smaller ones, such as α-1M, could indicate a severe impairment of the proximal tubular function. Thanks to its good correlation with the extension of tubular damage, some authors recommend measuring this protein during the follow-up of patients with BJP in order to monitor the tubular injury [7, 32]. In a recent study, we confirmed the role of low molecular-weight proteins in reflecting a tubular damage, and we extended the analysis to some high molecular-weight urinary proteins (albumin, transferrin and IgG) to also evaluate the glomerular permeability. We hypothesized that
141
these urinary markers can identify a subset of patients with initial renal disorder who could benefit by a thorough histological examination with a renal biopsy [8]. Among high-molecular-weight urinary proteins, IgG excretion reflects severe damage at the glomerular capillary wall, and is related to the degree of renal impairment [2]. The acid load response and the concentration ability have been reported as markers of distal tubule function. Coward et al. in fact observed that an acidification defect is usually present in patients with severe renal failure [9]. These patients usually also show a concentration defect. Few other studies have evaluated the role of the urinary concentration of THP for the identification of a distal tubular injury [16, 26]. THE ROLE OF URINARY PROTEINS IN THE DIAGNOSTIC AND THERAPEUTIC APPROACH Renal failure occurs variously and unpredictably in approximately 50% of patients with MM. Its presence is reported as significantly affecting survival for the high incidence of early deaths (within the first 2 months from diagnosis) [3], and because it always represented a limit in the choice of therapy. More recently, however, some authors have demonstrated the feasibility of high-dose protocols for the treatment of MM patients with renal failure. These more intensive approaches can exert an improvement of renal function until, in some cases, a complete normalisation [4, 22, 24, 30]. The overall survival of patients with renal failure treated with high-dose programs was reported to be similar to that of patients with normal renal function [13, 31]. However, patients recovering a normal renal function have a better prognosis than those with irreversible renal failure [3]. Therefore, renal failure should not hamper the use of high-dose programs and should not be considered per se a poor prognostic factor for survival. It is also known that the possibility to reverse renal damage depends on its severity and that a prompt therapy, started when the lesions are at the initial stage, increases the possibility to obtain a normalisation of renal function [1]. Thus, an early identification of renal damage together with an adequate therapy are the milestones to improving the prognosis in MM patients with renal involvement. As
142
A. Corso et al.
reported above, routine parameters used for the evaluation of renal impairment are not sufficient for an early identification of renal damage. Otherwise, the study of urinary proteins makes it possible to highlight even an initial tubular or glomerular injury [8]. The use of the urinary proteins in myeloma patients, however, has a different clinical impact in relation to the stage of the disease. In patients with early-stage myeloma, whether at first observation or slowly progressed from a previous history of MGUS, the identification of subclinical renal damage can motivate the decision to start therapy. Conversely, in patients with a high tumor burden, for whom treatment is always indicated, the accurate monitoring of renal function is important for a more exhaustive evaluation of response to therapy. At any rate, urinary proteins are useful for a better follow-up of all myeloma patients. They correlate well with the markers of the disease [33], and in some cases can reveal early a progression (unpublished results). CONCLUSIONS Renal failure remains an unpredictable complication in multiple myeloma. Some advances in the understanding of the mechanisms which underlie renal damage have been made, although the pathogenesis is not completely defined. Cast nephropathy has a central role and can be worsened by precipitating factors as volume depletion, hypercalcemia, infections, and administration of nephrotoxic drugs. High-dose treatments are suitable also for patients with renal impairment, producing response and survival rates similar to those of patients with normal renal function. An accurate definition of the renal involvement needs to highlight the lesions at initial stage. Actually, early diagnosis and prompt therapy before the damage becomes irreversible may permit a complete normalization of renal function. Urinary proteins are extremely useful for identifying the site of the injury (tubular, glomerular or mixed tubular/ glomerular) even when minimal lesions are present. Therefore, they should become the standard application for a better definition and monitoring of renal function, mostly in early-stage multiple myeloma. REFERENCES 1 Alexanian R, Barlogie B, Dixon D. Renal failure in multiple myeloma: pathogenesis and prognostic implications. Arch Intern Med 1990 ; 150 : 1693-5.
2 Bazzi C, Petrini C, Rizza V, et al. Urinary excretion of IgG and α1-microglobulin predicts clinical course better than extent of proteinuria in membranous nephropathy. Am J Kidney Dis 2001 ; 38 : 240-8. 3 Bladé J, Fernandez-Llama P, Bosch F, et al. Renal failure in multiple myeloma. Arch Intern Med 1998 ; 158 : 1889-93. 4 Cavo M, Baccarani M, Galieni P, et al. Renal failure in multiple myeloma: a study of presenting findings, response to treatment and prognosis in 26 patients. Nouv Rev Fr Hematol 1986 ; 28 : 147-52. 5 Clyne DH, Pesce AJ, Thompson RE. Nephrotoxicity of Bence Jones in the rat: importance of protein isoelectric point. Kidney Int 1979 ; 16 : 345-52. 6 Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976 ; 16 : 31-41. 7 Cooper EH, Forbes MA, Crockson RA, MacLennan ICM. Proximal renal tubular function in mielomatosis: observations in the fourth Medical Research Council Trial. J Clin Pathol 1984 ; 37 : 852-8. 8 Corso A, Serricchio G, Zappasodi P, et al. Assessment of renal function in patients with multiple myeloma: the role of urinary proteins. Ann Hematol 1999 ; 78 : 371-5. 9 Coward RA, Mallick NP, Delamore W. Tubular function in multiple myeloma. Clin Nephrol 1985 ; 24 : 180-5. 10 Daugaard G, Abildgaard U. Evaluation of nephrotoxicity secondary to cytostatic agents. Crit Rev Oncol-Hematol 1992 ; 13 : 215-40. 11 De Fronzo RA, Humphrey RL, Wright JR, Cooke CR. Acute renal failure in multiple myeloma. Medicine 1975 ; 54 : 209-23. 12 Feest TG, Burge PS, Cohen SL. Successful treatment of myeloma kidney by diuresis and plasmapheresis. Br Med J 1976 ; 1 : 503-6. 13 Goldschmidt H, Lannert H, Bommer J, Ho AD. Multiple myeloma and renal failure. Nephrol Dial Transplant 2000 ; 15 : 301-4. 14 Hill GS, Morel-Maroger L, Mery JP, et al. Renal lesions in multiple myeloma: their relationship to associated protein abnormalities. Am J Kidney Dis 1983 ; 2 : 423-38. 15 Hoyer JR, Seiler MW. Pathophysiology of Tamm-Horsfall protein. Kidney Int 1979 ; 16 : 279-89. 16 Huang ZQ, Kirk KA, Connelly KG, Sanders PW. Bence Jones proteins bind to a common peptide segment of Tamm-Horsfall glycoprotein to promote heterotypic aggregation. J Clin Invest 1993 ; 92 : 2975-83. 17 Ivànyi B. Frequency of light chain deposition nephropathy relative to renal amyloidosis and Bence Jones cast nephropathy in a necropsy study of patients with myeloma. Arch Pathol Lab Med 1990 ; 114 : 986-7. 18 Knudsen LM, Hippe E, Hjort M, et al. Renal function in newly diagnosed multiple myeloma. A demographic study of 1353 patients. Eur J Haematol 1994 ; 53 : 207-12. 19 Levi DF, Williams RC, Lindstrom FD. Immunofluorescent studies of the myeloma kidney with special reference to light chain disease. Am J Med 1968 ; 44 : 922-33. 20 Montseny JJ, Kleinknecht D, Meyrier A, et al. Long-term outcome according to renal histological lesions in 118 patients with monoclonal gammopathies. Nephrol Dial Transplant 1998 ; 13 : 1438-45. 21 Myatt EA, Westholm FA, Weiss DT, et al. Pathogenic potential of human monoclonal immunoglobulin light chains: relationship of in vitro aggregation to in vivo organ deposition. Proc Natl Acad Sci U S A 1994 ; 91 : 3034-8. 22 Pasquali S, Casanova S, Zucchelli A, Zucchelli P. Long-term survival in patients with acute and severe renal failure due to multiple myeloma. Clin Nephrol 1990 ; 34 : 247-54. 23 Pey Y, Cattran D, Greenwood C. Predicting chronic renal insufficiency in idiopathic membranous glomerulonephritis. Kidney Int 1992 ; 42 : 960-6.
Renal dysfunction in multiple myeloma
24 Rota S, Mougenot B, Baudouin B, et al. Multiple myeloma and severe renal failure: a clinicopathologic study of outcome and prognosis in 34 patients. Medicine 1987 ; 66 : 126-37. 25 Sanders P, Booker BB, Bishop JB, Cheung HC. Mechanisms of intranephronal proteinaceous cast formation by low molecular weight proteins. J Clin Invest 1990 ; 85 : 570-6. 26 Sanders PW, Booker BB. Pathobiology of cast nephropathy from human Bence Jones proteins. J Clin Invest 1992 ; 89 : 630-9. 27 Sanders PW, Herrera GA, Kirk KA, et al. The. spectrum of glomerular and tubulointerstitial renal lesions associated with monotypical immunoglobulin light chain deposition. Lab Invest 1991 ; 64 : 527-37. 28 Scarpioni L, Ballochi S, Bergonzi G, et al. Glomerular and tubular proteinuria in myeloma: relationship with Bence Jones proteinuria. Contrib Nephrol 1981 ; 26 : 89-95.
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29 Shemesh O, Golbetz H, Kriss JP, Myers BD. Limitations of creatinine as a filtration marker in glomerulopathic patients. Kidney Int 1985 ; 28 : 830-8. 30 Sirohi B, Powles R, Mehta J, et al. The implication of compromised renal function at presentation in myeloma. Med Oncol 2001 ; 1 : 39-50. 31 Tricot G, Alberts DS, Johnson CH, et al. Safety of autotransplants with high dose melphalan in renal failure: a pharmacokinetic study. Clin Cancer Res 1996 ; 2 : 947-52. 32 Yu H, Yanagisawa Y, Forbes MA, Cooper EH, Crockson RA. Alpha-1-microglobulin: an indicator protein for renal tubular function. J Clin Pathol 1983 ; 36 : 253-9. 33 Zappasodi P, Pascutto C, Bosoni T, Corso A. Urinary proteins in multiple myeloma: strong correlation with the indices of tumor burden. Haematologica 2001 ; 86 : 878.
Dossier: Myeloma
Urinary proteins and renal dysfunction in patients with multiple myeloma A. Corso*, P. Zappasodi, M. Lazzarino Division of Hematology, University of Pavia, IRCCS Policlinico San Matteo, Pavia, Italy (Received 1 March 2002; accepted 4 March 2002)
Summary – Besides bone pain, pathologic fractures, anaemia, and recurrent infectious diseases, renal failure is one of the most serious complications in multiple myeloma patients. Its incidence is generally underestimated because of the low reliability of the parameters routinely used for the evaluation of renal dysfunction. Other laboratory tests in the literature are reported to be more suitable to better define the extension of the renal impairment, namely urinary proteins or creatinine clearance. We here report on the clinical implication of urinary parameters in defining the renal function in myeloma patients. © 2002 Éditions scientifiques et médicales Elsevier SAS multiple myeloma / renal function / urinary proteins
One of the major complication in multiple myeloma (MM) is represented by renal failure. It is reported as affecting up to 20% of patients at onset and up to 50% of patients during the course of the disease. This incidence is, however, underestimated because of the scarce sensitivity of the parameters routinely used to evaluate renal function, which are inadequate to identify initial renal damage. The prognosis of MM patients depends on the degree of the damage, on the presence of precipitating factors, and on the effectiveness of a prompt antineoplastic therapy which may improve or even revert the renal impairment. The possibility to recover a normal renal function is higher when the damage is minimal. So, the adoption of reliable parameters to better evaluate the extension of renal involvement is mandatory, particularly in patients with low-burden disease. PATHOGENESIS OF RENAL DAMAGE The etiology of renal failure is multifactorial and not completely understood although the excessive pro*Correspondence and reprints. E-mail address: [email protected] (A. Corso).
duction of light chains fills a central role in determining the damage. Light chains are normally produced in excess by plasma cells to guarantee an efficient immunoglobulin synthesis, and this physiologically results in release of free light chains. Once in the circulation under monomeric and dimeric form they are filtered by the glomerulus and reach the proximal tubule where they are internalised and hydrolysed by lysosomal enzymes. The excess of monoclonal light chains provokes a saturation of this endocytotic system and through a proximal tubular overload leads to damage of the tubular cells. The increased load of light chains and the reduced reabsorption causes their appearance in the distal tubule and in the urine. At the distal tubule light chains bind to the Tamm Horsfall protein (THP), a membraneanchored glycoprotein synthesized exclusively by the cells of the thick ascending limb of the loop of Henle [15]. Thus, cast formation is determined by the precipitation of the light chains in the presence of THP. The intratubular obstruction destroys the nephron population, eventually leading to an overt renal dysfunction [25, 27]. The process of proximal and distal tubular injury is reported as a dose- and time- depen-
140
A. Corso et al.
dent mechanism although it does not seem suitable for all cases. In fact, many patients can excrete large amounts of light chains without manifesting renal dysfunction. Solomon et al. have shown that intraperitoneal injection in mice of light chains purified from myeloma patients elicits the development of cast nephropathy. The incidence of renal damage, however, was significantly lower in those animals receiving light chains from patients without renal failure. These findings support the importance of the physicochemical properties of the individual light chains. Some light chains, i.e., are resistant to proteolysis by tripsin and pepsin [13]; others show themselves able to self-aggregate into large multimers under physiological conditions [21]. A low isoelectric point, an acid urinary pH and a high-degree glycosylation of THP seem to enhance the cast formation [5, 15, 25]. The pathologic process of cast formation eventually leads to interstitial fibrosis, which is considered to be determinant for the occurrence of chronic renal failure. The tubular injury, in fact, induced by casts/nephrotoxic light chains causes a tubular epithelial desquamation and a basement membrane rupture with a consequent interstitial infiltrate of macrophages and T-lymphocytes. These cells activate fibroblasts through the release of several substances (cytokines, growth factors, etc.), triggering a progressive interstitial fibrosis. This provokes a chronic renal failure through two possible mechanisms: a peritubular capillary obliteration, or an impaired reabsorption of sodium chloride, which results in a decrease of glomerular filtration rate (GFR) [17]. Besides the cast formation and the fibrosis, other factors can contribute to determining the clinical renal failure. These precipitate the fragile balance of the impaired nephrons. One of the major factors is the extracellular fluid volume depletion which accelerates tubule obstruction, decreasing tubule flow rate and lengthening the period of interaction of the proteins. The increase of calcium concentration is another precipitating factor which facilitates cast formation by promoting self-aggregation of THP [15], and reducing the GFR through vasoconstriction. Several drugs may also trigger renal failure: diuretics can cause a fall of the GFR, raising the plasma concentration of light chains; nonsteroidal antiinflammatory agents, used frequently for bone pain, can give a reduced renal flow rate as well.
ROUTINE DIAGNOSTIC PATHWAY The incidence of renal involvement in multiple myeloma, reported in the literature, varies considerably. Possible reasons are the heterogeneity of the studied populations (selected patients with advanced renal damage in the nephrology centers, and all-stage newly diagnosed myeloma patients in the hematology departments) or the low sensitivity of the parameters usually adopted for the definition of the damage [18]. Serum creatinine and urea levels are unsatisfactory markers because they are not directly correlated with GFR. In fact, serum creatinine remains in normal ranges until the GFR is reduced as much as 50% [29]. Moreover, creatinine, largely produced by muscle mass, depends on age, sex and body weight [10], and so its serum concentration is not only related to the renal function. As a matter of fact, if based on these parameters the incidence of renal dysfunction is underestimated. It rises when creatinine clearance is adopted, since it correlates better with the GFR [6]. All these parameters, however, do not enable the exact definition of the site of the damage (tubular, glomerular, mixed tubular/ glomerular) or its severity. Consequently, they are not adequate in early identification of a renal impairment since they do not correlate with the degree of tubular atrophy [8, 10-12, 19], or the number of casts [14, 22]. The better instrument for the definition of renal damage is renal biopsy, which has an important diagnostic and prognostic role. It represents the only way to exactly evaluate the degree of tubular atrophy and the extension of the tubulointerstitial fibrosis [20, 22, 24]. Histologic patterns of renal damage in MM patients have been outlined mostly by nephrologists on patients with overt renal insufficiency. To our knowledge there is no evidence of pathologic studies on patients with subclinical renal failure. This is due to the fact that renal biopsy is an invasive procedure with a low but not negligible incidence of related complications. ALTERNATIVE MARKERS OF RENAL DYSFUNCTION The need for a more accurate definition of the renal damage in MM patients has driven several authors to search for new markers of renal function as alter
Renal dysfunction in multiple myeloma
natives to the more common laboratory parameters (serum creatinine and urea levels and creatinine clearance). In particular, attention has been focused on urinary proteins since they have proved to be good indices of tubular or glomerular function [23]. Proteins of low molecular weight such as α-1 microglobulin (α-1M), β-2 microglobulin (β-2M), α-1 acid glycoprotein (AGP), β-2 glycoprotein (β-2G), retinol binding protein (RBP), lysozyme (LZ), and N acetyl B D glucosaminidase (NAG) share the property of being filtered by the glomerulus and reabsorbed and catabolized by proximal tubular cells. Therefore, when these cells lose their capacity to reabsorb them completely from the tubular lumen they are excreted in large quantities. Scarpioni et al. found some low molecular weight proteins (RBP, LZ, α-1M, β-2G) increased in myeloma patients with an apparent normal renal function [28]. They hypothesized a competitive mechanism between light chains and other low molecular weight proteins, and consequently they considered the pathological amount of low molecular-weight proteins only an overflow. Coward et al. did not support this hypothesis [9]. They found, in fact, that an increase of RBP and LZ in the urine was correlated with a reduced nephron mass and an impaired GFR, while NAG was only correlated with a tubular injury. Cooper et al. observed as well that urinary excretion of NAG, AGP, and α-1M directly correlating with free urinary light chain excretion while RBP was found altered in patients with overt renal failure, irrespective of light chain excretion [7]. A possible temporal sequence in the excretion of the low-weight urinary proteins was hypothesized by Yu et al. [32]. They suggested that initial tubular damage could give a selective tubular proteinuria of the relatively large low molecularweight proteins such as AGP, while the smaller ones, such as α-1M, could indicate a severe impairment of the proximal tubular function. Thanks to its good correlation with the extension of tubular damage, some authors recommend measuring this protein during the follow-up of patients with BJP in order to monitor the tubular injury [7, 32]. In a recent study, we confirmed the role of low molecular-weight proteins in reflecting a tubular damage, and we extended the analysis to some high molecular-weight urinary proteins (albumin, transferrin and IgG) to also evaluate the glomerular permeability. We hypothesized that
141
these urinary markers can identify a subset of patients with initial renal disorder who could benefit by a thorough histological examination with a renal biopsy [8]. Among high-molecular-weight urinary proteins, IgG excretion reflects severe damage at the glomerular capillary wall, and is related to the degree of renal impairment [2]. The acid load response and the concentration ability have been reported as markers of distal tubule function. Coward et al. in fact observed that an acidification defect is usually present in patients with severe renal failure [9]. These patients usually also show a concentration defect. Few other studies have evaluated the role of the urinary concentration of THP for the identification of a distal tubular injury [16, 26]. THE ROLE OF URINARY PROTEINS IN THE DIAGNOSTIC AND THERAPEUTIC APPROACH Renal failure occurs variously and unpredictably in approximately 50% of patients with MM. Its presence is reported as significantly affecting survival for the high incidence of early deaths (within the first 2 months from diagnosis) [3], and because it always represented a limit in the choice of therapy. More recently, however, some authors have demonstrated the feasibility of high-dose protocols for the treatment of MM patients with renal failure. These more intensive approaches can exert an improvement of renal function until, in some cases, a complete normalisation [4, 22, 24, 30]. The overall survival of patients with renal failure treated with high-dose programs was reported to be similar to that of patients with normal renal function [13, 31]. However, patients recovering a normal renal function have a better prognosis than those with irreversible renal failure [3]. Therefore, renal failure should not hamper the use of high-dose programs and should not be considered per se a poor prognostic factor for survival. It is also known that the possibility to reverse renal damage depends on its severity and that a prompt therapy, started when the lesions are at the initial stage, increases the possibility to obtain a normalisation of renal function [1]. Thus, an early identification of renal damage together with an adequate therapy are the milestones to improving the prognosis in MM patients with renal involvement. As
142
A. Corso et al.
reported above, routine parameters used for the evaluation of renal impairment are not sufficient for an early identification of renal damage. Otherwise, the study of urinary proteins makes it possible to highlight even an initial tubular or glomerular injury [8]. The use of the urinary proteins in myeloma patients, however, has a different clinical impact in relation to the stage of the disease. In patients with early-stage myeloma, whether at first observation or slowly progressed from a previous history of MGUS, the identification of subclinical renal damage can motivate the decision to start therapy. Conversely, in patients with a high tumor burden, for whom treatment is always indicated, the accurate monitoring of renal function is important for a more exhaustive evaluation of response to therapy. At any rate, urinary proteins are useful for a better follow-up of all myeloma patients. They correlate well with the markers of the disease [33], and in some cases can reveal early a progression (unpublished results). CONCLUSIONS Renal failure remains an unpredictable complication in multiple myeloma. Some advances in the understanding of the mechanisms which underlie renal damage have been made, although the pathogenesis is not completely defined. Cast nephropathy has a central role and can be worsened by precipitating factors as volume depletion, hypercalcemia, infections, and administration of nephrotoxic drugs. High-dose treatments are suitable also for patients with renal impairment, producing response and survival rates similar to those of patients with normal renal function. An accurate definition of the renal involvement needs to highlight the lesions at initial stage. Actually, early diagnosis and prompt therapy before the damage becomes irreversible may permit a complete normalization of renal function. Urinary proteins are extremely useful for identifying the site of the injury (tubular, glomerular or mixed tubular/ glomerular) even when minimal lesions are present. Therefore, they should become the standard application for a better definition and monitoring of renal function, mostly in early-stage multiple myeloma. REFERENCES 1 Alexanian R, Barlogie B, Dixon D. Renal failure in multiple myeloma: pathogenesis and prognostic implications. Arch Intern Med 1990 ; 150 : 1693-5.
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