Renal involvement as the first symptom of multiple myeloma

Background . Renal involvement is a common complication of multiple myeloma (MM). However, most studies have focused on renal failure in MM, and little information is available about the other renal manifestations in MM and their association with immunophenotypes and renal pathology. Methods . We retrospectively analyzed the clinical, laboratory and pathology data of 283 MM patients treated in Provincial between January 1990 and May 2017. The patients were divided into a renal involvement group (n = 200) and a non-renal involvement group (n = 83). Results. In the renal involvement group, 90 (45.0%) patients were diagnosed with MM in the Nephrology department, and isolated proteinuria, renal failure and nephrotic syndrome were detected in 90(45.0%), 94 (47.0%) and 58 (29.0%) patients, respectively. 135 patients with renal involvement underwent immunofixation electrophoresis, and IgG, IgA, IgD, IgE, pure light chain and nonsecretory MM were detected in 52 (38.5%), 32 (23.7%), 1 (0.7%), 1 (0.7%), 45(33.3%) and 4 (3.0%) patients, respectively. 47 patients without renal involvement also underwent immunofixation electrophoresis, and IgG and IgA MM were found in 24 (51.0%) and 18 (38.3%) patients, respectively. Severe anemia and hypertension, hypercalcemia and pure light chain were more frequent in patients with renal involvement (P < 0.05).9 patients with renal involvement were performed renal biopsy, and cast nephropathy, renal amyloidosis were proved in 5 and 4 patients, respectively. Conclusions. Renal involvement was common at MM diagnosis and had diverse clinical manifestations. The most common clinical manifestations include renal failure, isolated albuminuria and nephrotic syndrome. Nephrologists should rule out MM in patients presenting with renal involvement.

Multiple myeloma (MM) is a neoplastic, plasma-cell disorder characterized by clonal proliferation of malignant plasma cells in the bone marrow microenvironment, the presence of monoclonal protein in the blood or urine and associated organ dysfunction.
Renal involvement is one of the main clinical manifestation threatening complication in MM patients [1,2] Tsakiris DJ et al. [3] reported that MM was the most common neoplasm causing end-stage renal disease, and the first malignancy to be considered an indication for dialysis. Studies on renal involvement in MM tend to focus on renal failure. Impaired renal function is a marker of poor prognosis [4]. Multiple pathogenic mechanisms can contribute to kidney injury in MM patients; some mechanisms are the result of nephrotoxic monoclonal Ig deposition in the kidneys and others are independent of Ig deposition [5].
However, renal involvement in MM has diverse manifestations, which include isolated proteinuria, proteinuria combined with hematuria, renal failure and renal tubular interstitial involvement. Little is known about the proportion of the different manifestations of renal involvement in MM. Studies on the relationship between immunofixation electrophoresis and renal involvement in MM patients have mainly analyzed immune phenotypes and renal failure. Patients with light chains were significantly more prone to develop renal failure (42%-52%) than patients with IgG (22%) or IgA (31%) [6]. However, the relationship between other results of immunofixation electrophoresis and renal involvement is unclear. Furthermore, we have found that most cases of MM with renal failure were reported from Departments of Hematology. Some MM patients with renal involvement as the first manifestation may be admitted in Departments of Nephrology, and the clinical features of these patients need to be studied.
The first symptom of MM varies among patients, and therefore, MM can be diagnosed in different hospital departments. However, few data are available on the proportion of the various presenting symptoms of MM and of the different departments in which MM is 4 diagnosed. In addition, little information is available on MM with renal involvement in the Chinese population. Therefore, to explore the incidence, manifestations of renal MM was diagnosed if any two of the following criteria were met: at least 10% clonal plasma cells in the bone marrow, serum or urinary monoclonal protein and radiographic evidence of osteolytic skeletal lesions [7]. In patients with true nonsecretory myeloma, the diagnosis was based on the presence of 30% monoclonal plasma cells in the bone marrow or the presence of a biopsy-proven plasmacytoma [7] . The clinical stages of the patients were classified according to the staging system of Durie-Salmon [8] . Only patients without previous diagnosis of MM were included into analysis. Patients with persistent proteinuria, hematuria, nephrotic syndrome, acute renal injury (AKI) and renal failure were clinically diagnosed with myeloma nephropathy. And patients with evidence of other renal diseases were excluded (for example advanced diabetes and hypertension with possible nephropathy, analgesic drug abuse, lupus, rheumatoid diseases, etc.) Proteinuria is defined as urine ACR values ≥30 mg/g or >1+ proteinuria on dipstick [9]. Nephrotic syndrome is defined as ACR values ≥2000 mg/g (≥200 mg/mmol) or >3+ proteinuria on dipstick with serum albumin <25 g/L (25 g/L).Hematuria is defined as the presence of red blood cells in the urine including gross hematuria and microscopic hematuria(as defined 5 as greater than or equal to 3 RBCs per HPF) [10]. AKI is defined as increase in SCr by ≥0.3 mg/dl (≥26.5 lmol/l) within 48 hours; or increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or urine volume <0.5 ml/kg/h for 6 hours [11]. According to the International Myeloma Working Group diagnostic criteria), renal failure was also defined as a serum creatinine level ≥ 177 μmol/l [12].
Clinical parameters such as the department in which the diagnosis was confirmed, gender, age, blood pressure, hemoglobin, blood urea nitrogen, serum creatinine, total protein, albumin, globulin, calcium, blood uric acid, urine routine and 24-h urinary protein were Continuous variables were expressed as mean and standard deviation. Categorical variables were presented as median with interquartile ranges (IQR).
The values between groups were analyzed by independent sample T test and nonparametric test. P values < 0.05 were considered statistically significant.

Clinical characteristics of MM with or without renal involvement
The departments in which the diagnosis of MM was confirmed have been shown in No significant differences were detected in gender, age, albumin, proportion of plasma cells and incidence of bone destruction between patients with and without renal involvement.

Characteristics of renal involvement in MM
We have summarized the incidence and manifestations of renal involvement in MM in

Characteristics of immunofixation electrophoresis and renal involvement
A total of 182 patients underwent immunofixation electrophoresis. The results of immunofixation electrophoresis in patients with and without renal involvement have been 7 summarized in respectively. There have found statistically significant in the distribution of λ chain disease between renal involvement and no-renal involvement group. No significant differences were observed in the distribution of IgG and IgA disease between the two groups. We further analyzed the relationship between clinical and immune phenotypes among the 135 patients with renal involvement who underwent immunofixation electrophoresis. We found that patients with IgA disease presented with mainly proteinuria and renal failure, while patients with pure light chain disease, whether κ or λ chain disease, presented with significantly proteinuria with hematuria, increased 24-h urinary protein excretion and renal failure ( Table 5).

Characteristics of renal pathology and renal involvement
There were 9 patients with renal involvement underwent renal biopsy. The results of renal biopsy have been summarized in that amyloid deposition in different organs or tissues causes dysfunction of these organs and tissues and leads to specific symptoms. In an analysis of light chain deposition disease (LCDD), Pozzi C et al. [15] found that 35% of LCDD cases were associated with extrarenal manifestations involving the heart (21%), which presented as congestive heart failure and arrhythmias, and the liver (19%), which could lead to portal hypertension.
Involvement of the lung (pulmonary cystic disorder), gastrointestinal tract and neurological system was less frequent. The above findings indicate that the presenting symptoms of MM are diverse and can easily be misdiagnosed; therefore, every physician should be familiar with these symptoms.
Renal failure in MM is one of the most common complications, and 50% of MM patients are reported to have renal failure at the time of diagnosis [16,17].Jalaeikhoo H et al. [14] reported that in a group of 345 patients, serum creatinine levels were (2.04 ± 2.56) mg/dL , range in(0.6-26.6) mg/dL. MacLennan IC et al. [18] reported that in a group of 1,205 patients, serum creatinine levels were >130 μmol/l in 42% of patients, >200 μmol/l in 20% and >300 μmol/l in 12%. Korbet SM et al. [19] reported that renal insufficiency (serum creatinine of 1.3 mg/dl) is found at presentation in almost 50% of patients with myeloma, and severe renal insufficiency (serum creatinine 2.0 to 2.5 mg/dl) is seen in 15 to 20% of cases . In our study, however, the most common type of renal involvement was proteinuria and/or hematuria, followed by renal failure. In all, 94 (47.0%) patients presented with renal failure (including26[13%]patients presented with AKI, the result is similar to those previously reported [16][17][18]. Moreover, MM patients with renal involvement had a higher degree of anemia, hypercalcemia and hypertension than patients without renal involvement. The incidence of stage III disease was also significantly higher in the renal involvement group than in the non-renal involvement group. These data suggested that MM with renal involvement is a more serious condition, and this conclusion is consistent with the findings of other studies [18]. Suzuki K et al. [20] reported that hypercalcemia associated with osteolysis by myeloma cells is also causes of renal dysfunction.
We were analyzed the relationship between renal involvement and the results of  [19] , which was higher than our study. In the literature, MM presenting as nephrotic syndrome is not common, although light chain and IgD MM can present as nephrotic syndrome [22]. It has been reported that patients of MM produce only light chains account for 40-60% of severe myeloma-associated kidney injury [23] .Consistent with this, our data also showed that patients with pure light chain MM were more prone to renal failure. The major cause of renal failure in patients with pure light chain disease is the overproduction of nephrotoxic light chains. Heher EC et al. [5] reported that mechanisms are the result of nephrotoxic monoclonal Ig deposition in the kidneys and others are independent of Igs. However, in our data 36.5% patients with IgG MM and 68.8% patients with IgA MM in the renal involvement group presented with renal failure, indicating that the development of renal failure is not dependent solely on the concentration of light chains. Wirk B et al. [24] reported that patients with large amounts of serum free light chains can have normal renal function, and patients with small concentrations of serum free light chains can present with renal failure. IgD and IgE overproduction is rare in MM. Only one patient in our study had IgD and IgE MM, which manifested as isolated proteinuria and renal failure. Tsakiris DJ et al. [3] reported that IgD MM is almost invariably associated with Bence Jones light chain proteinuria and renal failure.
Renal biopsies in MM patients with renal dysfunction help defining the types of renal injury, which can influence the extent of aggressive therapy and predict possible outcome [25].The single center of Mayo Clinic analyzed 190 cases of multiple myeloma kidney pathology, and the results showed that MCN accounted for 45%, renal amyloidosis 29%, and light chain deposition 26% [26].Su YT et al. [27] reported that the 46 cases of MM, cast nephropathy, renal amyloidosis and light-chain deposition disease accounted for 52.2%, 32.6%, and 4.3% patients, respectively. In our data, 9 patients with renal involvement were performed renal biopsy, cast nephropathy and renal amyloidosis were proved in 5 and 4 patients, respectively. 4 80.0% cases of light chain cast nephropathy were presented with AKI .
The main limitation of our study was that there was small sample size underwent renal biopsy. In our cohort, if a clinical diagnosis have already been established by other ways(eg, diagnosis of MM based on bone marrow findings and lytic bone lesions), nephrologist may not recommend MM patients with renal involvement undergo renal biopsy. Diagnosis of multiple myeloma does not require renal biopsy, however, a biopsy based diagnosis is important in the evaluation of patients with myeloma because each of the renal lesions has its own therapeutic and prognostic implications. In the future, we will recommend that MM patients with renal involvement undergo routine renal biopsy in our department. Another limitation of our work was that our study was lack of the clinical follow-up data of MM patients. The effect of immunosuppression on both renal disease and the hematologic disease and the prognostic effect of different clinical and histopathological parameters in predicting end-stage renal disease were not discussed.
Basit A et al. [28] reported that ISS stage and renal failure have a significant impact on prognosis of MM patients. In our study the most common type of renal involvement was isolated proteinuria and/or hematuria. Is there also a bad renal prognosis among those patients who present with isolated proteinuria and/or hematuria at onset ? In future, we need to collect follow-up data and assess the prognostic significance of these clinical parameters.

Conclusions
In summary, this is the first study to report the proportion of MM patients who presented with renal involvement as the first manifestation and were admitted in the Department of

Consent for publication
Not applicable.

Availability of data and material.
All data and material were obtained from Sichuan Provincial People's Hospital.

Competing interests
The authors report no conflicts of interest.

Funding
This work was supported by Sichuan Medical Research Project(S18040)