ABSTRACT
Objective
Cast nephropathy (CN) is the leading cause of acute kidney injury (AKI) in multiple myeloma (MM). Since it is sparsely documented why some patients with CN do achieve a renal response while others do not, we describe a single-center cohort of patients with multiple myeloma and biopsy-confirmed CN to evaluate potential markers of renal response.
Methods
The data was collected as a retrospective, single-center analysis of CN-patients treated at the Medical University Vienna between 01/01/2004 and 01/01/2022. Baseline parameters and clinical outcome was compared between renal responders and non-responders.
Results
Among 28 patients with CN, n = 23 were assessed for renal response (14 responders; 9 non-responders). Renal responders were younger (median age: 61 years; 77 years, p = 0.039), showed higher overall survival (153months; 58months, p = 0.044) and achieved hematologic response (≥PR) to first-line therapy (p = 0.029), and complete hematologic response (CR) at any time (p = 0.025) significantly more often. Further, we could show that rapid initiation of anti-myeloma therapy after initial presentation correlated significantly with renal response (median 9 days; 27 days, p = 0.016). Analyses of kidney biopsy specimens revealed that patients with a high IF/TA score showed end stage renal disease (dialysis ≥ 3 months) significantly more often (p = <0.001).
Discussion
In summary, our data suggests, that a rapid start with systemic hematologic treatment in patients with MM and CN is crucial and achieving an early hematologic response is important for renal recovery. Moreover, achieving a deep hematologic response and subsequent renal recovery improves clinical outcome as reflected by an overall survival benefit.
1. Introduction
Multiple Myeloma (MM) is a malignant plasma cell disorder, characterized by uncontrolled proliferation of monoclonal plasma cells in the bone marrow, leading to the overproduction of non-functional immunoglobin chains. These paraproteins can cause severe organ dysfunction such as renal impairment, cardiac impairment, bone lesions and polyneuropathy [Citation1].
Renal damage: Up to 40% of patients with MM have increased serum creatinine values and up to 10% require dialysis at time of diagnosis. Renal impairment has been recognized as a poor prognostic factor and is associated with a higher tumor burden, reduced response rate and shorter overall survival [Citation2–4]. Mild to moderate renal impairment at presentation of MM is frequent, but most patients will recover renal function. About 8% of all patients with MM will develop irreversible renal damage with permanent dialysis dependence, associated with a drastically reduced survival [Citation5, Citation6].
Therapy: Early and adequate systemic MM therapy leads to rapid reduction of serum light chain concentration, which is necessary to prevent chronic renal failure [Citation7–10]. Bortezomib plus high-dose dexamethasone or bortezomib/ dexamethasone–based combinations are the cornerstone for patients with multiple myeloma and severe renal impairment and exhibit better effectiveness than other regiments [Citation11–13].
Types of renal lesions: In patients with newly diagnosed MM (NDMM) and acute kidney injury (AKI), only 50–75% of patients show paraprotein-associated lesions in renal biopsy [Citation14, Citation15]. The predominant paraprotein-associated lesion is cast nephropathy (CN) (30–50%), followed by monoclonal immunoglobulin deposition disease (MIDD) and AL amyloidosis [Citation14–16]. The leading mechanism of CN is the accumulation of free light chains (FLC) in quantities that exceed the endocytic capacity of proximal tubules. The highly concentrated FLC interact with the Tamm-Horsfall glycoprotein (THP), forming intraluminal precipitations in the lumen of the distal nephrons, resulting in interstitial inflammation, fibrosis and tubular atrophy (IF/TA) [Citation17–19].
CN typically manifests as proteinuria without albuminuria because the glomerular basement membrane (GBM) remains intact. In contrast, MIDD and AL amyloidosis display both proteinuria and albuminuria as they involve the GBM [Citation20]. While certain laboratory markers may indicate a greater likelihood of CN, renal biopsy is the only method to accurately differentiate between cast nephropathy and other MM-associated renal pathologies [Citation3, Citation21, Citation22].
Since kidney biopsy is not included in the diagnostic guidelines for multiple myeloma patients with acute kidney injury (AKI), only limited data are available concerning the incidence of CN. Because it is sparsely documented why some CN patients achieve a renal response while others do not, we describe in this manuscript our cohort of patients with multiple myeloma and biopsy-proven cast nephropathy and potential markers for renal response.
Objective: The primary objective of this study was to characterize patients with MM and CN regarding their therapy response, survival, improvement of renal function and need for transient or permanent hemodialysis. Furthermore, we aimed to define disease characteristics that predict renal recovery.
2. Materials and methods
2.1. Study design and settings
This descriptive cohort study was carried out as a retrospective, monocentric evaluation at the Medical University of Vienna, Austria. Collecting and comparing clinical data like patient characteristics, laboratory values, parameters of renal functions, and number of treatment lines and drug- combinations. All predefined parameters under investigation were collected pseudonymized in a Microsoft Excel®-based database. This study got approved by the ethics committee of the medical university Vienna on 03/13/2022 under the number: EK Nr: 1014/2022.
2.2. Patient population
All patients included in this study were treated at the Medical University of Vienna. The investigation included data from all patients diagnosed with plasma cell dyscrasias and biopsy confirmed CN between 1st January 2004 and 1st January 2022. Patients were identified through a medical chart review (AKIM) at the Department of Medicine. 111 patients were biopsied who were suspected of having CN. In 54 patients, the suspicion of CN was confirmed.
Twenty-six of the available CN-biopsies, were submissions from other hospitals without the ability to diagnose a CN at their own hospital and therefore, information about the need for dialysis or treatment of myeloma was often not available. Twenty-eight patients matched our inclusion criteria. Out of the 28 identified patients, for 23 patients, enough data was available to assess renal response after one year. Using the IMWG response criteria, 14 renal responders and 9 renal non-responders could be identified. () ().
Figure 1. Description of patient population – for assessment of renal response, IMWG renal response criteria were used.
Table 1. Inclusion and exclusion criteria.
2.3. Standard processing of kidney biopsy samples
Each kidney biopsy specimen undergoes, depending to its size, a predefined processing with twenty to thirty section levels stained with HE, PAS, methenamine silver and AFOG trichrome, followed by immunohistochemistry for IgG, IgM, IgA, C3 and C1q. Immunohistochemistry for the light chains kappa and lambda is added depending on the indication of biopsy or upon the decision of the reporting renal pathologist.
2.4. Parameters
Cast nephropathy was diagnosed following international standards, with the detection of a various number of tubular casts with the typical aspect of whether irregular, angulated, fractured, crystal-like or lamellated cylinders, at times accompanied by intratubular leukocytes or multinucleated cells, in the PAS stain pale and the trichrome stain polychromatic character [Citation23]. When detecting these particular tubular casts, a varying acute tubular injury was the rule. Immunohistochemical verification of the monoclonal character of those protein casts with light chains kappa or lambda served as a validating ancillary technique. None of these CNs required ultrastructural confirmation. Interstitial fibrosis and tubular atrophy (IF/TA) scores were classified as: 0, absent; 1 (mild), < 25%; 2 (moderate), 25–50%; and 3 (severe), > 50% of the total area.
The baseline variables included age, gender, dialysis dependency, paraprotein type, BMI, serum calcium, sFLC, M-Protein, albumin, serum creatinine, eGFR, and hemoglobin levels and were collected at timepoint of diagnosis of CN. The data is shown in the tabular form for the cohort of 28 patients, as well as for renal responders and non-responders respectively to identify potential markers of renal response.
IMWG renal response criteria were used for renal response assessment. To compensate for the fact that some patients have been observed for a longer period than others, we have chosen to define renal response as a response within the first year after CN diagnosis. Renal responders either reached dialysis independency or minor, partial, or complete renal response as defined by the IMWG [Citation24] within one year after diagnosis of cast nephropathy.
For assessment of hematologic response, IMWG criteria were used. We merged stringent CR and CR, defined as negative serum and urine immuno-fixation because not all patients underwent bone marrow biopsy in the course of the disease.
Therapy lines were defined using the 2015 published criteria by Rajkumar et al. [Citation25].
2.5. Statistical analysis
The patients were pseudonymized. Every patient in the study got a number (001,002 …) Statistical analysis was performed using SPSS for Mac (Version 27.0) Graphical illustration was done with the online statistic software datatab and Excel.
Categorical variables were summarized as frequencies and percentages. Comparison for categorical variables among the group of renal responders and non-responders was done, using the Fisher’s Exact Test. For nominal variables, the range and the median are listed in tabular form for renal responders as well as for renal non-responders. The nonparametric Mann–Whitney U test was used to compare nominal variables.
To demonstrate the differences in overall survival, Kaplan Meier Analysis is performed. The differences between survival rates were calculated with the log-rank test.
Due to the limited cohort of 28 patients, the focus of this manuscript lies on the descriptive presentation of the group of renal non-responders and the group of renal responders.
3. Results
3.1. Leading symptoms on hospitalization day
Out of the 28 patients with CN, 43% presented with symptoms of renal failure (fatigue, nausea, loss of appetite). 32% of all patients showed no clinical symptoms of renal failure at initial presentation and 2 patients even showed no symptoms, and AKI was an incidental finding. For 7 patients, leading symptoms were not documented .
Figure 2. Leading symptoms on hospitalization day.
3.2. Renal response evaluation:
Out of the 28 patients with CN, enough data were available from 23 patients to evaluate the best renal response within one year. The five patients, which were lost for follow-up before the first year, were excluded from the renal response analysis. 89% (n = 25) of patients received the diagnosis of multiple myeloma at the same time as the diagnosis of CN. Only 3 patients were diagnosed with CN after they already started a therapy regimen for MM .
Figure 3. Renal response evaluation (IMWG renal response criteria) – Best renal response after one month, first therapy line and after one year.
After one month, 32% (n = 9) of all patients already achieved renal response. That in turn means, that 9 out of 14 renal responders (63%) already showed a renal response after one month. Two patients even showed complete renal response after one month.
After first therapy line (median 120 days), 47% (n = 13) of all patients reached some type of renal response. This means, that 13 of 14 renal responders ( = 93%) already had a renal response after the first line of myeloma therapy. But only 7% (n = 2) achieved complete renal response to first therapy line.
After one year of observation, 50% (n = 14) of all patients achieved renal response of any type and 18% (n = 5) even reached complete renal response. 32% (n = 9) of all patients had no renal response and 18% (n = 5) of all patients were lost to follow-up. Within one year the median number of therapy lines was two.
3.3. General characteristics
The median age of the complete patient population was 62.5. Patients, that showed renal recovery within the first year after diagnosis had a median age of 61, while patients, who did not achieve renal recovery were significantly older (77 years). The median serum level of the affected FLC was 2770.5 mg/l at baseline. Median baseline FLCs were numerically lower in patients that later achieved renal response, but that difference was not significant ().
Table 2. Patients‘ characteristics – renal responder and renal non-responder (defined as renal response within one year).
All patients presented with acute kidney injury and median serum creatinine (SCr) of 5 mg/dl. Renal responders had lower baseline SCr than renal non-responders. This difference was found to be not significant (p = 0.193). All patients had low hemoglobin levels at the timepoint of diagnosis, with a median hemoglobin level of 9 g/dl, ranging from 6.9 g/dl to 12.7 g/dl.
3.4. Renal pathological features
The mean number of casts/mm2 was 4.05 (0.7–14.21) in the cortex and 4.74 (2.56–35.78) in the medulla. Renal responders showed a lower mean number of casts/mm2, but this association was not found to be significant. Further, no significant association was found between the number of casts per square millimeter and baseline eGFR, affected free light chain, or age () ().
Figure 4. A: Mean number of casts/mm2 (total, cortical, medulla) compared between renal responders (green) and renal non-responders (red); B: Cortical IF/TA score compared between patients with end-stage renal disease(grey) and no end stage renal disease (blue).
Table 3. Pathological findings (number of casts and IF/TA) defined as described in paragraph 2.3 and 2.4.
High IF/TA score did not correlate with renal response. However high IF/TA was significantly associated with end-stage renal disease (p = <0.001). All patients with end-stage renal disease showed IF/TA 3.
3.5. Hematologic response
All renal responders had some type of documented hematologic response at any time ().
Figure 5. Percentage of hematologic responders in the group of renal responders and non-responders.
Compared to renal non-responders, the rate of complete hematologic response was significantly higher in the group of renal responders (p = 0.025) (). Patients with renal recovery also showed any type of hematologic response to first-line therapy (≥PR) significantly more often (p = 0.029).
Table 4. Hematologic response – renal responder and renal non-responder.
3.6. Myeloma therapy and dialysis
46% (n = 13) of patients needed dialysis at some point during the observation period. All but one dialysis patient, already presented with severe renal insufficiency requiring dialysis at baseline at time of diagnosis. The median duration of dialysis dependency was 46 days, ranging from only 7 days to 7 years. Most frequent treatment regiments used were VCD (n = 7) (Bortezomib/Cyclophosphamide/Dexamethasone) and VTD (n = 7) (Bortezomib/Thalidomide/Dexamethasone). More than 80% of patients received a PI-based regimen. There was no disparity in treatment received by renal responders and non-responders .
Figure 6. Therapy and dialysis – renal responders and renal non-responders. * Dialysis dependency > 3 months. ** PIs used were Bortezomib (n = 22) and Carfilzomib (n = 1)
A median of 15 days (4–68) elapsed between the first presentation of patients with elevated creatinine levels and the initiation of therapy. Patients who showed renal response during follow-up, started systemic therapy significantly earlier after initial presentation with acute kidney injury.
The time from initial presentation to the start of systemic therapy is composed of the time from initial presentation until CN diagnosis and then the time until the start of therapy. To analyze where a particularly large amount of time elapsed, we calculated the time from initial presentation with AKI to CN diagnosis and from CN diagnosis to the start of therapy (). Here it becomes clear that the time until the start of therapy is particularly determined by the time until the diagnosis is found (median: 9 days).
Figure 7. Time period (in days) from initial presentation (A) to CN-diagnosis (B) to therapy start (T).
3.7. Survival analysis
shows the survival function of all patients under observation. After 1 year, 92% of patients were still alive. The median overall survival was 92 months (7.7years). 10 patients died during our observation period.
Figure 8. Survival – complete cohort.
3.7.1. Survival function: renal recovery and dialysis dependency
Patients, who achieved renal recovery within the first year after diagnosis of CN had significantly better overall survival. Median survival for the group of renal responders was 153 months, while the renal non-responders’ median survival was only 58 months .
Figure 9. Survival analysis: A: renal response / B: dialysis dependency.
Patients that never were dialysis-dependent, had a median survival of 164 months ( = 13.6 years). Dialysis-dependent patients, that received renal replacement therapy for less than 3 months, showed a very similar median survival with 153 months ( = 12.8 years). However, dialysis-dependent patients, that were classified as patients with end-stage kidney disease, had a significantly decreased overall survival (80 months/6.7years).
4. Discussion
In this retrospective study, we analyzed 28 patients with cast nephropathy confirmed by renal biopsy. The goal of this study was to characterize the cohort of cast nephropathy patients, as well as to compare the subgroups of renal responders and renal non-responders. 89% (n = 25) of all patients simultaneously received the diagnosis of multiple myeloma and cast nephropathy. Only 3 patients (11%) were diagnosed with cast nephropathy after they already started a therapy regimen for MM. This data is consistent with data by Royal et al. where 8% of all CN patients had prior MM treatment [Citation19].
Renal response could be assessed for 23 patients. 61% (n = 14) achieved renal response and 39% (n = 9) were renal non-responders. Other studies found a proportion of renal responders between 46% and 70% [Citation19, Citation22]. In our population, renal recovery was also associated with significantly better overall survival (153 vs 58 months). Renal recovery has also been associated with improved overall survival in cast nephropathy patients in previous studies [Citation4, Citation26–29].
Trying to identify predictors of renal response is an important issue in the management of CN. In our cohort, patients of younger age were more likely to achieve renal response within one year (p = 0.039). This finding is supported by a large 2020 published multicenter study by Royal et al. [Citation19].
All patients with renal response also showed hematologic response. Complete hematologic response was a statistically significant marker for renal response (p = 0.025), as was any type of hematologic response (≥PR) after the first line of treatment (p = 0.029). 63% (n = 9) of all renal responders already showed a renal response after one month. 93% (n = 13) of all renal responders, already showed renal response after the first therapy line, underscoring the paramount importance of a rapid diagnosis and an early and urgent start with MM treatment. Our data is supported by multiple studies, that found similar relationships [Citation7, Citation19, Citation22]. Further, our data point out, that patients who showed renal response during follow-up, started systemic therapy significantly earlier after initial presentation with acute kidney injury (median 9 vs 27 days).
Baseline eGFR in our cohort did not correlate significantly with either reduced renal response or reduced OS. Some studies found a correlation between baseline eGFR and renal response [Citation19, Citation22, Citation29], while others did not find a significant difference [Citation7]. Research conducted by Khan et al. even showed that patients with an eGFR below 30 ml/min/1.73 m2 had worse outcomes, despite being renal responders. In our patient cohort, all except one patient had a baseline eGFR <30 ml/min/1.73 m2, so we could not investigate this particular question [Citation30].
In our cohort, the mean number of casts per/mm2 in the cortex was 4.05, whereas Royal et al's study reported 3.2. In their research, they further demonstrated that the extent of cast formation and the degree of IFTA correlated significantly with renal recovery. This relationship was also observed in our small cohort but not deemed statistically significant. However, we could demonstrate that patients with an IF/TA score of 3 had a significantly higher occurrence of end-stage renal disease (p = <0,001).
Dialysis dependency was documented for 13 patients (46%) which corroborates Royal et. al that showed 47% of patients with CN were dialysis dependent [Citation19]. Median dialysis time was 46 days (Range: 7 days-7 years). Dialysis dependency at some point, was not associated with decreased chances of renal recovery in our cohort. But dialysis dependency for ≥ 3 months ( = end stage renal disease) was found significantly more often in renal non-responders (p = 0.005). This shows that the need for transient dialysis should not be necessarily seen as a risk factor for permanent renal injury. It seems that if patients do not recover from dialysis within the first 3 months, the kidneys are already irreversibly damaged by the paraprotein.
4.1. Strength and weaknesses of the study
There are limitations to this study. Firstly, our study population contains 28 patients with cast nephropathy confirmed by kidney biopsy. Because renal biopsy in multiple myeloma patients is no standard procedure, the available literature about this group of patients is scarce. Consequently, the existing literature often includes small patient samples, limiting their validity. Higher patient numbers usually stem from large multicentered studies.
Also, not all laboratory values were available for all patients at all time points, which reduces the population size for some questions. However, since data on biopsy confirmed cast nephropathy patients, that are observed for such a long period of time are rather rare, this study helps to further characterize this special cohort.
4.2. Outlook
Prediction of reversibility of renal damage is crucial for the patients risks and outcome. For future treatment decisions, knowledge about the pathophysiology of renal damage might be of striking importance since a pathway-adapted targeted treatment regimen can be assembled and with a rapid and efficient response kidney function can be restored. Further studies should focus on finding the most efficient therapy options in patients with cast nephropathy. Especially with an increasing number of multiple myeloma drugs (IMiDs, PIs, monoclonal antibodies) there is a lack of studies focusing on finding the best treatment regimen and drug combination in this distinct patient group.
4.3. Summary
In this monocentric retrospective study, we found out that any type of hematologic response (≥PR) to first-line therapy is a statistically significant predictor for renal response (p = 0.029), while any type of hematologic response (≥PR) at a later time point, was no significant indicator for renal response.
Also, dialysis dependency per se was no risk factor for renal non-responsiveness but dialysis dependency over 3 months was a major risk factor (p = 0.005). We could also show, that 93% (n = 13) of all renal responders, already showed renal response after first line of therapy.
In addition, our data indicate that patients who achieved renal response during follow-up started systemic therapy significantly earlier at the course of disease (median 9 vs. 27 days; p = 0.016). This in turn means that, in order to reach renal recovery early action is extremely important.
In summary, our data highlight the importance of rapid initiation of anti-myeloma therapy in patients with renal impairment, and also the necessity of achieving early hematologic response to improve renal recovery and overall survival.
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References
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